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Nasopharyngeal Carcinoma

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

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Nasopharyngeal Carcinoma

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

  2. Nasopharyngeal CarcinomaA 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

  3. Nasopharyngeal CarcinomaA Particularly Unique Entity in Head and Neck Cancers • Anatomic features present unique treatment challenges • Surgery • Radiotherapy

  4. Nasopharyngeal CarcinomaA 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

  5. 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?

  6. 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

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

  8. 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

  9. 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

  10. What’s Wrong with Adjuvant PF?

  11. Subsequent Asian Trials Contradictory

  12. Meta-analysis in NPCMAC-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

  13. Meta-analysis in NPCMAC-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

  14. Shift From Adjuvant to Induction Chemotherapy • Chua, IJROBP, 2006 • Subgroup analysis of 2 induction studies with cis/epirubicin and cis/bleo/5FU  RTvs. 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%

  15. 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

  16. 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

  17. 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

  18. Proof of Principle • 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 EBV-Specific Immunotherapy in Post-Transplant Lymphoproliferative Disorder Donor PBMCs Donor PBMCs EBV Repeated wkly stimulations EBV-infected lymphoblastoid cell line (LCL) EBV-Specific Cytotoxic T Cell (CTL)Product

  19. EBV-Specific Immunotherapy in NPC • Straathoff, Blood, 2005

  20. EBV-Specific Immunotherapy in NPCNumerous 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

  21. Statements on NPCMaximizing 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

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