Nasopharyngeal cancer

Nasopharyngeal carcinoma management

1. Cancer Nasopharynx Dr. Ajay Manickam MS.,DNB.,(ENT) Fellow, Head and Neck Surgical Oncology Tata Medical Center , Kolkata

2. Introduction Uncommon cancer in most parts of world 84400 new cases and 51,600 deaths annually Age Adjusted Rate ranges from 0.6 in US to 26.9 in Southern China Bimodal age distribution(15-25 + 50-59) Male to female 2-3:1

3. Epidemiology Nasopharynx : Male - Thirteen north eastern registry areas had higher AAR, Nagaland PBCR being the highest . Delhi registry with an AAR of 0.7 stood at the fourteenth place. Female - Nine north eastern registry areas had higher AAR and Nagaland PBCR led the list . State Males (%) Females(%) Nagaland 19.3 10.9 Mizoram 2.8 2.3 Sikkim 3.7 NA Kolkata 0.36 0.2 Proportion among all cancers

4. AAR per 100,000 population

5. Etiology Distinct racial and geographical distribution Multifactorial cause Genetic factors Strong association with HLA Class 1 genes

6. Etiology Environmental factor High consumption of salted fish – Dimethyl nitrosamine Formaldehyde Tobacco smoking Wood dust

7. Epstein Barr V irus (EBV) Particularly non-keratinising type

8. Anatomy

9. Natural History

10. Local Spread Nasal cavity & PNS Orbital invasion Base of Skull, Clivus Sphenoid sinus Cavernous Sinus Lateral Parapharyngeal space Middle ear cavity Oropharynx (tonsillar pillars) C1 vertebrae

11. Site Frequency(%) Adjacent soft tissue Nasal Cavity Parapharyngeal space Pterygoid muscle Oropharyngeal wall, soft palate Prevertebral muscle 87 68 48 21 19 Bony erosion/PNS Clivus Sphenoid Pterygoid plate Petrous bone Ethmoid Maxillary antrum 41 38 27 19 6 4 Extensive/Intracranial extn Cavernous sinus Infratemporal fossa Orbit Cerebrum, meninges, cisterns Hypopharynx 16 9 4 4 2

12. Lymph metastases Vast avalvular lymph capillary network 85 to 90% present with lymph nodes Bilaterality in 50% Two lymph collectors – lateral and posterior

13. Distant metastases 3 to 6 % at presentation 18 to 50% in the course of disease

14. Clinical presentation Neck mass Nasopharyngeal mass symptoms(nasal obstruction, epistaxis, discharge) Nerve deficits

15. Workup Proper history and clinical examination Head and neck examination Complete CNS examination Mirror examination Routine Laboratory studies Chest Radiograph(PA+lateral)

16. Diagnostic workup Biopsy (direct visualisation/Fiberoptic endoscopy/exmn anaesthesia) FNAC of neck mass Absence of visible mass Pharyngeal recess(Fossa of Rosenmuller) on each of the lateral wall Supero posterior wall IgG anti-EA and IgA anti-VCA Baseline EBV DNA levels

17. Staging workup Locoregional extent – MRI>CT

18. Metastatic workup - if clinically indicated PET CT Chest and Abdomen Bone Scan

19. STAGING SYSTEMS AJCC UICC Ho(1978) Fletcher(1967)

20. Ho staging system T-stage T1 Confined to nasopharynx T2 Nasal fossa, oropharynx, parapharynx , muscle/ nerves below base of Skull T3 Bone below base of Skull Bone at base of skull Cranial nerve Orbit, infratemporal fossa, laryngopharynx

21. Ho Staging - Lymphnode N-stage N0 None N1 Upper neck N2 Mid neck N3 Supraclavicular fossa Group I T1N0M0 II T2N0–1M0, T1N1M0 III T3N0-2M0, T1-2N2M0 IV T1-3N3M0 V T1-4N0-3M1

