1. R2 민준기 / 정재헌 교수님

2. Introduction Patients with resected high-risk locally advanced head and neck cancer –Expect favorable outcomes after concomitant radiochemotherapy(CCRT) –Treatment-related oral mucositis (OM) is debilitating decrease nutritional support  Weight loss Infection  treatment interruption  limit Tx efficacy –Reliable and effective drugs targeting OM are lacking

3. Introduction Keratinocyte growth factor (KGF) –Fibroblast growth factor –Cytoprotective effects on epithelial cells Palifermin –alleviate OM in patients treated with CCRT for hematologic malignancies –Amifostine only comparator compound decreased xerostomia in patients irradiated for head and neck cancer did not protect from OM

4. Introduction Purpose of this study –Whether Palifermin reduces severe OM in patients undergoing postoperative radiochemotherapy for locally advanced head and neck cancer

5. Method (Patients) Inclusion criteria –older than 18 years –ECOG performance status of 0 to 2 –pathologically documented stages II to IVB squamous cell carcinoma of the oral cavity, oropharynx,hypopharynx, or larynx –expected to receive at least 50 Gy in oral or oropharyngeal mucosa

6. Method (Patients) Exclusion criteria –tumors of the lips, paranasal sinuses, salivary glands, or unknown primary site –metastatic disease –history of pancreatitis within the last year –prior radiation to the head and neck region or prior chemotherapy –previous treatment of keratinocyte growth factors

7. Method (Study Design) Double-blind, randomized, placebo-controlled trial Patients were enrolled between –2005.01.27~ 2007.08.17 Conducted at 38 centers –in Australia, Austria, Canada, France, Germany, Italy, Spain, and the United Kingdom

8. Method (Study Design) Initially, patients were allocated to three arms –Palifermin (180mcg/kg/wk) throughout radiochemotherapy –Palifermin (180mcg/kg/wk) for four doses and then placebo throughout the remainder of radiochemotherapy –Placebo throughout radiochemotherapy –One serious adverse event of respiratory insufficiency was reported 120mcg/kg/wk

9. Method (Efficacy and Safety End Points) The primary efficacy end point –incidence of severe OM (WHO grade 3 or 4)

10. Method (Efficacy and Safety End Points) Secondary efficacy end points –Duration of and time to onset of severe OM –xerostomia grade 2 at month 4 –Average mouth and throat soreness (MTS) scores –Incidence of treatment breaks –Incidence of cisplatin delays –Total dose of opioids

11. Method (Efficacy and Safety End Points) Safety end points –incidence of adverse events and laboratory abnormalities. –disease progression –time to disease progression –incidence of second primary tumors and other malignancies –overall survival

12. Method (Statistical Analysis) Efficacy analysis –intention to treat Treatment arms comparision –Cochran-Mantel-Haenszel methods Time to onset of an event, progression- free survival, and overall survival –Kaplan-Meier method

13. Results Palifermin (120g/kg/wk) for four doses and then placebo throughout the remainder of radiochemotherapy (n=38)  slow enrollment, Halted

14. Baseline patient characteristics

15. Results (Efficacy) <

16. < < > 67% 51% 32days 45days

17. Results (Safety end points) Palifemin > Placebo –dysphagia (35% and 21%) –diarrhea (12% and 5%) –asthenia (14% and 8%) –back pain(6%and 1%) –headache(10%and 4%) –abdominal pain(8%and 2%) Palifemin < Placebo –dehydration (6% and 14%) –leukopenia (13% and 21%) –insomnia (5% and 13%) –fatigue (8% and 15%) –mucosal inflammation (4% and 11%) Adverse events with a difference in incidence of at least 5%

18. Results (Safety end points) Overall survival and progression-free survival were similar 46 deaths (23deaths [25%] in each treatment arm) Disease recurred in 25 patients (27%)and 22 patients(24%)

19. Conclusion Palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherap y.

20. Discussion (30) (26) Missing data (grade 2) Sample size was chosen only for the primary end point reduced the incidence of severe OM  Clinical relevance ? Innovative administration schedules of the compound and its integration into modern radiation treatment techniques, may additionally elaborate the clinical relevance of our findings