Transcript 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.

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
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
40,000 New cases of SCCHN each year in
USA
2/3 Present with locally advanced lesions (T3
or T4)
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5 year survival <30%
The Past
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Classical chemotherapy is directed at
metabolic sites essential to cell replication
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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
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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:
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Myelosupression, mucocitis, alopecia, N/V and
Diarrhea Most common
Renal Toxicity in Higher Doses
5 - Fluorouracil
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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
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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
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Side Effects
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MUCOCITIS
Other side effects include bone marrow supression,
N/V, alopecia and anorexia
Cisplatin
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Cisdiamminedichlorplatinum (CDDP)
Approved by USDA in 1978.
Binds to Guanine on DNA, forming inter and
intra-strand crosslinks, inhibiting DNA
synthesis.
Cisplatin

Side Effects
–
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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
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Mechanism is similar to that of Cisplatin
Less Effective
Lower Toxicity
Multi Agent Chemotherapy

In Mid 1980’s a number of RCT controlled trials
compared the then available combinations of
chemotherapeutics.
–
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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).
–
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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
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Higher Response Rates and Longer time to progression in
combination
Median survival 7.3 months in both arms
The Taxanes
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Paclitaxel (Taxol) and Docetaxel (Taxotere)
Isolated in 1960’s from the bark of the pacific
Yew tree (Taxus brevifolia) and introduced in
1990’s
Binds to the B subunit of tubulin, and stabilizes
microtubules, interrupting mitosis and leading
to cell death.
The Taxanes

Side Effects
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NEUTROPENIA – Usually Dose Limiting
Hypersensitivity – (dyspnea, urticaria, hypotension)
Peripheral Neuropathy, Alopecia, Bradycardia
The Taxanes
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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.
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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

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
Induction or Neoadjuvant Chemotherapy
Concomitant Chemotherapy
Post Treatment or Adjuvant Chemotherapy
Concomitant Chemotherapy
Concomitant Chemotherapy

Theoretical Benefits of Chemo-XRT
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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
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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
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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.
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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.
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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
–
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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
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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
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Previous studies included suboptimal chemotherapy
regimens
Newer triple agent chemotherapy with Taxane
Chemotherapy followed by Chemo-XRT
Adjuvant Chemotherapy
Adjuvant Chemotherapy

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Post operative XRT has been the standard
approach for high risk H&N SCC since first
pioneered by Fletcher and Evers in the early
1970’s.
However, the few randomized studies of post
operative chemotherapy in the 1990’s 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.
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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
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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
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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
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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)
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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.
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Approved by FDA in 1998
Blocks dimerization of the receptor and therefore
intracellular phosphorylation.
Anti-Body Mediated Cytotoxicity
Trastuzumab (Herceptin)
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Several International RCT of Trastuzumab with total
enrollment >13,000 patients were initiated in 20002001, and initial results became available in 200520
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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 –
erbB-2 has an anti apoptotic role in normal myocytes,
interruption of which leads to increased stress related cardiac
damage
Imatinib (Gleevec)20
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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
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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)
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Imatinib – Orally bioavailable inhibitor of the
ABL protein
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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
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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)
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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
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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
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Block activation of receptor tyrosine kinase by EGF
or TGF Alpha
Induces antibody-mediated homodimerization and
destruction25
Cetuximab (Erbitux)
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ECOG trial (Burtness et al.) 2005 – 117 patients randomized to
Cisplatin vs. Cisplatin/Cetuximab.24
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Trigo et al. 2004 – 103 patients who had progressed on platinum
containing regimens.24
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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
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3 year survival rate of 57% vs. 44%
Locoregional Control Rate of 56% vs. 48%
Gefitinib, Erlotinib
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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
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More Studied in NSCLC – Where patients
refractory to conventional chemotherapy have
had up to 18% response rates
Studies in H & N Cancer
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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
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Why don’t EGFR antagonists work better?25
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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
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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
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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
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EpCAM – Epithelial Cell adhesion and activating molecule
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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
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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
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At the end of Jan 2005, there were a total of 1020
approved gene therapy clinical trials in the world
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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.
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H & N cancer is an ideal model
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Loco Regional Disease amenable to intratumoral injection
Often presents with advanced disease inamenable to current
therapies
Gene Therapy
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P53
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Tumor Suppressor Gene known as “The guardian of
the Genome”
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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
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Restoration of p53 function
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Clayman et al. 1998 treated 18 patients with relapsed HNC
with intratumoral injections of a replication deficient adenoviral
vector expressing wild type p53
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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
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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
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93% response vs. 79% however 64% Complete Response vs. 17%
– Multicenter randomized Phase IV trial is in progress
Gene Therapy
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Onyx – 015
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Replication competent viral vector containing a
deletion in the E1B 55KD gene which is responsible
for binding and inactivating p53
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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
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Based on 2 Principles
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Immune system should recognize and destroy
abnormal cells.
Tumor Cells are poorly immunogenic, and strongly
immunosupressive
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PGE2 produced by tumors inhibits lymphocyte proliferation
Cytokines produced by tumors inhibit lymphocyte function
Tumors down regulate antigen presenting molecules
Immunotherapy
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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
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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
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Non-Specific Active Immunomodulation
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BCG vaccine
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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
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Specific Active Immunization
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P53 – Mutated in >80% of SCCHN which leads to a
buildup of non functional p53 in cells.
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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
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HPV Vaccines
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Estimated that 25% of HNSCC are HPV associated31
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HPV viral oncogenes E6 and E7 are consistantly expressed in
HPV associated cancers
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Tend to arise in younger patients
Lingual and palatine tonsils
Occur predominantly in non smoker/drinker
Associated with a more favorable prognosis
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
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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
2.Jacobs C, Lyman G et al. A Phase III Randomized study comparing cisplatin and flurouracil as single agents
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
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5.Pignon JP, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell : Theree
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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
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20. Baselga j, et al. Adjuvant Trastuzumab: A Milestone in the Treatment of HER-2-Positive Early Breast
Cancer The Oncologist 2006;11(suppl 1)4-12
21. Litzow Mark Imatinib Resistance Obstacles and Opportunities Arch Pathol Lab Med Vol 130 May 2006 669679
22. Cohen, Ezra Role of Epidermal Growth Factor Receptor Pathway-Targeted Therapy in Patients With
Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck J Clin Oncol 2006 24:2659-2665
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Cancer Journal of Clinical Oncology 2003 21;14:2787-2799
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