Chemotherapy For H&N SCC

Past, Present and Future

Charles Gawthrop M.D.
Faculty Discussant:

Jason Newman M.D.

Otorhinolaryngology: Head and Neck Surgery at PENN

Excellence in Patient Care, Education and Research since 1870

The Past
40,000

New cases of SCCHN each year in

USA
2/3 Present with locally advanced lesions (T3
or T4)

5 year survival <30%

The Past
Classical

chemotherapy is directed at
metabolic sites essential to cell replication

Tumor Cells Replicate more frequently than normal

cells
However, currently available chemotherapy does
not specifically recognize neoplastic cells
Highest morbidities in rapidly dividing cells: bone
marrow, GI mucosa, and hair cells

Methotrexate
Most

widely used cytotoxic for H & N cancer

prior to 19781.
Structural analog of folic acid, binds to and
inhibits dihyrofolate reductase.
Decreases intracellular folate co-enzymes,
which decreases production of thymidilic acid
(precursor to adenine and guainine) and
eventually depressed DNA/RNA synthesis and
cell death.

Methotrexate

Methotrexate
Toxicities:

Myelosupression, mucocitis, alopecia, N/V and

Diarrhea Most common
Renal Toxicity in Higher Doses

5 - Fluorouracil
Antimetabolite

- Like Methotrexate deprives

cells of essential precursors of DNA synthesis
Pyrimidine analog which has a stable flourine
atom in place of hydrogen at position 5 of the
uracil ring.

5-FU

Converted to Fluoride-deoxyuridine monophosphate (FdUMP)

which competes with dUMP for thymidilate synthase, leading to a
lack of thymidine, imbalanced cell growth and death.

5-FU
Side

Effects

MUCOCITIS
Other side effects include bone marrow supression,
N/V, alopecia and anorexia

Cisplatin
Cisdiamminedichlorplatinum
Approved

(CDDP)

by USDA in 1978.
Binds to Guanine on DNA, forming inter and
intra-strand crosslinks, inhibiting DNA
synthesis.

Cisplatin
Side

Effects

Severe Nausea and Vomiting up to 5 days after

administration
Nephrotoxicity- Usually the dose limiting toxicity
Ototoxicity High Frequency Hearing Loss, Tinnitus
Neurotoxicity Paresthesias, Loss of Proprioception

Carboplatin
Mechanism

is similar to that of Cisplatin

Less Effective
Lower Toxicity

Multi Agent Chemotherapy

In

Mid 1980s a number of RCT controlled trials

compared the then available combinations of
chemotherapeutics.

Cisplatin as a single agent is not superior to

Methotrexate in terms of response or survival1
Multi-agent chemotherapy in general is associated
with higher response rates than single agent alone
Platinum containing combination regimens have the
highest response rates.

Multi Agent Chemotherapy

Jacobs et al2 1992 Compared Cisplatin and 5 FU alone

and in combination. Response rates were 32% (Cisplatin
+ 5FU), 17% (Cisplatin), and 13% (5FU).

Higher Toxicity in Combination

Median Survival (6months) same for all treatment arms

Clavel et al.3 1994 Compared Cisplatin vs Cisplatin +

5FU in 382 patients with metastatic or recurrent SCC of
the H & N

Higher Response Rates and Longer time to progression in

combination
Median survival 7.3 months in both arms

The Taxanes
Paclitaxel

(Taxol) and Docetaxel (Taxotere)

Isolated in 1960s from the bark of the pacific
Yew tree (Taxus brevifolia) and introduced in
1990s
Binds to the B subunit of tubulin, and stabilizes
microtubules, interrupting mitosis and leading
to cell death.

The Taxanes
Side

Effects

NEUTROPENIA Usually Dose Limiting

Hypersensitivity (dyspnea, urticaria, hypotension)
Peripheral Neuropathy, Alopecia, Bradycardia

The Taxanes

Several Studies of Taxane + Cisplatin with response

rates of 27% - 53%
Gibson et al.4 2005 218 Patients. Compared Cisplatin
and 5FU vs. Cisplatin and Taxol.

