STATE OF THE ART MANAGEMENT OF NASOPHARYNX CANCER

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1 STATE OF THE ART MANAGEMENT OF NASOPHARYNX CANCER Anthony TC Chan Chairman Department of Clinical Oncology Director Hong Kong Cancer Institute & Sir YK Pao Centre for Cancer The Chinese University of Hong Kong

2 Sir YK Pao Centre for Cancer, HK Cancer Institute CCTU Principal Investigators Research Nurses Statistician Administrator Research Assistants Data entry clerks Biostatistics Bioinformatics Anatomical & Cellular Pathology Chemical Pathology Clinical Oncology Surgery >125 million competitive grants last 5 years

3 SFDA approval 1 st August 2006

4 华南肿瘤学国家重点实验室伙伴实验室 Cancer Center Sun Yat Sen University Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong

5 State Key Lab in Oncology in South China Opening 16 th November 2006

6 Outline of talk Treatment of NPC Targeted therapy in NPC EBV DNA as diagnostic and monitoring tool Incorporating EBV DNA in clinical management

7 NPC: IMRT treatment results N Stage Median Dose (Gy) Local Distant Overall FU time relapse-free metastasis-free Survival Survival Survival UCSF 87 All 30 GTV 97% 66% 73% (Lee et al) (T3/4 45%) months 70Gy/33Fr (4y) (4y) (4y) (N+ 75%) PTV 59.4Gy/33Fr PWH 63 All 29 GTV 92% 78% 90% (Kam et al) (T3/4 51%) months 66Gy/33Fr (3y) (3y) (3y) (N+ 70%) PTV 60Gy/33Fr QMH 33 T1, N GTV 100% 100% 100% (Kwong et al) months 68-70Gy/34Fr (2y) (2y) (2y) PTV 64-68Gy MSKCC 39 All 24 Concomitant 97% 79% 97% (Wolden et al) (stage III/IV months Boost (2y) (2y) (2y) 75%) 54Gy/30Fr + 16Gy/10Fr

8 Overall survival after concurrent cisplatin-rt compared with RT alone 5yr 70.3% CRT 58.6% RT p = HR = JNCI 2005;97:536-9

9 Randomized studies on concurrent chemoradiation in NPC Study Chemotherapy Benefit 5yr PFS 5yr OS RT CRT RT CRT Intergroup 0099 cisplatin 100mg/m 2 D1 q3wk 3 cycles with RT local control 29% 58% 37% 67% n = adjuvant cisplatin 80mg/m 2 D1, and DM (p<0.001) (p<0.001) 5FU 1g/m 2 D1-4 q3wk 3 cycles Lin et al cisplatin 20mg/m 2 /day and 5FU 400mg/m 2 /day, local control 53.0% 71.6% 54.3% 72.3% n = hr infusion 2 cycles weeks 1 and 5 with RT (p=0.0012) (p=0.0022) QMH UFT 200mg t.i.d. with RT ± cisplatin 100mg/m 2 DM 3 yr PFS 3 yr OS n = 219 D1 5FU 1g/m 2 D1-3, alternating vincristine 2mg bleomycin 30mg methotrexate 50mg/m 2 D1, 57.8% (p = 0.14) 69.3% 76.8% (p = 0.06) 86.5% 6 cycles PWH cisplatin 40mg/m 2 weekly with RT local control 52.1% 60.2% 58.6% 70.3% n = 350 and DM (p = ) (p = ) NCC cisplatin 25mg/m 2 D1-4 q3wk, 3 cycles with local control 3 yr PFS 3 yr OS n = 221 RT + adjuvant cisplatin 20mg/m 2, and DM 53% 72% 65% 80% 5FU 1 g/m 2 D1-4 q4wks 3 cycles (p = ) (p = ) HKNPCSG Intergroup local control 3 yr PFS 3 yr OS n = % 70% 78% 78% (p = 0.1) (P = 0.97)

10 Meta-analysis based on 1753 individual data Timing of CT Trials Patients HR of death HR of PFS Induction (0.80; 1.21) 0.82 (0.68; 0.97) Concomitant ± adjuvant (0.48; 0.76) 0.63 (0.51; 0.78) Adjuvant (0.69; 1.38) 0.89 (0.67; 1.20) MAC-NPC Collaborative group IJROBP 06;64:47-56

11 Phase II trial of paclitaxel and carboplatin followed by concurrent cisplatin-rt with EBV DNA monitoring Week C C T T T T T T P P P P P P P P C = carboplatin AUC 6 mg/ml/min T = paclitaxel 70 mg/m 2 P = cisplatin 40 mg/m 2 RT (n = 31, 2yr OS 91.8%, PFS 78.5%) Chan et al JCO 2004;22:

12 A randomized phase II study of concurrent cisplatinradiotherapy with or without neoadjuvant chemotherapy using taxotere and cisplatin Week C C R A N D O M I Z E T T P P P P P P P P IMRT P P P P P P P P IMRT C = cisplatin 70mg/m 2 T = taxotere 70mg/m 2 P = cisplatin 40mg/m 2 Proc ASCO