22. AJCC/UICC 2010 7 Th T category TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor confined to the nasopharynx, or tumor extends to nasal cavity and/or oropharynxb without parapharyngeal extensionc T2 Tumor with parapharyngeal extension T3 Tumor involves bony structures of skull base and/or paranasal sinuses T4 Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, or with extension to the infratemporal fossa/masticator space N category NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Unilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral retropharyngeal lymph node(s), ≤6 cm in greatest dimension N2 Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa e,f N3 Metastasis in lymph node(s) e >6 cm and/or to supraclavicular fossa f N3a. >6 cm in dimension N3b. Extension to the supraclavicular fossa f M category M0 No distant metastasis M1 Distant metastasis Stage grouping 0 Tis N0 M0 I T1 N0 M0 II T1 N1 M0 T2 N0 M0 T2 N1 M0 III T1 N2 M0 T2 N2 M0 T3 N0 M0 T3 N1 M0 T3 N2 M0 IVA T4 N0 M0 T4 N1 M0 T4 N2 M0 IVB Any T N3 M0 IVC Any T Any N M1

23. Pathological classification WHO 2005 Keratinising squamous cell carcinoma

24. Non - keratinising squamous cell carcinoma a – Differentiated b - Undifferentiated

25. Basaloid squamous cell carcinoma

26. Rare histologies Lymphoma 5% Adenocarcinoma Plasmocytoma Melanoma Sarcoma

27. Prognostic factors Locoregional extent of disease T stage N stage Parapharyngeal extension Prevertebral space involvement GTV-P Histology Oropharynx involvement, Ethnicity – not significant

28. Prognostic factors - contd Role of EBV - Circulating cell free DNA Pre-treatment assay Response to treatment Follow up(better than FDG PET) Other biomarkers associated with poor prognosis - EGFR, HIF1α, CA IX, VEGF

29. Treatment Stage wise management Radiotherapy alone T1N0M0 Concurrent chemoradiotherapy alone T1NOMO(Bulky and old T2a) T2NOMO

30. Treatment - contd T2-4 N0-3 M0 Neoadjuvant chemotherapy 2# + CCRT CCRT + adjuvant chemotherapy ALSARAF – GAMECHANGER + DRAWBACK

31. Concurrent chemotherapy Cisplatin (30 mg/m2 weekly for 05 to 06 Cycles with RT) Cisplatin (100 mg/m2 Day 01, 22 and 43 with RT ) Non inferiority trial substituting CDDP with carboplatin in concurrent(weekly) and adjuvant setting showed no significant difference

32. Induction/Sequential chemotherapy Regime ( i ) TIP Protocol :Paclitaxel ( 175 mg/m2 Day 01),Cisplatin (20 mg/m2 Day 01 to Day 05), Ifosfamide (1200 mg/m2 Day 01 to Day 05 ) and Mesna ( 400 mg/m2 at 0, 4, 8 hrs Day 01 to Day 05) X 2 Cycles Regime (ii) DCF Protocol: Docetaxel (75 mg/m2 Day 01), Cisplatin (75 mg/m2 Day 01 ) and 5-FU ( 750 mg/m2 /day continuous IV infusion through PICC Day 01 to Day 05 Total dose in 5 days 3750 mg/m2) X 2 Cycles Regime (iii) Cisplatin (33mg / m2 / day x 3 days) + Ifosfamide (2gm/m2 / day x 3 days) + Mesna rescue X 2 Cycles Regime (iv) Cisplatin (100 mg/m2 day 01 and 5 FU 1000 mg/m2/day continuous IV infusion through PICC Day 01 to Day 05) X 2 cycles Adjuvant Chemotherapy: Cisplatin (100 mg/m2 day 01 and 5 FU 1000 mg/m2/day continuous IV infusion through PICC Day 01 to Day 05) X 3 cycles

33. Metastatic NPC Platinum based combination chemotherapy RT to metastatic sites if clinically indicated Cisplatin/carboplatin + Taxane Cisplatin + 5FU Carboplatin + cetuximab Cisplatin + gemcitabine Gemcitabine + Vinorelbine If CR after chemotherapy, patient should be considered for RT/CRT to npx and neck

34. RT dose and fractionation Conventional fractionation 70 Gy given over 7 weeks 2 Gy# Mon-Fri High risk subclinical disease – 60 Gy Elective sites – 50 Gy

