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

2. 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

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

4. 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

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
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

12. 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 )
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 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

14. 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%

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
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

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

20. 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

21. 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