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Chemotherapy For H&N SCC Past, Present and Future Charles Gawthrop M. D. Faculty Discussant: 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 l l 40, 000 New cases of SCCHN each year in USA The Past l l 40, 000 New cases of SCCHN each year in USA 2/3 Present with locally advanced lesions (T 3 or T 4) – 5 year survival <30%

The Past l Classical chemotherapy is directed at metabolic sites essential to cell replication The Past l 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 l l l Most widely used cytotoxic for H & N cancer prior Methotrexate l l l 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

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

5 - Fluorouracil l l Antimetabolite - Like Methotrexate deprives cells of essential precursors 5 - Fluorouracil l l 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 l Converted to Fluoride-deoxyuridine monophosphate (Fd. UMP) which competes with d. UMP 5 -FU l Converted to Fluoride-deoxyuridine monophosphate (Fd. UMP) which competes with d. UMP for thymidilate synthase, leading to a lack of thymidine, imbalanced cell growth and death.

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

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

Cisplatin l Side Effects – – Severe Nausea and Vomiting up to 5 days Cisplatin l 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 l l l Mechanism is similar to that of Cisplatin Less Effective Lower Carboplatin l l l Mechanism is similar to that of Cisplatin Less Effective Lower Toxicity

Multi Agent Chemotherapy l In Mid 1980’s a number of RCT controlled trials compared Multi Agent Chemotherapy l In Mid 1980’s a number of RCT controlled trials compared then available combinations of chemotherapeutics. – – – Cisplatin as a single agent is not superior to Methotrexate in terms of response or survival 1 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 l Jacobs et al 2 – 1992 Compared Cisplatin and 5 Multi Agent Chemotherapy l Jacobs et al 2 – 1992 Compared Cisplatin and 5 FU alone and in combination. Response rates were 32% (Cisplatin + 5 FU), 17% (Cisplatin), and 13% (5 FU). – – l Higher Toxicity in Combination Median Survival (6 months) same for all treatment arms Clavel et al. 3 – 1994 Compared Cisplatin vs Cisplatin + 5 FU 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 l l l Paclitaxel (Taxol) and Docetaxel (Taxotere) Isolated in 1960’s from The Taxanes l l l 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 l Side Effects – – – NEUTROPENIA – Usually Dose Limiting Hypersensitivity The Taxanes l Side Effects – – – NEUTROPENIA – Usually Dose Limiting Hypersensitivity – (dyspnea, urticaria, hypotension) Peripheral Neuropathy, Alopecia, Bradycardia

The Taxanes l l Several Studies of Taxane + Cisplatin with response rates of The Taxanes l l Several Studies of Taxane + Cisplatin with response rates of 27% - 53% Gibson et al. 4 2005 – 218 Patients. Compared Cisplatin and 5 FU vs. Cisplatin and Taxol. – l 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 5 FU (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 l l l Induction or Neoadjuvant Chemotherapy Concomitant Chemotherapy Post Chemotherapy for Curable Disease l l l Induction or Neoadjuvant Chemotherapy Concomitant Chemotherapy Post Treatment or Adjuvant Chemotherapy

Concomitant Chemotherapy Concomitant Chemotherapy

Concomitant Chemotherapy l Theoretical Benefits of Chemo-XRT – – – Inhibiting repair of lethal Concomitant Chemotherapy l 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 l Meta-Analysis of Chemotherapy on Head and Neck Cancer (Pignon et al. Concomitant Chemotherapy l Meta-Analysis of Chemotherapy on Head and Neck Cancer (Pignon et al. ) 20005 – – l 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

Neoadjuvant Chemotherapy l l Theoretically should reduce possibility of distant metastasis, and decrease tumor Neoadjuvant Chemotherapy l l 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 l GSSTC (Paccagnella et al. ) 19948. 237 Patients with stage III Neoadjuvant Chemotherapy l GSSTC (Paccagnella et al. ) 19948. 237 Patients with stage III and IV SCC of the head and neck. Cisplatin, 5 FU followed by local tx vs. local tx alone. – l 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 l Meta-Analysis of Chemotherapy on Head and Neck Cancer 5 – – Neoadjuvant Chemotherapy l Meta-Analysis of Chemotherapy on Head and Neck Cancer 5 – – 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-5 FU induction regimens there was a significant 5% absolute survival benefit.

