Nasopharyngeal Carcinoma

1. DR. ARJUN MANDADE
DM ONCOLOGY RESIDENT
MODERATOR- DR. SANTOSH

2. NPC is a squamous-cell carcinoma arising from epithelial lining of the
nasopharynx.
Nasopharyngeal malignancies
SCC (nasopharyngeal carcinoma)
Lymphoma
Salivary gland tumors
Sarcomas

3. Race: More in Chinese & North Africanpeople
Sex: Male preponderance of 3:1
Age: Its incidence rate starts to rise after the second decade of life.
-Median age is 50 years .
Gross: Proliferative, Ulcerative & Infiltrative types
The most common location is Fossa of Rosenmuller

5. Lateral Retropharyngeal L.N also called as
nodes of Röuviere, are the first nodes in the
lymphatic drainage of Nasopharynx.
Extends from base of skull to C3 cervical
vertebra.

7. GENETIC
ENVIORMENTVIRAL

8. Genetic:
 Genomic studies have revealed 3 HLAlocus.
 HLAA2; HLAB46; HLAB17 are associated with increased risk of NPC
 EBV- well documented viral “fingerprints” in tumor cells and also EBV
serologies with WHO type II and III NPC.
 HPV - possible factor in WHO type I lesions
 Lack of vit C in diet
 Burning of incense & woods: polyaromatic hydrocarbon- carcinogen
 Alcohol consumption & Cigarette smoking
 occupational exposure to dust, smoke, and chemical fumes
 salted fish food contain nitrosamines: carcinogen

9. Theory of the roles of Epstein-Barr virus (EBV) infection and genomic changes in the development of
nasopharyngeal carcinoma* LMP- Latent membrane protein.
PATHOGENESIS

11. Upper neck swelling 50%

12. Nasal symptoms 30%
Blood-stained post-nasal discharge
progressive nasal obstruction
Epistaxis
Otological symptoms:
Hearing loss
Otalgia
Otorrhoea
Tinnitus
Ophthalmologic symptoms :
Diplopia & ophthalmo-plegia (involvement of CN
III, IV,VI),
Proptosis (orbit invasion) &
Blindness (involvement of CN II).
Neurologic (25-40 %):
Headache: s/o skull base erosion
Facial pain – Trigeminal,
Xerophthalmiagreater sup. Petrosal nerve
Jugular foramen syndrome: CN IX, X, XI involved by l
ateral retropharyngeal lymph node

14. High index of suspicion required for early diagnosis
• Clinical evaluation
• Radiological evaluation
• Laboratory evaluation
• Histopathological evaluation

15. Clinical examination of nasophyrnx:
Indirect nasophayrngoscopy with mirror
Direct nasopharyngoscopy with fiber-optic scope
Rigid 0 and 30* Hopkins rod endoscope

18. CT Scan
 Extent of tumor
 Neck node involvement
 Skull base erosion
MRI – radiologic modality of choice
MRI allows for a more accurate evaluation of local disease extension, especially
parapharyngeal tumor extension, oropharyngeal extension, and ethmoid sinus.
MRI > CT for displaying both superficial and deep nasopharyngeal soft
tissue and for differentiating tumor from soft tissue.

21. Positron emission tomography (PET) :-
-Useful in diagnosing recurrent /residual lesion followingRT.
-Useful to exclude distant metastasis before major salvage .
 Peng et al showed PET/CT examination resulted in modification of N categories and overall
stage for 135 (28.7%) and 46 (9.8%) patients, respectively.
 In a study by Law et al, PET-CT was valuable in terms of impacting management in 33% of
patients (major impact in detecting M1 disease in 8% and medium impact by upstaging the N
category or showing the exact lymph node in 25%).
 Combining ¹⁸FFDGPET derived parameters and EBV DNA stratifies patients with
nasopharyngeal carcinoma into different risk subgroups better than the conventional TNM
system.

22. Special diagnostic tests (for types II & III)
IgA antibodies for viral capsid antigen (VCA)
IgG antibodies for early antigen (EA)
Antibody Dependent Cellular Cytotoxicity assays

23. As the current anatomy based staging system is insufficient for predicting
prognosis or treatment benefits, many studies have assessed whether incorporating
other clinical factors and molecular biomarkers into the system would better predict
survival.
A recent study proposed a nomogram combining pretreatment plasma EBV DNA
and clinic-pathological variables, and found that it resulted in more accurate
prognostic prediction for patients with nasopharyngeal carcinoma.