Response rates and Median Survival were virtually identical with

higher number of high grade toxicities in Cisplatin + 5 FU Group

Triple Agent Protocols including Docetaxol, Cisplatin,

and 5FU (TPF) have shown response rates approaching
60%, with median survival of 6 9 months.1 However no
improvement in 1 year survival and increased toxicity. To
date, no controlled trials

Chemotherapy for Curable Disease

Induction

or Neoadjuvant Chemotherapy
Concomitant Chemotherapy
Post Treatment or Adjuvant Chemotherapy

Concomitant Chemotherapy

Concomitant Chemotherapy
Theoretical

Benefits of Chemo-XRT

Inhibiting repair of lethal and sublethal damage

induced by radiotherapy
Radiosensitizing hypoxic cells
Reducing tumor burden, leading to an improved
blood supply
Redistributing tumor cells to a more radiosensitive
cell cycle phase
Inducing apoptosis

Concomitant Chemotherapy

Meta-Analysis of Chemotherapy on Head and Neck Cancer

(Pignon et al.) 20005

Meta-analysis of >10,000 patients in 63 clinical trials

Chemo-XRT vs. XRT alone associated with absolute survival benefit
of 8% at 5 years

Intergroup RTOG 91-11 (Forastiere et al.) 20036

547 Patients with stage III or IV resectable laryngeal cancer.

Randomized to Induction Chemo + XRT vs. Chemo-XRT vs. XRT
alone
43% absolute reduction in laryngectomy rate with Chemo-XRT
8% vs. 16% rate of distant metastasis
No change in overall survival

Neoadjuvant Chemotherapy

Neoadjuvant Chemotherapy
Theoretically

should reduce possibility of

distant metastasis, and decrease tumor burden
while patient is healthy, thus leading to
improved disease free survival.
However Numerous studies over 2 decades
showed no benefit in survival when compared
with local treatment. Though some reported a
decrease in distant metastases

Neoadjuvant Chemotherapy

GSSTC (Paccagnella et al.) 19948. 237 Patients with

stage III and IV SCC of the head and neck. Cisplatin,
5FU followed by local tx vs. local tx alone.

Increase in 10 year survival

GETTEC (Domenge et al.) 20009. 318 patients with

curable disease of oropharynx randomized to chemo
followed by local treatment vs. local treatment alone.

Overall Median Survival 5.1 years vs. 3.3 years with Chemo
No change in locoregional control or distant metastases

Neoadjuvant Chemotherapy
Meta-Analysis

of Chemotherapy on Head and

Neck Cancer5

In the initial study, induction chemotherapy was

associated with only a 2% survival benefit at 5 years
- not statistically significant
However in a subset analysis including only
cisplatin-5FU induction regimens there was a
significant 5% absolute survival benefit.

Neoadjuvant Chemotherapy
TAX

323 (Vermorken et al. 2004)10 358

patients with locally advanced and
unresectable HNSCC. Induction chemo with
cisplatin 5FU (PF) or cisplatin/5FU/docetaxel
(TPF) All patients received post chemo XRT

Overall response rate with TPF was significantly

improved 68% vs. 54%
Both progression free and overall survival times
were longer with TPF

Neoadjuvant Chemotherapy
So

why give induction chemotherapy another

chance?11,12

Previous studies included suboptimal chemotherapy

regimens
Newer triple agent chemotherapy with Taxane
Chemotherapy followed by Chemo-XRT

Adjuvant Chemotherapy

Adjuvant Chemotherapy
Post

operative XRT has been the standard

approach for high risk H&N SCC since first
pioneered by Fletcher and Evers in the early
1970s.
However, the few randomized studies of post
operative chemotherapy in the 1990s yielded
disappointing results.

Adjuvant Chemotherapy

Intergroup Study #0034 (Al-Sarraf et al 1997)13. 447

patients, complete resection with post op XRT alone
vs. resection + XRT + Chemo.

No difference in overall survival

However, subgroup of patients at higher risk (malignant cells in
2 or more lymph nodes, extracapsular spread, microscopic
involvement of margins), were more likely to benefit both in
terms of tumor control and survival

Bachaud et al.14,15 1996 83 patients. Surgery followed

by XRT or Chemoradiation.

