ENT

1. NEWER DRUGS IN CANCER
MANAGEMENT
.

2. Concomitant chemotherapy/radiation

3. NEOADJUVANT CHEMOTHERAPY
 Reduce possibility of distant metastasis
 Decrease tumor burden

4. ADJUVANT CHEMOTHERAPY
 Leads to a significant increase in local control and
increased survival
 The impact of post op Chemo-RT is greatest in
tumors with extracapsular spread and/or
microscopically involved margins.
 No change in incidence of distant metastases

5. CONCOMITANT CHEMOTHERAPY
 Inhibiting repair of lethal and sublethal damage induced
by radiotherapy
 Radiosensitizing hypoxic cells
 Reducing tumor burden
 Redistributing tumor cells to a more radiosensitive cell
cycle phase
 Inducing apoptosis

6. CELL CYCLE

8. CLASSIFICATION OF DRUGS

9. THE PAST
 Chemotherapy directed at metabolic sites essential
to cell replication
 Tumor Cells Replicate more frequently than normal cells
 Highest morbidities in rapidly dividing cells.

10. METHOTREXATE
 Widely used for H & N cancer prior to 1978
 Structural analog of folic acid

11. METHOTREXATE
 Dosage : 40 mg/m 2 IV weekly every 3 weeks
 Side Effects:
 Myelosupression
 Mucositis
 Alopecia
 Nausea, vomitting and Diarrhea
 Renal Toxicity in Higher Doses

12. 5 - FLUOROURACIL
 Antimetabolite
 Pyrimidine analog.

13. 5-FU

14. 5-FU
 Dosage :
 120 hour infusion schedule:1000mg/m2/day IV on
days 1-5 every 21-28 day
 Side Effects
 Anorexia, Nausea and vomitting
 Mucositis
 Myelosuppression
 Hand foot syndrome
 Neurotoxicity

15. CISPLATIN
 Cis-diamminedichlorplatinum (CDDP)
 Binds to Guanine on DNA, forming inter and intra-
strand crosslinks, inhibiting DNA synthesis.

16. CISPLATIN
 Dosage:
 50-75mg/m2 IV every 3-4 week
 Side Effects
 Severe Nausea and Vomiting
 Nephrotoxicity
 Ototoxicity
 Neurotoxicity

17. CARBOPLATIN
 Mechanism is similar to that of Cisplatin
 Decreased Nephrotoxicity and Neurotoxicity
 Ease of administration
 Dose limiting toxicity: Myelosupression
* Oxaliplatin: another platinium compound currently in
clinical trial for head and neck cancer

18. 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
Stabilizes Microtubules
Interrupt Mitosis
Cell Death

19. THE TAXANES
 DOSAGE :
Paclitaxel: 135-200mg/m2 IV over 3 hour OR
135mg/m2 IV over 24 hour every 3 week
Docetaxel: 60-100mg/m2 IV over 1 hour every 3
week
 Side Effects
 Myelosupression
 Hypersensitivity reaction
 Neurotoxicity
 Transient asymptomatic bradycardia
 Elevation in serum transaminases
 Alopecia

20. THE TAXANES
 Several Studies of Taxane + Cisplatin with
response rates of 27% - 53%
 Gibson et al.2005 1– 218 Patients
 Compared Cisplatin and 5FU vs. Cisplatin and Taxol.
 Response rates and Median Survival identical with higher
toxicities in Cisplatin + 5 FU Group
 Triple Agent Protocols: Docetaxol, Cisplatin, and
5FU (TPF)
 Response rates approaching 60%,
 Median survival of 6 – 9 months2
1. Gibson MK et al. Randomized phase III evaluation of cisplatin plus Fluorouracil vs. cisplatin plus paclitaxel in advanced head
and neck cancer. An intergroup trial of the Eastern Oncology Group. J Clinical Oncology 23:3562-3567, 2005
2. 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

21. THE PRESENT

22. THE PRESENT
 Recent advances in molecular biology, including the
human genome project have allowed for the
introduction of Targeted therapies for cancer.