Neoadjuvant Chemotherapy l TAX 323 (Vermorken et al. 2004)10 – 358 patients with locally Neoadjuvant Chemotherapy l TAX 323 (Vermorken et al. 2004)10 – 358 patients with locally advanced and unresectable HNSCC. Induction chemo with cisplatin 5 FU (PF) or cisplatin/5 FU/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 l So why give induction chemotherapy another chance? 11, 12 – – Neoadjuvant Chemotherapy l 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

Adjuvant Chemotherapy l l Post operative XRT has been the standard approach for high Adjuvant Chemotherapy l l 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 l Intergroup Study #0034 –(Al-Sarraf et al 1997)13. 447 patients, complete resection Adjuvant Chemotherapy l Intergroup Study #0034 –(Al-Sarraf et al 1997)13. 447 patients, complete resection with post op XRT alone vs. resection + XRT + Chemo. – – l 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 l EORTC Study (Bernier et al. 2004)16 334 patients with high risk Adjuvant Chemotherapy l 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 – – l 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 Chemotherapy 18 l l Adding chemotherapy to post op XRT for high risk Adjuvant Chemotherapy 18 l l 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 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 l Recent advances in molecular biology, including the human genome project have The Present l Recent advances in molecular biology, including the human genome project have allowed for the introduction of targeted therapies for cancer.

Trastuzumab (Herceptin)19 l The type one receptor tyrosine kinases (Erb. B receptors) – – Trastuzumab (Herceptin)19 l The type one receptor tyrosine kinases (Erb. B 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 (PI 3 K)-Akt pathway. Through these pathways the EGF receptor sitmulates cell growth, division, differentiation, migration, adhesion and angiogenic activity HER 2 (erb. B 2) 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 http: //www. biooncology. com/bioonc/index. m

Trastuzumab (Herceptin)20 l Trastuzumab- A recombinant humanized antierb. B 2 monoclonal antibody which binds Trastuzumab (Herceptin)20 l Trastuzumab- A recombinant humanized antierb. B 2 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) l Several International RCT of Trastuzumab with total enrollment >13, 000 patients Trastuzumab (Herceptin) l Several International RCT of Trastuzumab with total enrollment >13, 000 patients were initiated in 20002001, 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 – erb. B-2 has an anti apoptotic role in normal myocytes, interruption of which leads to increased stress related cardiac damage

Imatinib (Gleevec)20 l l ABL 1 Protoncogene – A tyrosine kinase found in both Imatinib (Gleevec)20 l l ABL 1 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, PI 3 K 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) l Imatinib – Orally bioavailable inhibitor of the ABL protein – – Imatinib (Gleevec) l 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) l Prior to Imatinib, CML typically followed an inexorable course that resulted Imatinib (Gleevec) l 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) l l l Phase 2 studies of IM in patients with accelerated Imatinib (Gleevec) l l l 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 l l EGFR = Erb. Epidermal Growth Factor Receptor in Head and Neck Cancer l l EGFR = Erb. B 125 EGFR m. RNA is upregulated in 92% of HNSCC 22 EGFR levels increase in in advanced stage tumors and in poorly differentiated tumors. Increased EGFR correlates with poorer clinical outcome 22

Cetuximab (Erbitux) l Recombinant monoclonal antibody which binds to the extracellular domain of the Cetuximab (Erbitux) l 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 destruction 25

Cetuximab (Erbitux) l ECOG trial (Burtness et al. ) 2005 – 117 patients randomized Cetuximab (Erbitux) l ECOG trial (Burtness et al. ) 2005 – 117 patients randomized to Cisplatin vs. Cisplatin/Cetuximab. 24 – – – l Trigo et al. 2004 – 103 patients who had progressed on platinum containing regimens. 24 – l 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 + Cetuximab 24 – – 3 year survival rate of 57% vs. 44% Locoregional Control Rate of 56% vs. 48%

Gefitinib, Erlotinib l l l Low molecular weight tyrosine kinase inhibitors which compete with Gefitinib, Erlotinib l l l 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 Japan 22