13 Overall survival for distant metastases stratified by metastatic site Hui.Chan (HKNPCSG) Cancer 2004;101:300-6

14 Newer agents and platinum-based doublets in metastatic NPC 1 st Author Year Sample Size Regimen Overall Complete Response (%) response (%) Wang Cisplatin-5FU 76 8 Au Cisplatin-5FU Stein Cisplatin-ifosfamide Yeo Carboplatin-paclitaxel Tan Carboplatin-paclitaxel 75 3 Foo pre-treated Gemcitabine untreated Ngan Cisplatin-gemcitabine Chua pre-treated Xeloda Poon Irinotecan 17 0

15 Gemox in metastatic NPC Phase II single arm study Previously untreated pts with recurrent or metastatic NPC Sample size: 35 (two-stage design) Primary endpoint: overall response rate Secondary endpoints: toxicity, overall survival, time to progression, duration of response Gemcitibine (1000mg/m 2 ) 10mg/m 2 /min infusion D1 Oxaliplatin (100mg/m 2 ) over 2 hrs D2 q 2/52 Proc ASCO

16 Targeted therapy Targets in NPC: brief overview on molecular biology Targeting signal transduction Targeting gene expression via epigenetic mechanisms

17 Proposed model of NPC pathogenesis Key 1: EBV is oncogenic Key 2: gene inactivation is frequent event Young. Nature Cancer Review 2004; *Pathmanathan et al. NEJM 1995;

18 EBV latent infection Once EBV infects a cell, EBV exists in a latent state : Some viral genes are NOT expressed: lytic antigens Some viral genes are expressed (see fig): (1) Less immunogenic than lytic viral antigens evade T-cell killing (2) Oncogenic: eg LMP-1: 20-50% NPC.

19 EBV proteins confer survival advantage & invasiveness to NPC cells LMP-1: (a) Induces expression of proteins that apoptosis, metastasis & invasion, angiogenesis (b) Activate signaling proteins* that promotes growth EGFR, MMP-9, COX-2, HIF-1α,, FGF, VEGF, IL-8 Raab-Traub. Semin Cancer Biol;12: 2002( )

20 Potential Targets in NPC Signaling pathways Gene expression Cell cycle Apoptosis Angiogenesis Protein homeostasis

21 EGFR expression in stage III-IV NPC NPC showing strong EGFR staining (Chua et al 2004) Overall survival, Ma et al 2003 Expressed > 80% of NPC (Ma et al 2003) Poor prognostic factor in advanced NPC (Ma et al 2003, Chua et al 2004) Relapse-free survival, Chua et al 2004

22 Some drugs that target EGFR signaling Cetuximab 100 Extracellular domain (Receptor) Tyrosine kinase domain

23 Multi-center, single arm, Phase II study Cetuximab: weekly Chemo: carboplatin, q3wk Eligible: metastatic or recurrent disease failed prior platinum-based chemo Endpoints: response rate, time to progression, survival time, safety

24 Patient characteristics Sample size = 60 Median age: 45 yrs (23-64) 76% male, Lines of Prior chemo: 1 line = 42 (70.0%) > 2 lines = 18 (30%)

25 RESULT RESPONSE RATE All patients (n=60) Complete Response (CR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) Not Assessable Objective Response Rate (confirmed CR+PR) Disease Control (CR+PR+SD) 0 (0%) 7 (11.7%) 29 (48.3%) 23 (38.3%) 2 (3.4%) 11.7% [ ] 60.0% [ ] Median Time to Progression: 2.7 months (Partial responders: 5.77m)

26 Phase II study of gefitinib in metastatic or locoregionally recurrent nasopharyngeal carcinoma (NPC) Anthony TC Chan, Brigette Ma, Edwin P Hui, Ann King, Michael Kam, WH Kwan, Tony Mok, SF Leung. (ASCO abstract 2006) Eligibility: failed 1-2 lines of prior chemo (platinum-based) for metastatic / locally recurrent NPC Gefitinib 500mg daily for 28-day cycle Endpoints: response rate, toxicity, time to progression Completed accrual to 1 st stage (N=15) Correlative studies

27 Phase II study of concurrent cetuximab-cisplatin and radiotherapy in the treatment of advanced nasopharyngeal carcinoma Eligibility: NPC - T3 or 4, & any N, M0, or any T, & N2 or N3, M0. Endpoints: (1) Safety and feasibility of adding cetuximab to RT & weekly cisplatin (2) Loco-regional control rate at 3 months Ongoing (target = 30-35) Correlative studies

28 SCHEMA Departmental Usual practice Scope & Biopsy MRI, CT CXR, abdo US Bone scan FU 2-4wk Scope 3/12 FU MRI, Scope & Biopsy (T2b,T3,4) 3-6 m FU RT + weekly cisp (40mg/m2) MRI DCE 5ml blood C225 Wkly C225, cisp 20-30mg/m2 5ml blood Late Tox DCE MRI Extra Tissue to Cesar 12/12 MRI Additional Study Requirement