23. EPIDERMAL GROWTH FACTOR RECEPTOR
INHIBITORS
 EGFR = ErbB1
 EGFR mRNA is upregulated in 92% of HNSCC
 EGFR levels increase in in advanced stage tumors
and in poorly differentiated tumors
 Gefitenib
 Erlotinib
 Cetuximab

24. 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
 Prevent both homodimerization and heterodimerization
of EGFR thus inhibition of EGFR signaling

25. CETUXIMAB (ERBITUX)
 DOSAGE:
Loading dose: 400mg/m2 IV administered over 90
minutes
Maintenance dose: 250mg/m2 IV given on a
weekly basis
 Side effects:
 Infusion related symptoms
 Pruritis ,acneiform rash
 Pulmonary toxicity
 Asthenia, generalized malaise
 Paronychial inflammation

26. 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(Non squamous
cell lung cancer)

27. GEFITINIB(IRESSA), ERLOTINIB
 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.

28. GEFITINIB(IRESSA), ERLOTINIB
 DOSAGE:Gefitenib 250mg/day per oral
Erlotenib150mg/day per oral
 Side effects:
 Elevation in Blood pressure
 Pruiritus,acneiform skin rash
 Elevation of serum transaminases
 Asthenia and anorexia
 Nausea ,Vomiting,Mucositis

29. ANGIOGENESIS INHIBITORS
 VEGF (Vascular Endothelial Growth Factor) – promoters of
angiogenesis, identified as a fundamental regulator of tumor
neovascularization
 Overexpressed in H&N Cancer
 Indicates a poor response to chemo-RT
 High levels of VEGF induced by RT
 Bevacizumab – (Avastin) – recombinant humanized
monoclonal antibody which binds to and neutralizes VEGF
 A phase II study in H & N cancer in combination with Erlotinib has
recently opened.

30. ANTIBODY BASED THERAPY
 Monoclonal antibodies (Mab)
U-36
Cetuximab(Erbitux)
Herceptin(anti-c-erb-B2)
MN-14(Anti-CEA monoclonal antibody)

31.  U36
186RE-labeled chimeric Mab U36
Dosage:27 mCi/m2
Side Effects: Myelotoxicity-only toxicity
 Cetuximab(Erbitux)
can be safely administered with RT
Side Effects: Fever, transient hepatic enzyme
elevation,

32.  Trastuzumab- A recombinant humanized anti-erbB2
monoclonal antibody.
 Approved by FDA in 1998
 Blocks dimerization of the receptor and therefore
intracellular phosphorylation.

33. TYROSINE KINASE INHIBITORS
 Imatinib(Gleevac) – Orally bioavailable inhibitor of
the ABL protein
 Approved by FDA in May 2001
 Also blocks other kinases including PDGF, and c-Kit
 Vandetanib: 300mg per oral daily
 Carbozantinib: 140 mg per oral daily

34. THE FUTURE

35. ANTI-EPCAM ANTIBODY
 EpCAM – Epithelial Cell adhesion and activating molecule
 Over-expressed in a large variety of adenocarcinoma and SCC.
 Protects tumor cells from self proteolysis
 Displays proliferative signalling activity
 Overeexpression correlates with negative prognosis
 Proxinium 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
 Phase II/III trial is in progress

36. GENE THERAPY

37. GENE THERAPY
 Cancer Gene Therapy is the delivery of specific
genetic sequences into cells or tissues to achieve a
therapeutic effect against malignant tumors.

38. 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 point on Damage
Recognition
 Initiates Apoptosis if DNA damage appears irrepairable

39. GENE THERAPY
 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

40.  Gendicine – Recombinant human serotype 5
adenovirus containing a human wild type p53
Approved for use in H & N cancer in China
Phase III trial of 135 patients with late HN Ca
(85%NPC) randomized to Gendicine +RT vs
RT
93% response vs. 79%
Multicenter randomized Phase IV trial is in
progress

41. 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

42. GENE THERAPY
 HPV Vaccines
 Estimated that 25% of HNSCC are HPV associated
 Both protein and DNA vaccines targeting HPV DNA are
currently in phase I and phase II trials

43. IMMUNOTHERAPY

44. 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

45. IMMUNOTHERAPY
 Interleukin – 2 – 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.

46. IL-12 TH1
TNF
IFN-gamma
IL2
TH1
In Tumor
TH2

47. CYTOKINE BASED THERAPY
 Recombinant Cytokins and lymphocytes have
been used to augment anti-tumor response.
 IL2:
Perilymphatic Injection of natural IL2 for 10 days.
13 out of 20 patients with recurrent, inoperable
SCCHN showed clinical response.3
*Subsequent courses of IL2 were poorely effective.
 rIL2: recombinant IL2
Peritumoral and Intranodal injections
TIL (tumor infiltrating lymphocytes)4
3. Cortesina G, De Stefani A, Giovarelli M, et al: Treatment of recurrent squamous cell carcinoma of the head and neck with
low doses of interleukin -2 injected perilymphatically . Cancer 62:2482,1988 .
4. Whiteside TL, Letessier E, Hirabayashi H,et al: evidence for local and systemic activation of immune cells by peritumoral
injections of interleukin 2 in patients with advanced squamous cell carsinoma of the head and neck.Cancer Res
53:5654,1993.
1.