24. Other biomarkers such as DNA methylation, miRNAs, and mRNAs also have
demonstrated their prognostic value and potential clinical applications in
nasopharyngeal carcinoma.
A six–hypermethylated gene panel and a five miRNA signature have been
associated with survival in nasopharyngeal carcinoma.
A gene expression–based signature was recently proposed as a reliable prognostic
tool for distant metastasis in nasopharyngeal carcinoma, and might be able to
predict which patients might benefit from concurrent chemotherapy as well.

25. Histopathological Evaluation
Biopsy : first necessary investigation for NPC
Endoscopic biopsy : Ideally it shuold be carried outduring the patient’s ist outpatient visit in
suspected cases.
The most common sites are roof of nasopharynx and fossae of Rosenmuller.
FNA biopsy : should be done in suspiciousnecklump.

28. UNSETTLED ANATOMIC ISSUES
Classification of T0 In the eighth edition of the AJCC staging manual for NPC, the
definition of T0 is added for EBV-positive unknown primary tumors with CLN involvement.
 EBV is not only related to NPC but also lymphoepithelioma-like carcinoma, which arises
from mucosal sites outside the nasopharynx, including the salivary gland, oropharynx,
sinonasal tract, and non-head and neck regions .
 Lymphoepithelioma-like carcinoma is morphologically similar to undifferentiated NPC
with a high frequency of concurrent CLN metastases but could occur in multiple sites.
Therefore, it is an arbitrary assumption that all occult primary tumors with EBV-related CLN
metastases originate from the nasopharynx.

29. In patients with EBV-positive CLNs, Mao et al showed the most common primary sites was-
nasopharynx (52.3%) f/by
salivary gland (24.8%),
lung (7.9%),
oropharynx (3.4%),
nasal cavity/maxillary (3.4%),
oral cavity (1.1%),
orbit (1.1%), and
liver (0.4%).

30. PROGNOSTIC SIGNIFICANCE OF PREVERTEBRAL SPACE
INVOLVEMENT:
 In the current eighth edition of the staging system, prevertebral muscle involvement was added
as a T2 criterion. Several retrospective studies have shown that prevertebral space involvement
(PSI) is an independent prognostic factor.
 For patients with treatment using two-dimensional RT, PSI was associated with a poor
prognosis on local and distant control.

31. Lee”s study, distant metastasis-free survival (DMFS) increased from 72 to 100%
after adjuvant chemotherapy in the patients with PSI. However, this effect was not
observed in the group without PSI.
Zhou et al retrospectively reviewed 506 patients in the intensity modulated
radiotherapy (IMRT) era and found that PSI was an independent prognostic factor
for both overall survival (OS) and DMFS, and suggested a classification of T4.
Pan et al, in which prevertebral muscle involvement was added as a T2 criterion, the
OS of patients with PSI was similar to that of those with parapharyngealspace
involvement.

32. CERVICAL VERTEBRAE & PAROTID GLAND INVOLVEMENT
 The eighth TNM staging system added the cervical vertebrae and parotid gland,
which were not classified in the previous versions of the staging system.
The incidence rate of concurrent tumor invasion into the cervical vertebrae and
parotid gland observed by MRI was <5%.
In the study by Pan et al, the subgroup of patients with parotid gland infiltration
showed poor OS, similar to that of the subgroup with intracranial extension and/or
cranial nerve palsy.

33. Moreover, there was no statistically significant difference in OS between those
showing involvement of pterygoid structures alone and those presenting with erosion
of the skull base and/or cervical vertebra (86% vs 79%).
At present, there is no research on the prognosis of cervical vertebra and parotid
gland invasion, and further investigation is needed on the staging of cervical vertebra
and parotid gland invasion.

34. NCCN Flash Update: NCCN Guidelines and NCCN Compendium for
Head and Neck Cancers
• Cancer of the Nasopharynx: For T1, N1-3 disease, or T2-4, any N
disease, the option of induction chemotherapy followed by chemo/RT
has been changed from a category 3 recommendation to a category
2A.
• The following has been added to the Principles of Radiation Therapy:
“Proton therapy can be considered when normal tissue constraints
cannot be met by photon-based therapy.”

