Nasopharyngeal Carcinoma Site Specific Approaches, 2008 Lori J. Wirth, MD Dana-Farber Cancer Institute

Nasopharyngeal Carcinoma A Particularly Unique Entity in Head and Neck Cancers Epidemiologic features Endemic pattern, EBV association Southern China, Southeast Asia, Northern Africa, Mediterranean basin, Inuit peoples, Caribbean

Nasopharyngeal Carcinoma A Particularly Unique Entity in Head and Neck Cancers Anatomic features present unique treatment challenges Surgery Radiotherapy

Nasopharyngeal Carcinoma A Particularly Unique Entity in Head and Neck Cancers NPC is more sensitive to both chemotherapy and radiotherapy compared to other head and neck cancers But paradoxically more likely to involve lymph nodes and spread distantly

Up-Front NPC Treatment There is agreement that concurrent chemoradiotherapy is the best approach to locally advanced NPC Role of chemotherapy – radiation sensitization, locoregional control Also of interest – chemotherapy to treat micrometastatic disease and reduce the risk of distant metastasis Here’s where the controversy lies What is the optimal chemotherapy sequencing/schedule? What is the optimal chemotherapy regimen?

Up-Front NPC Treatment At least 15 RCTs involving chemotherapy and radiotherapy in NPC 4 meta-analyses performed Still no broad consensus Inconsistent results from similar studies Studies involved different patient populations Variable EBV-association Dominant WHO histologies vary Ethnicity Different staging systems Different treatments-chemo and radiotherapy Less than ideal study design

U.S. Intergroup 0099 cis PF RT 193 of 270 pts enrolled RT Al-Sarraf, JCO, 1998

U.S. Intergroup 0099 3Y PFS 69% (CRT) vs. 24% (RT alone), p<0.001 3Y OS 78% (CRT) vs. 47% (RT alone), p=0.005 Local control & distant mets also improved

U.S. Intergroup 0099 Issues Flawed study design Are the benefits from chemo due to concurrent administration, adjuvant, or both? Terminated early after interim analysis showed survival benefit RT alone arm performed worse than expected Old RT techniques Many patients enrolled had WHO type I NPC (not EBV-associated) Adjuvant PF chemotherapy only feasible in some patients

What’s Wrong with Adjuvant PF?

Subsequent Asian Trials Contradictory 3Y OS Rate of DM Wee, JCO, 2005 (Singapore) 221 pts WHO type II/II Mostly T3-4 +/or N2-3 Cis/RT  PF X3 80% 18% RT alone 65% 38% p=0.0061 p=0.0029 Lee, JCO, 2005 (Hong Kong) 348 pts Mostly N2-3 78% 24% 27% p=0.97 p=0.96

Meta-analysis in NPC MAC-NPC Collaborative Group To assess the impact of adding chemotherapy to RT on survival 8 trials, 1753 pts HR for death=0.82 (95% CI 0.71-0.95) 6% absolute survival benefit at 5 years Greatest benefit from concurrent chemo HR=0.60 (concurrent) HR=0.97 (adjuvant) HR=0.99 (induction) Baujat, IJROBP, 2006

Meta-analysis in NPC MAC-NPC Collaborative Group Conclusions Chemotherapy added to RT in NPC yields a small but statistically significant improvement in survival Benefit almost entirely from concurrent chemotherapy However Heterogeneity of studies, patients, chemotherapy regimens, and radiotherapy techniques limits lessons learned No clear chemotherapy regimen superior to others e.g. Al-Sarraf, PFL induction, bleo/epi/cis induction, concurrent UFT, adjuvant PF alternating with vincr/bleo/mtx More effective chemotherapy regimens may exist

Shift From Adjuvant to Induction Chemotherapy Chua, IJROBP, 2006 Subgroup analysis of 2 induction studies with cis/epirubicin and cis/bleo/5FU  RT vs. RT alone Early stage pts (T1-2N0-1, st. IIB) had fewer distant mets with induction and improved survival Yau, Head and Neck, 2006 Phase II study of gemcitabine/cis X3  cis/accelerated concomitant boost RT 3Y OS = 76%, 3Y PFS = 63% Chan, JCO, 2004 Phase II study of carbo/paclitaxel X2  cis/RT Overall CR rate=97% 2Y OS = 92%, 2Y PFS = 79%

NPC Trials Currently Underway Hong Kong Randomized trial of adjuvant gem/cis in pts with elevated EBV titers following RT or CRT Randomized trial of induction vs. adjuvant PF with concurrent CRT (cis/RT) Induction PF  cis/radiation (Lee, IJROBP, 2005) Well-tolerated, 92% completed all chemo, 96% completed radiation 3Y PFS 75%, OS 71% also compares capecitabine to 5FU and accelerated concomitant boost RT to conventional fractionation RTOG 0615 Phase II study of concurrent bevacizumab/cis/RT  bevacizumab/PF X3

Targets for Targeted Therapy in NPC Numerous molecular determinants identified EGFR, VEGF, survivin, CDKs All overexpressed, prognostic, druggable targets High-throughput screening underway to identify more druggable targets EBV Causal in >80% NPC cases worldwide EBV found in every NPC cell Clonal EBV present in nasopharyngeal carcinoma in situ EBV-encoded RNA (EBER) in situ hybridization

EBV as a Therapeutic Target in NPC EBV proteins represent ideal non-self targets for cancer immunotherapy EBV-associated NPC must somehow emerge by escaping the patient’s viral immune surveillance Restoration or supplementation of EBV immunity by immunotherapy should be effective treatment

Proof of Principle Rooney, Blood, 1998 EBV-Specific Immunotherapy in Post-Transplant Lymphoproliferative Disorder Donor PBMCs Rooney, Blood, 1998 Prophylactic treatment with EBV-specific T cells prevented PTLD (0/63 vs. 11.5% in historical controls) Therapeutic treatment with EBV-specific T cells successful in 4/5 patients with established PTLD Donor PBMCs EBV Repeated wkly stimulations EBV-infected lymphoblastoid cell line (LCL) EBV-Specific Cytotoxic T Cell (CTL)Product

EBV-Specific Immunotherapy in NPC Straathoff, Blood, 2005

EBV-Specific Immunotherapy in NPC Numerous Challenges Mismatch between viral gene expression & CTL specificity Longevity of infused CTL T cell depletion in immunocompromised PTLD host vs. “full tank” in NPC CTL precursor frequency Quality of immune response in cancer patients Homing to mucosal tumor site Tumor milieu T cell infiltrates (lymphoepithelioma) contain suppressive T regulatory cells What are the determinants for clinical efficacy? T cell product LMP2 and/or EBNA-1 CTL? Tumor phenotype LMP2 protein expression? 100% of tumors express RNA, but only 50% express protein

Statements on NPC Maximizing Treatment Approaches Now and Into the Future Room for improvement to Al-Sarraf regimen Concurrent platinum-based chemotherapy with definitive radiation should remain the mainstay of treatment With rates of DM exceeding 20%, we need more effective systemic therapy than adjuvant PF Induction regimens theoretically preferential to adjuvant Highly effective regimens, such as taxane/platinum/5FU, are understudied More exploration of targeted therapy added to definitive treatment also warranted EBV-specific immunotherapy is a potentially useful treatment modality