29 Control of gene expression Gene expression in cancer is frequently altered Genetic mechanisms Epigenetic mechanisms Change in DNA sequence Mutations Chromosomal aberrations DNA hypermethylation or Histone acetylation can both cause silencing of gene expression (1) Host genes: Altered expression of tumor suppressor genes loss of function uncontrolled growth (2) Viral genes: EBV lytic antigens

30 Concept 1: Epigenetic gene silencing - DNA promoter methylation Normal gene expression: CpG regions at promoter region of DNA stay unmethylated transcription CpG Islands Promoter DNA strand Silenced gene expression: CpG regions at promoter region of DNA = methylated by DNA methyltransferase repressed downstream mrna expression loss of gene function (eg TSG) X Miyamoto. Jpn J Clin Oncol 2005;35(6)

31 Viral genes: Silencing of EBV genes by methylation in NPC EBV-specific CTLs NPC cell: Lytic viral antigens Evade immune surveillance m m Cp mm m mm Wp m EBNA3a 3b Silenced 3c

32 Hypothesis 1: Demethylating agent (azacitidine) may induce EB gene re-expression in NPC NPC cell: azacytidine azacytidine azacytidine azacytidine azacytidine EBV-specific CTLs EBNA3a3b 3c m m mm m m m Cp Wp EBNA3a3b 3c

33 First-in-human study Patients exhausted options 8 NPC,1 Hodgkin,1 HIV-NHL Azacitidine 75mg/m2 D1-7 ivi 1-6 cycles 5 adequate biopsies < 72hrs of 1 st injection DNA extraction from fixed samples Azacitidine effect on methylation status & gene expression

34 Two effects of Azacitidine were studied: (1) Could AZA demethylate methylated promoter region of selected viral genes? (2) Can AZA re-activate selected viral gene expression? Genes selected: (Latent) EBNA-2, LMP1 & LMP2B (Lytic) Zta, Rta Promoters selected: Cp, Zp, Rp, LMP-1p, LMP-2p, EBNA-2p

35 Result: Demethylation of EBV promoters in patient biopsies (1) Cp methylation - MSP NPC-A1 NPC-A2 NPC-A3 NPC-A5 NPC-666 AIDS-BL Pre PostPre Post Pre Post Pre Post Pre Post Pre Post u m u m u m u m u m u m u m u m u m u m u m u m u m u m B95-8 Rael Cp (2) Re-expression of the EBV gene, Zta Pre Post Zta JCO 04;22:

36 Azacitidine + HDACi in NPC Phase I/II study H N O O N H OH SAHA (Suberoylanilide hydroxamic acid) PI: Wenson Hsieh

37 Objectives Define toxicity profile of escalating doses of suberoylanilide hydroxamic acid (SAHA) given in conjunction with a fixed dose of 5 azacytidine (5AC) Define the biologically optimal dose of SAHA given in conjunction with a fixed dose of 5AC Study the effect of 5AC on the pharmacokinetic of SAHA Assess the effect of SAHA on histone acetylation as measured in tumor and peripheral blood mononuclear cells Assess the effect of 5AC on EBV promoter demethylation as measured in tumor

38 Plasma cell-free circulating EBV DNA NPC Cell EB Virus Blood Stream

39 Plasma EBV DNA IN NPC diagnosis Blood level of EBV DNA (copies/ml) Sensitivity: 96% Specificity: 93% NPC Controls Cancer Res 1999;59:

40 EBV DNA after surgical resection

41 EBV DNA MONITORING Week C C T T T T T T P P P P P P P P RT C = carboplatin AUC 6 mg/ml/min T = paclitaxel 70 mg/m 2 P = cisplatin 40 mg/m 2 Chan et al JCO 2004;22:

42 EBV DNA monitoring for patients in clinical remission C C T T T T T T P P P P P P P P RADIOTHERAPY C = carboplatin T = paclitaxel P = cisplatin

43 EBV DNA monitoring for a patient with distant metastases start treatment died of disease distant metastases clinical CR

44 OS analysis using post-treatment cutoff 500 copies/ml P < Chan et al JNCI 2002;94:1614-9

45 HKNPCSG 0502 study Plasma EBV DNA in the risk stratification of patients with NPC 1500 patients detectable plasma EBV-DNA at 6-8 weeks after completion of RT or chemo-rt R A N D O M I S E EBV-DNA PET/CT (0 month) Adjuvant Chemotherapy Arm A GP or GC x 6 Arm B No chemotherapy EBV-DNA PET/CT (6 months) Partially supported by Health Bureau of HKSAR

46 Conclusions Concurrent cisplatin-rt ± adjuvant PF should be offered as standard treatment strategy in locally advanced NPC Platinum-based doublet is standard first-line treatment for metastatic NPC Anti-EGFR targeted therapy is promising Demethylation of EBV promoters by Azacytidine provides model for future work EBV DNA monitoring is applicable to clinical setting

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