35. The management of NPC is unique for two reasons:
1-Tumor is in a relatively inaccessible location
2-Tumors is extremely radiosensitive

38. CHEMOTHERAPY IN NON-METASTATIC NASOPHARYNGEAL
CARCINOMA:
While early stage nasopharyngeal carcinoma is treated with only radiotherapy as the main
curative treatment, locoregionally advanced disease requires more than radiotherapy.
 Chemotherapy combined with radiotherapy is a crucial development for treating locoregionally
advanced disease.
 At present, NCCN Guidelines recommend both concurrent chemo radiotherapy with adjuvant
chemotherapy or induction chemotherapy followed by concurrent chemo radiation as level 2A
evidence, and concurrent chemo radiotherapy alone as level 2B evidence for stage II–IVA
nasopharyngeal carcinoma.

39. CONCURRENT CHEMORADIOTHERAPY
A number of trials have demonstrated the survival benefit of concurrent chemo radiotherapy
with or without adjuvant chemotherapy versus radiotherapy alone in locoregionally advanced
nasopharyngeal carcinoma.
Recently, a meta analysis has shown that the most significant benefits of chemotherapy on
overall survival are seen with either concurrent plus adjuvant chemotherapy (HR 0·65 [95% CI
0·56–0·76]) or concurrent chemotherapy (0·80 [0·70–0·93]); by contrast, there was no significant
benefit following treatment with only adjuvant chemotherapy (0·87 [0·68–1·12]) or only
induction chemotherapy (0·96 [0·80–1·16]).

40. However, whether adjuvant chemotherapy after concurrent chemoradio therapy can
confer further survival benefits - remains controversial.
Concurrent chemotherapy regimens vary between studies:
 cisplatin is commonly the first choice;
-Dosing schedules of 40 mg/m² once a week or
-80–100 mg/m² every 3 weeks are acceptable in clinical practice.
 Other alternative concurrent agents include uracil plus tegafur, oxaliplatin, and
nedaplatin
Bottom-line: Concurrent chemo radiotherapy is deemed the mainstay treatment
in loco-regionally advanced disease.

41. ADJUVANT CHEMOTHERAPY
 Typically, adjuvant chemotherapy consists of cisplatin (80–100 mg/m²) and
fluorouracil (800–1000 mg/m² every day for 4–5 days) every 4 weeks over three
cycles.
As mentioned above, adjuvant chemotherapy alone cannot improve survival, and
additional adjuvant chemotherapy following concurrent chemoradiotherapy may not
yield further benefits in locoregionally advanced disease.

42. Despite using EBV DNA in the plasma to identify adjuvant chemotherapy patients
with higher relapse risk, and using gemcitabine and cisplatin, which is more successful
than cisplatin and fluorouracil in metastatic disease, the authors did not observe
improved 5year relapse free survival (adjuvant chemotherapy vs obser vation: 49% vs
55%; HR 1·09 [95% CI 0·63–1·89]) or overall survival (64% vs 68%; 1·09 [0·56–
2·11]).

43. The ongoing NRGHN001 trial (NCT02135042) also uses postradiotherapy plasma
EBV DNA to establish whether adjuvant gemcitabine and paclitaxel is better than
cisplatin and fluorouracil for patients with detectable EBV DNA in the plasma, and
whether adjuvant cisplatin and fluorouracil can be omitted in patients with undetectable
plasma EBV DNA; it might provide more evidence for biomarker guided use of
conventional adjuvant chemotherapy.

44. Metronomic use of oral chemotherapy agents such as capecitabine or uracil plus
tegafur as adjuvant chemotherapy may be an alternative choice after concurrent
chemoradiotherapy.
Metronomic chemotherapy describes the close, regular administration of chemotherapy
drugs at less toxic doses over prolonged periods, with the advantages of good compliance,
low toxicities, and convenience.
 The mechanisms of metronomic chemotherapy include antiangiogenic effects,
induction of tumour dormancy, and activation of immunity.
Two retrospective analyses showed that 12month metronomic adjuvant uracil plus
tegafur substantially reduced distant failure and improved survival in high risk patients.

