Transcript 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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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
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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
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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
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Role of chemotherapy – radiation sensitization, locoregional
control
 Also of interest – chemotherapy to treat
micrometastatic disease and reduce the risk of
distant metastasis
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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
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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
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Less than ideal study design
U.S. Intergroup 0099
cis
RT
PF
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
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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 EBVassociated)
Adjuvant PF chemotherapy only feasible in some patients
What’s Wrong with Adjuvant PF?
Subsequent Asian Trials Contradictory
3Y OS
Rate of
DM
80%
18%
65%
38%
p=0.0061
p=0.0029
Cis/RT  PF X3
78%
24%
RT alone
78%
27%
p=0.97
p=0.96
Wee, JCO, 2005 221 pts
Cis/RT  PF X3
(Singapore)
WHO type II/II
Mostly T3-4 +/or
N2-3
RT alone
Lee, JCO, 2005
(Hong Kong)
348 pts
WHO type II/II
Mostly N2-3
Meta-analysis in NPC
MAC-NPC Collaborative Group
 To assess the impact of adding chemotherapy to RT on
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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
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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
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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
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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
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Phase II study of gemcitabine/cis X3  cis/accelerated concomitant
boost RT
3Y OS = 76%, 3Y PFS = 63%
 Chan, JCO, 2004
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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
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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
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 RTOG 0615
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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
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All overexpressed, prognostic, druggable targets
High-throughput screening underway to identify more
druggable targets
 EBV
 Causal in >80% NPC cases worldwide
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EBV found in every NPC cell
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Clonal
EBV present in nasopharyngeal
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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
EBV-Specific Immunotherapy in Post-Transplant
Lymphoproliferative Disorder
 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
EBV-infected
lymphoblastoid cell
line (LCL)
Donor
PBMCs
Repeated
wkly
stimulations
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
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LMP2 and/or EBNA-1 CTL?
Tumor phenotype
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LMP2 protein expression?
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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