Gefitinib, Erlotinib 24 l l More Studied in NSCLC – Where patients refractory to Gefitinib, Erlotinib 24 l l 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 l Why don’t EGFR antagonists work better? 25 – – G Protein Gefitinib, Erlotinib l Why don’t EGFR antagonists work better? 25 – – G Protein coupled receptors Constitutively activated downstream pathways Increased levels of VEGF Activation of other Erb. Bs

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

Bevacizumab 26 (Avastin) l VEGF (Vascular Endothelial Growth Factor) – one of the most Bevacizumab 26 (Avastin) l VEGF (Vascular Endothelial Growth Factor) – one of the most potent promoters of angiogenesis, has been identified as a fundamental regulator of tumor neovascularization – – – l 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.

Ep. CAM 30 l Ep. CAM – Epithelial Cell adhesion and activating molecule – Ep. CAM 30 l Ep. CAM – Epithelial Cell adhesion and activating molecule – – – l 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 Proxinium. R – anti-Ep. CAM antibody fused to a subunit of the bacterial Pseudomonas endotoxin – – After Ep. CAM 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 Ep. CAM immunotoxin is in development which is selectively cleaved by tumor cells.

Gene Therapy 27 l At the end of Jan 2005, there were a total Gene Therapy 27 l At the end of Jan 2005, there were a total of 1020 approved gene therapy clinical trials in the world – l 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 l l Loco Regional Disease amenable to intratumoral injection Often presents with advanced disease inamenable to current therapies

Gene Therapy l P 53 – Tumor Suppressor Gene known as “The guardian of Gene Therapy l P 53 – Tumor Suppressor Gene known as “The guardian of the Genome” l l l Activates DNA Repair proteins when DNA has sustained damage Holds the cell cycle at G 1 Regulation pointon Damage Recognition Initiates Apoptosis if DNA damage appears irrepairable

http: //www. biovita. fi/suomi/terveyssivut/p 53. html http: //www. biovita. fi/suomi/terveyssivut/p 53. html

Gene Therapy 27 l Restoration of p 53 function – Clayman et al. 1998 Gene Therapy 27 l Restoration of p 53 function – Clayman et al. 1998 treated 18 patients with relapsed HNC with intratumoral injections of a replication deficient adenoviral vector expressing wild type p 53 l – One pathologic complete response, two partial responses, and 6 patients with disease stabilization Gendicine – Recombinant human serotype 5 adenovirus containing a human wild type p 53 expression cassette 28 l l 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 l Onyx – 015 – Replication competent viral vector containing a deletion Gene Therapy l Onyx – 015 – Replication competent viral vector containing a deletion in the E 1 B 55 KD gene which is responsible for binding and inactivating p 53 l l l Virus replicates preferentially in in p 53 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 l Based on 2 Principles – – Immune system should recognize and destroy Immunotherapy l Based on 2 Principles – – Immune system should recognize and destroy abnormal cells. Tumor Cells are poorly immunogenic, and strongly immunosupressive l l l PGE 2 produced by tumors inhibits lymphocyte proliferation Cytokines produced by tumors inhibit lymphocyte function Tumors down regulate antigen presenting molecules

Immunotherapy l Interleukin – 2 – Produced by the body during an immune response, Immunotherapy l 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

Immunotherapy 29 l Non-Specific Active Immunomodulation – BCG vaccine l l l Used to Immunotherapy 29 l Non-Specific Active Immunomodulation – BCG vaccine l l l 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 l Specific Active Immunization – P 53 – Mutated in >80% of SCCHN Immunotherapy l Specific Active Immunization – P 53 – Mutated in >80% of SCCHN which leads to a buildup of non functional p 53 in cells. l l Since most mutations involve only one amino acid, Cytotoxic T cells which recognize WT p 53 should also attack cells which express mutated p 53 In truth, patients who express mutated p 53 are resistant

Immunotherapy l HPV Vaccines – Estimated that 25% of HNSCC are HPV associated 31 Immunotherapy l HPV Vaccines – Estimated that 25% of HNSCC are HPV associated 31 l l – HPV viral oncogenes E 6 and E 7 are consistantly expressed in HPV associated cancers l – 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: l l Jason Newman M. D. Duane Sewell M. D. Special Thanks To: l l Jason Newman M. D. Duane Sewell M. D.