45. Induction chemotherapy
Compared with adjuvant sequencing, induction chemotherapy is better tolerated and
eradicates micrometastases earlier; therefore, induction chemotherapy followed by
concurrent chemoradiotherapy may represent a promising treatment strategy for
nasopharyngeal carcinoma in the IMRT era.
However, randomized trials showed inconsistent results regarding the efficacy of
additional induction chemotherapy, probably due to insufficient sample size or different
induction regimens.

46. Recently, two large scale multicentre phase 3 trials from Guangzhou have been reported:
induction docetaxel, cisplatin, and fluorouracil significantly improved 5year overall
survival (HR 0·65 [95% CI 0·43–0·98]), failure free survival (0·65 [0·43–0·98]), and
distant failure free survival (0·60 [0·38–0·95]) in locoregionally advanced nasopharyngeal
carcinoma (excluding N0 disease) when added to concurrent chemoradiotherapy;
Induction cisplatin and fluorouracil significantly improved 3year disease free survival
(0·67 [0·47–0·95];
In summary, induction chemotherapy plays an increasingly important role in
managing locoregionally advanced nasopharyngeal carcinoma in the IMRT era,
which helps further improve distant control and subsequently survival; patients with
high risk of distant metastasis may benefit from additional induction chemotherapy
over concurrent chemoradiotherapy alone.

47. The gemcitabine and cisplatin regimen has demonstrated its superiority in metastatic
nasopharyngeal carcinoma, and is being tested as an induction regimen in a phase 3 trial
(NCT01872962), with the results being greatly anticipated.
 Pretreatment EBV DNA or relevant genomic signatures may help identify patients most likely
to benefit from induction chemotherapy; EBV DNA surveillance during induction chemotherapy
may also provide Realtime information on tumor response for therapeutic adaptation.

48. A total of 480 patients were included in the trial (242 patients in the induction
chemotherapy group and 238 in the standard-therapy group).
At a median follow up of 42.7 months, the 3-year recurrence-free survival was 85.3%
in the induction chemotherapy group and 76.5% in the standard-therapy group
(stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34
to 0.77; P = 0.001).

49.  Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for
death, 0.43; 95% CI, 0.24 to 0.77).
 A total of 96.7% of the patients completed three cycles of induction chemotherapy.
 The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction
chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of
neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy
group.
 The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group
and 11.4% in the standard-therapy group.

51. CONCLUSIONS
Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free
survival and overall survival, as compared with chemoradiotherapy alone, among patients with
locoregionally advanced nasopharyngeal carcinoma.

52. ROLE OF IMMUNOTHERAPY
The Prognostic Significance of PD-L1 and PD-1 Expression in Patients with Nasopharyngeal
Carcinoma: A Systematic Review and Meta-Analysis-
Our meta-analysis indicated that higher/positive expression of PD-L1/PD-1 may not serve as
suitable biomarkers for the prognosis of NPC, which was not in consistent with some conclusions
drawn from previous studies about the prognostic value of PD-L1/PD-1 in some types of tumors,
including NPC, Despite the positive results obtained in subgroup analysis and study about
clinicopathological features, it may still need corroboration of prospective and large-scale studies.

53. The Role of Immunotherapy in Nasopharyngeal Carcinoma in the Future- Evidence from
the Era of Conventional Radiotherapy:
For the first time in the exclusion of the hematological influence, this study verified the survival
outcome was extremely related to the original status of immune before radiotherapy in NPC
patients.
Immunotherapy might play an essential role in the treatment of NPC in the future

54.  Ongoing trials are investigating the role of immunotherapy in the treatment of NPC in the
primary setting as a neoadjuvant, concurrent, and adjuvant therapy that will further define its
role.
 Nivolumab and ipilimumab (CTLA-4 inhibitor) as a combinatorial therapy are being
evaluated in rare tumors that include NPC (ClinicalTrials.gov Identifier: NCT02834013), and
 Nivolumab with chemoradiation in advanced-stage NPC is being evaluated in a phase 2
clinical trial (ClinicalTrials.gov Identifier: NCT03267498) and
 Randomized phase 3 trial of adjuvant PD-1 antibody or observation in patients with
locoregional advanced NPC (ClinicalTrials.gov Identifier: NCT03427827).

