This document summarizes chemotherapy options for head and neck squamous cell carcinoma (HNSCC). It discusses commonly used chemotherapies like methotrexate, 5-fluorouracil, cisplatin, carboplatin and taxanes. It also covers multi-agent chemotherapy regimens and the roles of neoadjuvant, concurrent and adjuvant chemotherapy when combined with radiation or surgery. Recent advances with targeted therapies like trastuzumab are also mentioned.

1. Chemotherapy For H&N SCC
Deepak passi
.

2.  40,000 New cases of SCCHN each year in
 2/3 Present with locally advanced lesions (T3
or T4)
– 5 year survival <30%

3.  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

4. 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.

5. Methotrexate

6. Methotrexate
 Toxicities:
– Myelosupression, mucocitis, alopecia, N/V and
Diarrhea Most common
– Renal Toxicity in Higher Doses

7. 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.

8. 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.

9. 5-FU
 Side Effects
– MUCOCITIS
– Other side effects include bone marrow supression,
N/V, alopecia and anorexia

10. Cisplatin
 Cisdiamminedichlorplatinum (CDDP)
 Approved by USDA in 1978.
 Binds to Guanine on DNA, forming inter and
intra-strand crosslinks, inhibiting DNA
synthesis.

11. 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

12. Carboplatin
 Mechanism is similar to that of Cisplatin
 Less Effective
 Lower Toxicity

13. Multi Agent Chemotherapy
 In Mid 1980’s 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.

14. 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

15. The Taxanes
 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.

16. The Taxanes
 Side Effects
– NEUTROPENIA – Usually Dose Limiting
– Hypersensitivity – (dyspnea, urticaria, hypotension)
– Peripheral Neuropathy, Alopecia, Bradycardia

17. 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

18. Chemotherapy for Curable Disease
 Induction or Neoadjuvant Chemotherapy
 Concomitant Chemotherapy
 Post Treatment or Adjuvant Chemotherapy

19. Concomitant Chemotherapy

20. 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

21. 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

22. Neoadjuvant Chemotherapy

23. 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

25. 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

26. 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.

27. 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

28. 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

29. Adjuvant Chemotherapy

30. 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
1970’s.
 However, the few randomized studies of post
operative chemotherapy in the 1990’s yielded
disappointing results.

31. 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

32. 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.

33. 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

35. The Present
 Recent advances in molecular biology,
including the human genome project have
allowed for the introduction of targeted
therapies for cancer.

36. 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.

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

39. Trastuzumab (Herceptin)20
 Trastuzumab- A recombinant humanized anti-
erbB2 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

40. Trastuzumab (Herceptin)
 Several International RCT of Trastuzumab with total
enrollment >13,000 patients were initiated in 2000-
2001, and initial results became available in 200520
– 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

41. 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

42. 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

43. 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%

44. 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

45. 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

48. 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

49. Cetuximab (Erbitux)
 ECOG trial (Burtness et al.) 2005 – 117 patients randomized to
Cisplatin vs. Cisplatin/Cetuximab.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
 Trigo et al. 2004 – 103 patients who had progressed on platinum
containing regimens.24
– 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%

50. 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

51. 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.

52. Gefitinib, Erlotinib
 Why don’t EGFR antagonists work better?25
– G Protein coupled receptors
– Constitutively activated downstream pathways
– Increased levels of VEGF
– Activation of other ErbBs

53. The Future
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870

54. 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.

55. 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.

56. 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

57. 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

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

59. 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

60. 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

61. 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

62. 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

63. 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

64. 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

65. Immunotherapy
 HPV Vaccines
– Estimated that 25% of HNSCC are HPV associated31
 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