35. Conventional technique SHRINKING FIELD TECHNIQUE 3 phases Phase I RT to the primary tumor and upper neck nodes in one volume – 2 lateral fields Lower neck by single AP field Continued upto 40- 44Gy

36. Phase II RT to the primary by 2 lateral fields Or by 2 lateral fields and a matching anterior field

37. Phase III Boost to the gross disease

38. 3DCRT 3DCRT Better LC and OS Jen et al T4 control (86% vs 47%) Xerostomia (69.2% vs 98%) No significant improvement in late toxicities

39. IMRT Supplanted conventional technique Typical plans 70 Gy to Gross disease 59.4 Gy to high risk subclinical disease 54 Gy to low risk TMC – 66 Gy in 30 # <42 days - Tumour Repopulation

40. IMRT - contd Acceleration using dose painting/ SMART Boost for persistent disease Recurrent disease

41. TREATMENT PLANNING - TMC

42. Sequelae to RT Temporal lobe necrosis Late complication Classical symptoms - hallucinations, absence attacks, déjà vu Other symptoms – headache, confusion, convulsions, hemipareisis Accounts for up to 65% of radiation related deaths 1-3% with conventional RT 12% with hypofractionated IMRT

43. Sequelae - contd Cranial neuropathy Nerves IX to XII Slurring of speech, dysphagia, twitching of neck muscles Radiation induced fibrsosis Parapharyngeal boost Rarely nerve VI, V also

44. Sequelae - contd Xerostomia Accompanied by dental sequelae Lower rates with IMRT Aural toxicity Cisplatin based chemotherpay SNHL with mean cohclear dose > 48 Gy Pharyngotympanic tube damage

45. Sequelae - contd Endocrine dysfunction Hyperprolactinemia Hypothyroidism Hypoadrenalism Second malignancy Maxillary osteosarcoma and soft tissue sarcoma Surgery – only chance of cure

46. Follow up History and physical examination 1 to 3 months the first year after treatment 2 to 6 months the second year 4 to 8 months 3 to 5 years Every year thereafter With Imaging every 6 months Thyroid function testing every 6 to 12 months Speech and swallowing evaluation. Post treatment plasma EBV DNA surveillance if facilities available

47. Cranial nerve palsies 6 months post Rx The complete recovery rate was 51% Partial recovery rate was 19% Worst for 7, 12 th CN Best for 2, 9, 11 th CN

48. Patient usually assessed after 6 weeks Residual disease after 8 weeks – persistent Persistent disease – boost Brachytherapy IMRT SRT EBRT

49. Persistent nodal disease Electron boost Neck dissection

50. Results of treatment 5 yr local control rate with conventional radiation T1 – 76 to 90% N0 – 82 to 100% T2 – 75 to 85% N1 – 70 to 92% T3 – 60 to 70% N2 – 42 to 70% T4 – 40 to 60% N3 – 32 to 52% 5 yr distant metastases rates – 10, 20, 30, 50% for T1,2,3,4 respectively

51. Salvage irradiation Local relapse at a median period of 3 years post RT Reirradiation requires atleast 60 Gy 2D EBRT ± brachytherapy boost/3DCRT boost IMRT Late toxicities were high Local control better with SRS>IMRT>EBRT+BT

52. Role of brachytherapy Intracavitary or interstitial implants Rotterdam applicator

53. Role of brachytherapy Routine boost to the primary site in T1-3 lesions after EBRT Earlier studies – showed benefit Boost post CCRT showed no improvement in local control Residual disease Recurrrent disease

54. Role of SRT SRT boost 7 to 12 Gy foll 66 Gy by EBRT - Excellent LC of 98% included T1-4 Persistent disease Recurrent disease Increased rates of distant failure Temporal lobe necrosis Retinopathy

55. Conclusion Management of NPC is of significant importance in NE India due to high incidence Being a systemic disease requires concurrent chemoradiation along with systemic chemotherapy either as induction/adjuvant EBV associated and could be used for diagnosis/followup Future trends employ EBV association to develop immunotherapy, adoptive therapy, epigenetic therapy, vaccines leading to a better understanding of the disease

56. - Thank you