55. There is emerging data supporting the potential application of cytotoxic T
lymphocyte (CTL)-based therapy to NPC, on the backbone of chemotherapy and as a
salvage treatment.
Immunotherapy may serve as another new platform to explore the potential
therapeutic efficacy in combination with chemotherapy in recurrent or metastatic NPC
disease, and as a potential prophylactic strategy to reduce risk of recurrence in high risk
patients.

56.  Radiotherapy (modality of choice)
 early stage nasopharyngeal carcinoma -only radiotherapy
 locoregionally advanced disease- Chemotherapy combined with radiotherapy -appears to
improve overall results.
 Chemotherapy is believed to act as radio-sensitizer.
 It helps to reduce the chance of distant metastasis.
 Combination cisplatin/5-flurouracil is the most widely used
 Concurrent chemoradiotherapy has a major role in advanced stage NPC
 Immunotherapy might play an essential role in the treatment of NPC in the future
 Surgery : To salvage local and regional failure
SUMMARY OF TREATMENT

66. TNM
EBV
pathologic type
Old age
Cranial nerve palsy
Level and Fixity of nodes

67. Beyond pretreatment EBV DNA, unfavourable EBV DNA response after induction
chemotherapy, midcourse of radiotherapy, or post-treatment is also adverse
prognosticators for clinical outcomes.
These observations present the possibility of incorporating EBV DNA for risk
stratified treatment adaptation, based on liquid biopsy of biomarker response.
Well conducted studies with regular longitudinal EBV DNA measurements during
and after treatment are warranted to further assess the role of EBV DNA in treatment
modification during active therapy and in tumor surveillance after therapy has been
completed.

68. In 2016, at a National Cancer Institute EBV testing harmonisation workshop for nasopharyngeal
carcinoma -experts spoke on the limitations of the current quantitation assays and discussed approaches
for improving harmonized assays in the future.
They made key suggestions to guide assay harmonization and validation efforts in the future; one of
which was focusing on an assay that would target two EBV sequences in parallel: a single copy sequence
for comparing between patients, and a multicopy sequence for enhancing the assay sensitivity.
Considerations were also made for adapting new technologies such as next generation sequencing or
digital PCR to improve the assay quantitation. At least two laboratories are currently working to optimize
the assay, which, once validated, can substantially improve the staging system and promote daily use of
this biomarker in the clinic.

69. TAKE HOME MESSAGE
• The most common location is Fossa of Rosenmuller.
• More in Chinese & North African people, Male preponderance of 3:1
• After the second decade.
• Nodes of Röuviere, are the first nodes in the lymphatic drainage of
Nasopharynx.
• HLAA2; HLA B46; HLAB17 are associated with increased risk of
NPC.
• EBV- with WHO type II and III NPC; HPV -type I lesions.
• MRI – radiologic modality of choice.
• Special diagnostic tests (for types II & III)-
IgA antibodies for viral capsid antigen (VCA)
IgG antibodies for early antigen (EA)
Antibody Dependent Cellular Cytotoxicity
assays

70. TAKE HOME MESSAGE
• Upper neck swelling 50% - most common presentation
• The management of NPC is unique for two reasons:
1-Tumor is in a relatively inaccessible location
2-Tumors is extremely radiosensitive
• Radiotherapy (modality of choice).
• For locally advanced disease (stage iii-iv ) chemotherapy in addition to
radiotherapy appears to improve overall results.
• Combination chemotherapy produces better responses.
• Combination cisplatin/5-flurouracil is the most widely used, Indicates that
concurrent chemoradiotherapy has a major role in advanced stage NPC

71. References
• The new england journal of medicine, published on May 31, 2019, at NEJM.org.
• NCCN guidelines 2019
• Volume 14 / Issue 10 / October 2018 n Journal of Oncology Practice Copyright ©
2018 by American Society of Clinical Oncology Clinical Review.
• © 2019 The Authors. Published by the British Institute of Radiology- Br J
Radiol;92:20190244.
• Lancet 2019; 394: 64–80 Published Online June 6, 2019 http://dx.doi.org/10.1016/
S0140-6736(19)30956.
• F1000Research 2018, 7(F1000 Faculty Rev):1829 Last updated: 21 NOV 2018