Chemotherapy For H&N SCC Past, Present and Future

1. Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 Chemotherapy For H&N SCC Past, Present and Future Charles Gawthrop M.D. Faculty Discussant: Jason Newman M.D.

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

3. The Past • 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. Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 The Present “Drug therapies are replacing a lot of medicines as we used to know it” -George W. Bush

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

37. 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.

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

40. 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

41. 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

42. 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

43. 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

44. 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%

45. 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

46. 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

49. 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

50. 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%