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
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.
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
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
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.
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
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
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
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.
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.
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.
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
Editor's Notes
Hand foot syndrome-tingling numbness pain erythema dryness rash swelling inc pigmentation npruiritis of hand and feet
avoid nephro and amifostine
High freq hearing loss tinnitus
Loss of proprioception paresthesia
Can be given on opd baasis without vigorous hydration