Chemoradiation group had lower locoregional failure

Adjuvant Chemotherapy

EORTC Study (Bernier et al. 2004) 16 334 patients with high risk head and
neck tumors randomly assigned to post op XRT vs. post op Chemo-XRT

High Risk = Vascular invasion, Perineural invasion, Stage III/IV disease,

Microscopically + Margins, extracapsular spread
Progression free survival of 55 vs. 23 months
Locoregional recurrence of 31% vs. 18%
No Significant change in toxicity

RTOG Trial (Cooper et al. 2004)17 459 patients with High risk SCC
randomized to post op XRT vs. post op Chemo-XRT

High Risk = two or more positive lymph nodes, extracapsular spread,

microscopic involvement of margins
Increased disease free survival, increased locoregional control
Overall Survival not significantly significant
Substantial increase of severe side effects.

Adjuvant Chemotherapy18

Adding chemotherapy to post op XRT for high risk

H & N SCC leads to a significant increase in local
control and disease specific survival
The impact of post op Chemo-XRT is greatest in
tumors with extracapsular spread and/or
microscopically involved margins
Other risk factors include perineural invasion, vascular
invasion, stage III/IV disease, and or level IV-V lymph
nodes from tumors in the oral cavity or oropharynx.
No change in incidence of distant metastases

The Present

Drug therapies are replacing

a lot of medicines as we used
to know it
-George W. Bush

Otorhinolaryngology: Head and Neck Surgery at PENN

Excellence in Patient Care, Education and Research since 1870

The Present
Recent

advances in molecular biology,

including the human genome project have
allowed for the introduction of targeted
therapies for cancer.

Trastuzumab (Herceptin)19

The type one receptor tyrosine kinases (ErbB receptors)

Composed of an extracellular ligand binding domain,a transmembrane

segment and an intracellular protein tyrosine kinase domain.
Tyrosine Kinase receptor, that when activated, stimulates many
intracellular signaling pathways, mainly mitogen activated protein kinase
(MAPK) and the phosphatidylinositol 3 kinase (PI3K)-Akt pathway.
Through these pathways the EGF receptor sitmulates cell growth,
division, differentiation, migration, adhesion and angiogenic activity
HER2 (erbB2) overexpressed in 20-25% of invasive breast cancer, and is
associated with an increased risk of chemotherapy resistance,
metastases, relapse and death in these patients.

http://www.biooncology.com/bioonc/index.m

Trastuzumab (Herceptin)20
Trastuzumab-

A recombinant humanized antierbB2 monoclonal antibody which binds to the

extracellular domain of the receptor and blocks
intracellular signalling.

Approved by FDA in 1998

Blocks dimerization of the receptor and therefore
intracellular phosphorylation.
Anti-Body Mediated Cytotoxicity

Trastuzumab (Herceptin)

Several International RCT of Trastuzumab with total

enrollment >13,000 patients were initiated in 20002001, and initial results became available in 2005 20

Significantly Lower (46%) risk of metastases, longer disease

free survival and a trend towards longer overall survival
Low incidence of adverse effects- in particular none of the
toxic effects typically produced by chemotherapy: nausea,
vomiting, hair loss or myelosupression
Cardiac Dysfunction When used with an anthracycline erbB2 has an anti apoptotic role in normal myocytes, interruption of
which leads to increased stress related cardiac damage

Imatinib (Gleevec)20

ABL1 Protoncogene A tyrosine kinase found in both the

nucleus and the cytoplasm that when activated, interacts
with a number of signal transduction pathways including
Ras, MAP, STAT, PI3K and Myc involved I gene
transcription, apoptosis, cytoskeletal organization
BCR-ABL Results from a reciprocal translocation between
chromosomes 9 and 22

This gene re-arrangement is present in nearly 100% of cases of

CML
The gene product is found exclusively in the cytoplasm, and is
constitutively active leading to a proliferative advantage and
decreased apoptosis in affected cells

Imatinib (Gleevec)
Imatinib

Orally bioavailable inhibitor of the

ABL protein

Approved by FDA in May 2001

Also blocks other kinases including PDGF, and c-Kit

Imatinib (Gleevec)

Prior to Imatinib, CML typically followed an inexorable

course that resulted in the death of the patient

Only allogenic hematopoietic stem cell transplant has been

shown conclusively to provide long term disease eradication
Chronic Phase-> Intermediate Phase -> Blast Phase
Traditional Chemotherapy with cytarabine and alpha-interferon
was associated with significant toxicity and 5 year survival of
less than 60%

Imatinib (Gleevec)

