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Flashcards in NPC Deck (24):
1

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

2

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

3

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

4

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

5

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.

6

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

7

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

8

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%

9

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)

10

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)

11

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

12

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

13

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

14

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

15

What does the pharynx consist of?

1) Nasopharynx
2) Oropharynx
3) Hypopharynx

16

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)

17

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

18

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%

19

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)

20

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%

21

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

22

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

23

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

24

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