1. Empowering induction therapy for locally advanced head and neck cancer A. Argiris1* & M. V. Karamouzis2 1Division of Hematology–Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA; 2Department of Biological Chemistry, University of Athens Medical School, Athens, Greece Annals of Oncology 22: 773–781, 2011 doi:10.1093/annonc/mdq426 Published online 23 September 2010. R3 김태영 /Prof. 정재헌 review

2. introduction More than 500 000/year are affected by head and neck cancer two-thirds of patients who present with locally advanced SCCHN CRT - improve overall survival (OS) progression-free survival (PFS) local disease control TNM staging tables are separated according to head and neck site. Oral cavity Nasopharynx Oropharynx Hypopharynx Larynx Nasal cavity and paranasal sinuses Salivary glands

3. introduction Induction (or neoadjuvant) chemotherapy for locally advanced SCCHN - high overall responses rates RRs, CRs (EORTC) study - patients with cancer of the hypopharynx shows OS benefit induction PF before RT compared with immediate surgery followed by RT (MACH-NC) study - an absolute improvement of OS 2.4% at 5 years using PF, no statistically significant variation

4. taxane-containing induction therapy EORTC 24971/TAX323 TAX324 French Head and Neck Oncology Radiotherapy Group Spanish Head and Neck Cooperative Group TPF seems to produce higher rates of grade 3/4 neutropenia and febrile neutropenia than PF lower rate of prolonged neutropenia, treatment delay, toxic deaths with TPF four phase III randomized trials have proven the superiority of a triplet with docetaxel or paclitaxel added to PF

5. EORTC 24971/TAX323 TAX324 Spanish Head and Neck Cooperative Group French Head and Neck Oncology Radiotherapy Group TPF :TTF 20 versus 12 months) P = 0.006 RR (80% versus 68%) P = 0.001 Median survival (43 versus 37 months) P = 0.06 N=382=> PF, TPF responded to induction =>RT or CRT Not respond => total laryngectomy followed by radiation ± chemotherapy

6. randomized studies to validate the induction therapy approach Spanish Head and Neck Cancer Cooperative Group DeCIDE induction TPF followed by RT concurrently with docetaxel,5-FU,hydroxyurea OS compared with the same CRT regimen alone Paradigm’ study NCT00705068 TPF plus CRT increases 3-year OS compared with CRT alone GSTTC CR rates (primary end point) were higher with TPF (50%versus 21.2%, P = 0.004) median PFS and OS were 30.4 and 39.6 months versus 19.7 and 33.3 months TPF induction and CRT alone

7. incorporating targeted agents into induction therapy EGFR in SCCHN - poor survival Cetuximab - a recombinant monoclonal antibody Cetuximab in SCCHN improving OS with platinum-based chemotherapy adding cetuximab to TPF adding cetuximab to TP adding cetuximab to paclitaxel/carboplatin

8. incorporating targeted agents into induction therapy adding cetuximab to TPF - phase I trial conducted at the Dana-Farber Cancer Institute - to determine the maximum tolerated dose of 5-FU with docetaxel and cisplatin every 3 weeks plus the standard dose of cetuximab Induction TPF plus cetuximab,in a phase II trial in patients with unresectable locally advanced-stage IV SCCHN weekly cetuximab plus accelerated RT with a concomitant boost to a total dose of 69.9 Gy

9. incorporating targeted agents into induction therapy adding cetuximab to TP standard RT to a dose of 70 Gy concurrently with weekly cisplatin and cetuximab University of Pittsburgh Cancer Institute

10. incorporating targeted agents into induction therapy adding cetuximab to paclitaxel/carboplatin MD Anderson Cancer Center Eastern Cooperative Oncology Group at week 9, radiation (total dose 50 Gy) -The patients with a negative biopsy receive CRT to a total dose of 68–72 Gy - biopsy-positive patients underwent salvage surgery with neck dissection for N1-3 disease

11. incorporating targeted agents into induction therapy ongoing studies of induction therapy involving cetuximab

12. incorporating targeted agents into induction therapy ongoing studies of induction therapy involving cetuximab The phase III INTERCEPTOR trial -N=278 patients -TPF followed by cetuximab/RT with standard concurrent CRT without prior induction. -The primary end point is OS NCT00716391 - N= 458 patients - OS as primary end point - induction TPF=> cisplatin-based CRT versus RT plus cetuximab

13. incorporating targeted agents into induction therapy clinical trials of other targeted therapies in induction Sarah Cannon Research Consortium - Gefitinib (tyrosine kinase inhibitors) to induction (docetaxel, carboplatin, and 5-FU) and subsequent CRT - in a 62-patient community-based phase II EORTC 24051 study - lapatinib plus TPF associated to unacceptable renal toxic effect Bevacizumab plus paclitaxel/carboplatin/5-FU followed by concurrent RT with paclitaxel, bevacizumab, and erlotinib in a 60-patient phase II study

14. selecting patients for induction therapy cumulative toxic effects - a major impact on treatment tolerability TREMPLIN- phase II study -three cycles of induction TPF=> RT plus cisplatin versus RT plus cetuximab -57% assigned to CRT could not receive their full planned treatment -29% for the RT/cetuximab

15. selecting patients for induction therapy molecular biomarkers -low expression levels of the marker b-tubulin II -low baseline levels of VEGF and IL -6 -low VEGF IL-4, IL-6, and PDGF, among other hypoxia-related cytokines -HPV-positive tumor- reduction of locoregional failure (not in heavy smoker)

16. conclusions and future directions Induction TPF superior outcomes over PF Induction therapy is still under validation against definitive CRT alone alternative strategy - a platinum/taxane backbone studies with cetuximab - many possible strategies only one cycle of PF as a guide to assign patients to organ-preserving CRT and to immediate salvage surgery HPV-negative SCCHN expected to have worse prognosis Ongoing and planned clinical investigations will define optimal strategies of multimodal treatment of locally advanced SCCHN.