Phase 2 studies of IM in patients with accelerated

phase CML showed hematologic response in 82% of
patients. Complete in 17%
Large randomized trial of IM vs. IFN Alpha in patients
with newly diagnosed chronic phase CML, showed a
major response in 87% of patients as compared to
35% and an 95% freedom from progression at 30
months.
Minimal side effects most common being myalgias
and diarrhea

Epidermal Growth Factor Receptor

in Head and Neck Cancer
EGFR

= ErbB125
EGFR mRNA is upregulated in 92% of
HNSCC22
EGFR levels increase in in advanced stage
tumors and in poorly differentiated tumors.
Increased EGFR correlates with poorer clinical
outcome22

Cetuximab (Erbitux)
Recombinant

monoclonal antibody which binds

to the extracellular domain of the EGF receptor
with high affinity

Block activation of receptor tyrosine kinase by EGF

or TGF Alpha
Induces antibody-mediated homodimerization and
destruction25

Cetuximab (Erbitux)

ECOG trial (Burtness et al.) 2005 117 patients randomized to Cisplatin

vs. Cisplatin/Cetuximab.24

Trigo et al. 2004 103 patients who had progressed on platinum

containing regimens.24

Objective response improved in combined arm (26% vs. 10%)

However, Primary end point of Disease free survival did not meet statistical
significance (4.2 vs. 2.7 months)
Cutaneous toxicity correlates with efficacy

Overall response rate of 13% with 5 complete responses

Harari et al. 2004 424 patients with LR advanced H & N Cancer

randomized to XRT vs. XRT + Cetuximab24

3 year survival rate of 57% vs. 44%

Locoregional Control Rate of 56% vs. 48%

Gefitinib, Erlotinib
Low

molecular weight tyrosine kinase inhibitors

which compete with ATP binding to the
intracellular portion of the EGFR, blocking
phosphorylation, and therefore activation of
downstream signalling proteins.
Erlotinib approved in US for NSCLC
Gefitinib approved in Japan22

Gefitinib, Erlotinib24
More

Studied in NSCLC Where patients

refractory to conventional chemotherapy have
had up to 18% response rates
Studies in H & N Cancer

Gefitinib- Phase II trial of 47 patients showed 10.6%

response rate. Second study at low dose was less
effective. Cutaneous toxicity correlated with efficacy.
Erlotinib Phase II trial of 115 patients showed a
4% partial response rate.

Gefitinib, Erlotinib
Why

dont EGFR antagonists work better?25

G Protein coupled receptors

Constitutively activated downstream pathways
Increased levels of VEGF
Activation of other ErbBs

The Future

Otorhinolaryngology: Head and Neck Surgery at PENN

Excellence in Patient Care, Education and Research since 1870

Bevacizumab26 (Avastin)

VEGF (Vascular Endothelial Growth Factor) one of the most

potent promoters of angiogenesis, has been identified as a
fundamental regulator of tumor neovascularization

Overexpressed in H&N Cancer

Indicates a poor response to chemo-XRT
High levels of VEGF induced by XRT

Bevacizumab (Avastin) recombinant humanized monoclonal

antibody which binds to and neutralizes VEGF

Has been studied in more than 30 different clinical trials, in multiple

types of cancer
A phase II study in H & N cancer in combination with Erlotinib has
recently opened.

EpCAM30

EpCAM Epithelial Cell adhesion and activating molecule

Over-expressed in a large variety of adenocarcinoma and SCC.

Protects tumor cells from self proteolysis, and displays proliferative signalling
activity
Overeexpression correlates with negative prognosis

ProxiniumR anti-EpCAM antibody fused to a subunit of the

bacterial Pseudomonas endotoxin

After EpCAM binding and endocytosis, endotoxin is cleaved and inhibits protein
synthesis leading to cell death.
Phase I/II trial shows 88% tumor response and median survival of 301 days vs.
125 days.
Phase II/III trial is in progress
Novel EpCAM immunotoxin is in development which is selectively cleaved by
tumor cells.

Gene Therapy27

At the end of Jan 2005, there were a total of 1020

approved gene therapy clinical trials in the world

66% were for the treatment of cancer

Cancer Gene Therapy is the delivery of specific genetic

sequences into cells or tissues to achieve a therapeutic
effect against malignant tumors.

