NPC Flashcards
What are the staging investigations that are required?
Nasophayngoscopy
CT scan or MRI of nasopharynx, Base of Skull and neck
- MRI preferred if available
Consider Bone scan and CT scan of Chest/abdomen
- If not, must at least have CXR
Consider PET-scan
Blood investigations to evaluate end-organ functions, especially kidney function
Epstein-Barr Viral DNA
Give me the broad treatment principles for NPC according to stage.
Stage I - RT alone
Stage II - Concurrent ChemoRT
Stage III, IVA and IVB are treated by concurrent ChemoRT +/- adjuvant chemotherapy
Elective nodal irradiation is recommended for N0 stage disease
How can we minimize the risk of late toxicity in the treatment of NPC?
We should avoid:
- Fractional dose of >2Gy per daily fraction
- Excessive accleration with multiple fractions >1.9Gy/fraction
How do you follow-up a patient treated for PC?
1) Need to document complete remission in the nasopharynx and neck
- through clinical and endoscopic examination and imaging studies
- ESP for T3/T4 lesions, MRI might be used on a 6-12 monthly basis to evaluate the nasopharynx and the BOS at least for the fist few years after treatment
2) Periodic examination of the:
- nasopharynx and neck
- CN function
3) Evaluation of systemic complaints to identify distant mets
4) Evaluation of thyroid function
Tell me about the T staging for NPC
T1 =
- confined to the nasopharynx, or extends to oropharynx and/or nasal cavity
- No parapharyngeal extension
T2 =
- Tumor with parapharyngeal extension
T3 =
- Involves bony structures of skull base and/or paranasal sinuses
T4 =
- Intracranial extension
- and/or involvement of CN, hypopharynx, orbit, OR with extension to the infratemporal fossa/masticator space.
Tell me about the N staging of NPC
N1 =
- Unilateral mets in cervical LN, 6cm or smaller
- above the Supraclavicular fossa
- and/or unilateral/bilateral retropharyngeal LN, 6cm or less
N2 =
- Bilateral mets in cervical LN, 6cm or smaller, above the Supraclavicular fossa
N3 =
- Mets in a lymph node(s) >6cm and/or to Supraclavicular space
- 3a = >6cm in dimension
- 3b = Extension to Supraclavicular fossa
Tell me some generalizations for the NPC staging system
T4Nx = Stage IVA T3Nx = Stage III N2 = At least Stage III N3 = At least Stage IVB
Tell me about the Intergroup 0099 study
Al-Sarraf INT 0099
JCO 1998
76% WHO II/III
AJCC Stage III/IV
N=150
2arms:
1) RT
- 70Gy (1.8-2 Gy/day in 35# - 39#)
2) ChemoRT
- CDDP (100) Week 1,4,7 –> 3# CDDP (20)+5FU(1000) D1-4 Q28days
Results: med f/u close to 3 years
1) Closed early as interim analysis showed a significant advantage in favor of CRT.
2) Decreased Local/Regional/Distant recurrences rates
3) 3y PFS rates: 70% (CRT) vs 25%
4) 3y OS rates: 80% vs 45%
Tell me about the Anthony Chan Study
A Chan JNCI 2005
Locoregionally advanced NPC
N2/3 disease or N1+nodal size>4cm
N=350
2 arms:
1) Concurrent CDDP-RT
- CDDP (40) weekly during RT
- no adjuvant
2) RT
- 66Gy in 33# over 6.5 weeks
- +/- parapharyngeal boost of 10-20Gy if involved
RESULTS:
- 5y OS 70% vs 60% (RT)
- 5y PFS 60% vs 50% (RT)
Between CDDP and Carboplatin, which is preferred?
CDDP
More data to support the use of CDDP in this setting
Chitapanarux Eur J Cancer 2007
Randomized non-inferiority study
N=200
2 Regimens:
1) 3# Weekly Carboplatin 100mg/2 + RT–> Carbo (AUC5) dL + 5FU (1000) over 96 hours Q28days
2) Intergroup regimen
RESULTS:
- 70% completed chemo in Carboplatin group vs 60%
- 70% completed adjuvant chemo cf 40% CDDP
- 0% renal tox in Carbo group vs 25%
- 3y DFS: CDDP 65% vs 60% (trend)
- 3y OS CDDP 79% vs 80% (trend)
What is the etiology of NPC?
1) Familial
- 4 to 10-fold excess risk in individuals with 1st deg relatives who had NPC, cf to those without family history
- up to 15% will give a family history
2) Salt fish and other preserved foods
3) Tobacco
4) Traditional herbal medications
- ?EBV activating herbs
5) Occupational exposures
- Formaldehyde
- Fumes
- Smoke
- Print
- Dust
6) Betel Nut chewing
7) EBV
Tell me about EBV
Infects >90% of the population
EBV infection is usually sub clinical
A/w NPC, Hodgkin’s, Burkitt’s CNS Lymphoma
EBV levels may be useful for Dx, monitoring of prognosis, treatment response monitoring, detection of recurrence
How is EBV Detected?
In-situ hybridization for EBV-encoded small RNA 1 from biopsy samples
- EBER-ISH
IgA to EBV may be used for screening in high risk populations
NPC patients have elevated IgG and IgA titles to the EBV viral capsid antigen IgA and early antigen,
- as well as increased IgG against the latent viral nuclear antigens 1 and 2 (EBNA-1, EBNA-2) and neutralizing antibodies against EBV-specific Dnase
What are the histologies of NPC
1) Keratinizing Squamous Cell Carcinoma (Type I)
2) Non-Keratinizing carcinoma
- differentiated (Type II)
» Sporadic type, similar to HNSCC
- undifferentiated (Type III)
3) Basaloid squamous cell carcinoma
- a rare, aggressive poor prognosis
What does the pharynx consist of?