48. CYTOKINE BASED THERAPY
 IFN α 5
 IFN α alone
 IFN α + retinoic acid / standard Chemotherapeutic
agents 6-7
*Low response rates
*Frequent Toxicities
5. Vlock DR, Andersen j, kalish LA, et al: phase II trial of interferon –alpha in locally recurrent or meta static spamas cell
carsinoma of the head and neck: immunological and clinical corelate. J Immunother Emphasis Tumor Immunol 19:433,1996.
6.Voravud N, lippman SN, Weber, et al : Phase II et al 13-cisretinoic acid+Interpheron alfa in advance squamous cell carsinoma of
head and neck, refractory to chemotherapy invest new drugs 11:57,1993.
7. Gonclaves A, Camerlo J, Bum H, et al : Phase II combination of a combination of cisplatin, all-trans-retinoic acid and interferon-
alpha in squamous cell carcinoma : Clinical result and pharmacokinetics. Anticancer Res 21:1431,2001.

49. CYTOKINE BASED THERAPY
 IFN α + Chemoradiotherapy8-9
 In locoregionally advance SCCHN
 Improved survival rates compared to standard
therapy
*Significant toxicities including 6 deaths among 93
patients
8. Shin DM, Khuri FR, Murphy B,et al: Combined interferon-alfa, 13-cis retinoic acid, and alpha-tocopherol in locally advanced
head and neck squamous cell carcinoma: Novel bioadjuvant phase II trial. Jclin Onclon 19:3010,2001.
9. Mantz CA, Vokes EE, Kies Ms et al:sequential induction chemotherapy and concomitant chemoradiotherapy in the
management of locoregionally advanced laryngial cancer. Ann oncol 12:343,2001.

50. CYTOKINE BASED THERAPY
 IFNα + 13-cis-retinoic acid + alpha tocopherol10
 To prevent recurrence or second primary tumors
 Current Phase II Trial
 Median 1 and 2 year survival rates of 98%
 Intralesional IFNα
 Currently Phase I trials are investigating
intralesional IFNα in SCCHN
10. Mantz CA, Vokes EE, Stenson K et al: induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of
locoregionally advanced oropharyngeal cancer. Cancer J 7:140,2001.


51. CYTOKINE BASED THERAPY
 IL-12
 Potent anti-tumor properties
 Alone or in combination with IL-2 in SCCHN
 IRX-2 11
 Natural cytokine mixture
 Increases lymphocyte mobilisation and infiltration
 Minimal toxic effects
 In combination with:
Cyclophosphamide
Indomethacin
Zinc
11. Barrera JL, Verastegui E, Meneses A, et al:Combination immunotherapy of squamous cell carcinoma of head and neck: A
phase II trial. Arch Otolaryngol Head Neck Surg 126:345,2000.

52. OBSTACLES REMAINING

53.  FAS ligand produced by SCCHN cells 14
 CD34+ cells inside the tumor inhibit immunity
(Young et al)15
 ?? GM-CSF produced by SCCHN cells15
14. Gastman BR, Atarshi Y, Reichert TE, et al: Fas ligand is expressed on human squamous cell carcinoma of head and neck,
and it promotes apoptosis of T Lymphocytes. Cancer Res 59:5356,1999.
15. Young MR, Petruzzelli GJ, Kolesiak K ,et al: Human squamous cell carcinoma of head and neck chemoattract immune
suppressive CD34(+) progenitor cells. Hum Immunol 62:332,2001.

54. FUTURE DIRECTIONS

55.  Understanding anti-tumor immune response
 Tumor evasion mechanisms
 3 fundamental goals
1.) Inhibit the effect of negative regulatory factors
2.) Attack tumor cells without inducing auto
immune toxicity
3.) Tumor should be accessible for processing by
immune system