H & N cancer is an ideal model

Loco Regional Disease amenable to intratumoral injection
Often presents with advanced disease inamenable to current
therapies

Gene Therapy
P53

Tumor Suppressor Gene known as The guardian of

the Genome
Activates

DNA Repair proteins when DNA has sustained

damage
Holds the cell cycle at G1 Regulation pointon Damage
Recognition
Initiates Apoptosis if DNA damage appears irrepairable

http://www.biovita.fi/suomi/terveyssivut/p53.html

Gene Therapy27

Restoration of p53 function

Clayman et al. 1998 treated 18 patients with relapsed HNC with

intratumoral injections of a replication deficient adenoviral vector
expressing wild type p53

One pathologic complete response, two partial responses, and 6

patients with disease stabilization

Gendicine Recombinant human serotype 5 adenovirus

containing a human wild type p53 expression cassette28
Approved for use in H & N cancer in China
Phase III trial of 135 patients with late HN Ca (85%NPC) randomized
to Gendicine + XRT vs. XRT

93% response vs. 79% however 64% Complete Response vs. 17%
Multicenter randomized Phase IV trial is in progress

Gene Therapy
Onyx

015

Replication competent viral vector containing a

deletion in the E1B 55KD gene which is responsible
for binding and inactivating p53
Virus

replicates preferentially in in p53 deficient tumor cells

and leads to cell death
Phase II trial of intratumoral ONYX-015 in 36 patients with
relapsed HNC, there were 4 partial responses and 12
patients with stable disease
More dramatic results in combination cisplatin

Immunotherapy
Based

on 2 Principles

Immune system should recognize and destroy

abnormal cells.
Tumor Cells are poorly immunogenic, and strongly
immunosupressive
PGE2

produced by tumors inhibits lymphocyte proliferation

Cytokines produced by tumors inhibit lymphocyte function
Tumors down regulate antigen presenting molecules

Immunotherapy

Interleukin 2 Produced by the body during an

immune response, binds to the IL-2 receptor,
stimulating the growth, differentiation, and survival of
cytotoxic T cells

Systemic injection associated with severe side effects

Local injection into tumor short half life requires frequent
injections.
IRX-2 human cytokine mixture injected perilymphatically
near tumor. Currently in clinical trials

Immunotherapy29
Non-Specific

Active Immunomodulation

BCG vaccine
Used

to induce active, non specific stimulation of the

immune system
Reports of increased tumor free survival which could not
be substantiated
Trials with other vaccines (strep pyogenes, trypanosoma
cruzi, levamisole) show no benefits in long term survival

Immunotherapy
Specific

Active Immunization

P53 Mutated in >80% of SCCHN which leads to a

buildup of non functional p53 in cells.
Since

most mutations involve only one amino acid,

Cytotoxic T cells which recognize WT p53 should also
attack cells which express mutated p53
In truth, patients who express mutated p53 are resistant

Immunotherapy

HPV Vaccines

Estimated that 25% of HNSCC are HPV associated 31

Tend to arise in younger patients
Lingual and palatine tonsils
Occur predominantly in non smoker/drinker
Associated with a more favorable prognosis

HPV viral oncogenes E6 and E7 are consistantly expressed in

HPV associated cancers

Thought to integrate into the host DNA, and when expressed,

bypass the regulation of cell proliferation

Both protein and DNA vaccines targeting HPV DNA are

currently in phase I and phase II trials

Special Thanks To:

Jason

Newman M.D.
Duane Sewell M.D.

References

1. Colevas, Dimitrios Chemotherapy Options for Patients With Metastatic or Recurrent Squamous Cell
Carcinoma of the Head and Neck Journal of Clinical Oncology 24:2644-2652 2006
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and in combination for advanced SCC of the H & N J Clinical Oncol 10:257-63, 1992
3. Clavel M, et al. Randomized comparison of Cisplatin, Methotrexate, bleomycin and vincristine vs Cisplatin 5
FU in recurrent or metastatic Squamus cell carcinoma of the head and neck: A phase III study of the EORTC
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References

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References

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Cancer J Clin Oncol 24:2629-2635 2006
19. Marty, Chantal Bernard et al. Monoclonal Antibody-Based Targeted Therapy in Breast Cancer Drugs 2006
66(12)1577-1591
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Cancer The Oncologist 2006;11(suppl 1)4-12
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669-679
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Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck J Clin Oncol 2006 24:26592665
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