1) Nasopharynx
2) Oropharynx
3) Hypopharynx
What is the evidence for concurrent CRT in stage II NPC?
Chen et al, JNCI 2011
N=230
Chinese Stage II NPC patients
2 arms:
1) Conventional 2D RT 68-70Gy
2) CDDP (30) weekly
RESULTS:
1) CR rate 99.1%
2) CR for RT 96.5%
3) 5y OS 95% (CRT) vs 86% HR 0.3
4) 5y PFS 88% vs 78%
5) Distant Metastasis Free Survival Rate (DMFS)
- CRT 95% (vs RT ) 84%
6) Loco-regional relapse free Survival (LRRFS):
- CRT 93%
- RT 91%
- HR 0.61 (trend)
Where did the initial evidence for concurrent CRT for locally advanced NPC come from?
Baujat et al
Int J Rad Oncology 2006
Meta-analysis of 8 RCTs with 1700 patients
Locally advanced NPC
Undergoing curative RT +/- chemo
Chemo may be used as induction/concurrent/adjuvant
RESULTS:
1) 20% reduction in the HR of death with chemotherapy
2) Absolute survival benefit
- 4% at 2 years (77% to 81%)
- 6% at 5 years (56% to 62%)
- Concurrent CRT shows the best risk reduction with HR 0.6
What about the local study done in Singapore
J Wee JCO 2005
N=200
Stage III/IV NPC
2 arms:
1) ChemoRT
- Chemo: CDDP (100) W1,4,7 –> 3# CDDP (20)+5FU(1000) D1-4Q28days
2) RT
- 70Gy in 35#
RESULTS:
3y DFS 50% (RT) vs 70% HR 0.5
3y OS 65% (RT) vs 80% HR 0.5
Updated after 5 years:
5y DFS 45% (RT) vs 60% H 0.7
5y OS 50% (RT) vs 70% HR 0.6
5y Distant met rate 35% (RT) vs 15% (CRT)
Toxicities:
- Mucositis/pharyngitis G3/4/5: 30% (RT) vs 50%(CRT)
- Anorexia 3.7% vs 21%(CRT)
- Neutropenia 0% (RT) vs 15%
- Thrombocytopenia 0% (RT) vs 2%
Any other evidence for Adjuvant chemotherapy in regionally advanced NPC?
Yes Anne Lee JNCI 2010
NPC-9901
N=200
Stage III/IV, N2/3 disease only
2 arms:
1) ChemoRT–> Chemo
- CDDP (100) W1, 4, 7
- Adjuvant chemo of 3# CDDP (80) D1/ 5FU (1000) D1-4 Q28d
2) RT
- 66 Gy at 2Gy per fraction
- +/- parapharyngeal boost
RESULTS: 5y FF 55% (RT) vs 65% (CRT) 5y PFS: 50% vs 60% (CRT) 8y OS: 55% vs 60% (CRT) - 3y OS identical, 5yOS 64% s 68% 5y Distal FFR 70% vs 75%(CRT)
Is there any head-to-head study comparing CRT–> Adjuvant chemo vs CRT alone?
Yes
Chen Lei et al Lancet 2011
Stage III/IV
N=500
2 arms:
1) CRT–> Chemo
- Adjuvant chemo: 3# CDDP (80) D1, 5FU (800) D1-5
2) CRT
- RT >66 Gy (~50% received 2DRT)
- CDDP (40) Weekly
RESULTS:
- 80% received adjuvant treatment, but only 60% of those who started completed all 3#
- 70% required treatment delays during adjuvant and 50% required dose reductions
- Results all not statistically significant
- CR ~98%
- 2y FFS ~85%
- 2y OS 93%~
- 2y DFFS 88% vs 86%(CRT alone)
- 2y local failure free survival 98% vs 95%
Any study that you know about for Neo-adjuvant chemotherapy? For NPC ?
Yes
Edwin Hui et al JCO 2009
2 arms:
1) 2# Neoadjuant chemo –> CRT
- Docetaxel (75) D1 + CDDP (75) D1 Q3w
2) CRT alone
- 8# RT + CDDP (40) Weekly
RESULTS:
- CR 80% (Neoadj) vs 60% (trend)
- 3y PFS 90% (Neoadj) vs 60% (trend)
- 3y OS 95% (Neoadj) vs 65% (significant) **
- FN 10% from neoadjuvant chemo, no related deaths
- during CRT phase, no differences in rates of hematological toxicities
- no differences in late toxicities
- No differences in deliver of concurrent CDDP in both arms
- All pts in both arms completed RT
What are the options for locally recurrent NPC?
Require multi-disciplinary input.
Need to restage fully, consider PET-CT
1) Nasopharyngectomy +/- neck dissection
2) Endoscopic laser resection
3) RT +/- chemo
4) Photodynamic therapy
5) Palliative chemotherapy
Are there any evidence to guide management in advanced NPC?
Yes. Systematic review of 44 trials of 1300 patients
All were phase II trials
N=9 to 100 in each trial
Pooled analysis showed RR to be 44%
Median TTP 5m
Median OS 12m
Platinum trials:
RR 60% TTP 8m OS 14m
Non Platinum trials:
RR 30% TTP 5m OS 12m
Gemcitabine:
RR 60% TTP 5m OS 15m
Taxanes:
RR 50% TTP 5.5m OS 12.5m
What emerging therapeutics to you know about?
1) Immunotherapy
2) Other signal transduction pathways
- JAK-STAT pathway
- AKT-MEK pathway
3) Viral latent-lyric switch
- SAHA (Vorinostat)
- LBH (Panobinostat) + RAD001