References l l l l 1. Colevas, Dimitrios Chemotherapy Options for Patients With Metastatic References l l l l 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 FU in recurrent or metastatic Squamus cell carcinoma of the head and neck: A phase III study of the EORTC Head and neck cancer collaborative group. Ann Oncology 5: 521 -526, 1994 4. 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 5. Pignon JP, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell : Theree meta-analyses of updated individual data. MACH-NC Collaborative Group Lancet 2000; 355: 949 -955 6. Forastiere AA et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer N England J of Medicine 2003; 349; 2091 -2098 7. Bernier J. Cooper J, Chemoradiation after Surgery for High Risk Head and Neck Cancer Patients: How Strong is the Evidence? The Oncologist 2005; 10: 215 -224 8. Paccagnella A et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo. J National Cancer institute 1994; 86: 265 -272

References l l l l l 9. Domenge c et al. Randomized trial of References l l l l l 9. Domenge c et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d’Etude des Tumeurs de la Tete et du Cou GETTEC. Br. J Cancer 2000; 83: 1594 -1598 10. Vermorken JB et al. Standard Cisplatin/infusional 5 -FU vs. docetaxel plus PF as neoadjuvant chemotherapy for nonresectable locally advanced squamus cell carcinoma of the head and neck. A phase III trial of the EORTC. J Clin Oncol 2004; 22: 14 s 11. Posner, marshall, Paradigm Shift in the Treatment of Head and Neck Cancer: The Role of Neoadjuvant Chemotherapy The oncologist 2005; 10(suppl 3): 11 -19 12. Gibson M, Forastiere A, Reassessment of the role of induction chemotherapy for head and neck cancer. Lancet Oncol 2006; 7: 565 -74 13. Al-Saffaf et al. Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional control of advanced, resectable head and neck cancers: RTOG 88 -24 Int J Radiat Oncol Biol Phys 1997; 37: 777 -82 14. Bernier et. Al. Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the Evidence? The Oncologist 2005; 10: 215 -224 15. Bachaud JM et al. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 1996; 36: 999 -1004 16. Bernier J, Domenge C et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Medicine 2004; 350 : 1945 -1952 17. Cooper JS et al Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous cell carcinoma of the head and neck. N Engl J Med 350; 19: 1937 -1944

References l l l l l 18. Bernier, J, Vermorken J et al. Adjuvant References l l l l l 18. Bernier, J, Vermorken J et al. Adjuvant Therapy in Patients With Resected Poor Risk Head and Neck 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 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 23. Caponigro et al Monoclonal antibodies targeting epidermal growth factor receptor and vascular endothelial growth factor with a focus on head and neck tumors Current ? Opinion in Oncology 2005 17: 212 -217 24. Mendelsohn et al. Status of Epidermal Growth Factor Receptor Antagonists in the biology and Treatment of Cancer Journal of Clinical Oncology 2003 21; 14: 2787 -2799 25. Kalyankrishna Shailaja et al Epidermal Growth Factor Receptor Biology in Head and Neck Cancer J Clin Oncol. 24: 266 -2672 26. Chen, Helen Expanding the Clinical Development of Bevacizumab The oncologist 2004; 9(suppl 1): 27 -35

References l l l 27. Harrington K et al Gene Therapy for head and References l l l 27. Harrington K et al Gene Therapy for head and neck cancer Cancer and Metastasis reviews 24: 147 -164, 2005 28. Current Status of Gendicine in China: Recombinant Human Ad-p 53 Agent For Treatment of Cancers. Human Gene Therapy 16: 1016 -1027 29. Targeting the immune system: novel therapeutic approaches in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 2004 53: 1055 -1067 30. Baeuerle PA, Gires O Ep. CAM (CD 326) finding its role in cancer. British Journal of Cancer 2007 Meeting Report 31. Devaraj, K, Gillison Maura et al Development of HPV Vaccines for HPV associated Head and Neck Squamous Cell Carcinoma. Critical Rev Oral Biol Med 14(5): 345 -362 (2003)