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Role of hpv in head and neck tumors

Role of HPV in Head and neck tumors

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Role of hpv in head and neck tumors

  1. 1. ROLE OF HPV IN HEAD AND NECK CANCER Dr. Ayush Garg Senior Resident
  2. 2. 1. Sparano JA et al. Springer New York 2010 2. Best SR et al. Otolaryngol Clin North Am 2012 3. Parkin DM Int J Cancer 2006 4. Kreimer AR et al. Cancer Epidemiol Biomarkers Prev 2005 Double-stranded DNA virus; over 100 subtypes1,2 Cancer link;3 subtypes classified as low- or high-risk according to oncogenicity1,4 87% of HPV+ OPC caused by HPV164 Primary transmission route: sexual contact1 Text Here WHAT IS HPV?
  3. 3. x x1. Best SR et al. Otolaryngol Clin North Am 2012 2. Sparano JA et al. Springer New York 2010 3. Smeets SJ et al. Int J Cancer 2011 E1 E4L2 7.9 kb dsDNA E5 L1 HPV genome2 E2 E1 E7 E6 E6 E7 p53 pRb E6 and E7 bind and inactivate tumor suppressor proteins3 HOW DOES HPV CAUSE CANCER? ‣ HPV genome encodes six early (E) and two late (L) proteins1
  4. 4. RADIOSENSITIVITY ▸ Suppression of p53 & pRb lead to failure to delay cell cycle progression & suppression of downstream regulators by E6 & E7 contribute to cellular immortality. ▸ This leads to genetic instability & may lead to tumor resistance Wu et al, Oncology Letters 2016
  5. 5. Wounded Epithelia HPV infected epithelia • Selection of integrated cell clones • Lower viral load • Cell cycle dysfunction • Genomic instability Potentially malignant disorders with dysplasia Infection HPV • Episomal replication to high viral load • High probability of integration Progression Squamous Cell CarcinomaINVASION HPV Particles HPV INDUCED CARCINOGENESIS
  6. 6. Variable HPV+ n=206 HPV‒ n=117 p16+ p16– p-value* OS rate (%) 82.4 57.1 83.6 51.3 <0.001 Progression-free survival rate (%) 73.7 43.4 74.4 38.4 <0.001 LRC failure rate (%) 13.6 35.1 <0.001 Distant metastases rate (%) 8.7 14.6 0.23 Second primary rate (%) 5.9 14.6 0.02 Ang KK et al. N Engl J Med 2010 Approximately 25% greater absolute survival in HPV+ populations after 3 years Approximately 25% greater absolute survival in HPV+ populations after 3 years In patients who had received CRT in the RTOG0129 study, 3-year outcomes varied by HPV and p16 status RTOG 0129: HIGHER 3-YEAR SURVIVAL RATES OBSERVED IN PATIENTS WITH HPV+ VS HPV– TUMORS
  7. 7. WHY DE-ESCALATE TREATMENT? ▸ Reduction of long term toxicities of CCRT ▸ Affects 21-43% of patients (Non-IMRT data) ▸ Reduce economic & social burden of toxicities ▸ Allow replacement of Cisplatin with other agents Machtay M et al, JCO 2008;26:3582–89
  8. 8. NOVEL TREATMENT STRATEGIES FOR HPV+ HNSCC ▸ Induction chemotherapy followed by reduced dose/volume CCRT ▸ Rationale: Selection of good responders ▸ Replacement of cisplatin with cetuximab ▸ Rationale: Reduced toxicity of Cetuximab ▸ Surgery (TORS) followed by adjuvant RT (with reduced dose) ▸ Rationale: Reduce morbidity by selecting patients based on histopathological characteristics ▸ Modulating immune response & T-cell activation by vaccination
  9. 9. INDUCTION CHEMO FOLLOWED BY REDUCED DOSE CCRT ▸ ECOG 1308 ▸ Phase II RCT ▸ HPV positive oropharyngeal HNSCC with Stage III/IV ▸ Utilised Induction Chemo (TP+Cetuximab) for 3 cycles ▸ Complete responders received reduced dose RT (54 Gy/ 27 Fr) ▸ Partial responders/stable disease received standard dose RT (69.3 Gy/ 33 Fr) REGISTER 3c - TP+Cmab ASSESS RESPONSE CR PR/SD Reduced dose RT + Cmab Standard dose RT + Cmab
  10. 10. INDUCTION CHEMO FOLLOWED BY REDUCED DOSE CCRT ▸ ECOG 1308 ▸ Primary endpoint - 2yr PFS ▸ Results (N=90): ▸ 96% successfully received Induction chemo ▸ 71% CR rate ▸ 2yr PFS = 84% ▸ 2yr Primary LC = 94% ▸ 2yr Nodal LC = 95% REGISTER 3c - TP+Cmab ASSESS RESPONSE CR PR/SD Reduced dose RT + Cmab Standard dose RT + Cmab
  11. 11. INDUCTION CHEMO FOLLOWED BY REDUCED VOLUME CCRT ▸ NCT01133678 (U. Chicago) ▸ Phase II RCT ▸ No stratification by HPV positivity and included Stage III/IV HNSCC (all sites) ▸ Utilised Induction Chemo (TP+Cetuximab) with or without Everolimus ▸ Utilised hyperfractionated RT (75 Gy with twice daily RT) ▸ Concurrent chemo was TFH (Taxane, 5-FU & Hydoxyurea) REGISTER ASSESS RESPONSE Good Poor RANDOMISE 2c - TP+Cmab 2c - TP+Cmab + Everolimus Reduced field RT + TFH Standard field RT + TFH
  12. 12. INDUCTION CHEMO FOLLOWED BY REDUCED VOLUME CCRT ▸ NCT01133678 (U. Chicago) ▸ Response was judged by reduction of volume of disease by 50% ▸ Reduced field RT consisted of RT to primary disease site only ▸ Standard field RT consisted of RT to primary disease site & 1st echelon nodes ▸ Primary endpoint - response rates
  13. 13. INDUCTION CHEMO FOLLOWED BY REDUCED VOLUME CCRT ▸ NCT01133678 (U. Chicago) ▸ Results (N=94): ▸ 39% Good response rate, 91% LRC rate ▸ 14/15 LRF were in RT treatment volume ▸ Similar toxicity rates between good & poor responders ▸ Lower PEG dependency in good responders
  14. 14. REPLACEMENT OF CISPLATIN WITH CETUXIMAB ▸ RTOG 1016 ▸ Phase III RCT ▸ Includes Stage III-IV Oropharyngeal Ca ▸ Utilises Accelerated RT (70 Gy/ 6 wks) in both arms ▸ Standard Cetuximab dosing ▸ Cisplatin 100mg/m2 D1, D22 ▸ Primary outcome - 5yr OS REGISTER STRATIFY T1-2N1-3 or T3-4N0, PS, Smoking RANDOMISE Acc RT + Cetuximab Acc RT + Cisplatin HPV p16 testing
  15. 15. REPLACEMENT OF CISPLATIN WITH CETUXIMAB ▸ De-ESCALaTE ▸ Phase III RCT ▸ Includes Stage III-IV Oropharyngeal Ca ▸ Utilizes standard RT (70 Gy/ 7 wks) in both arms ▸ Standard Cetuximab dosing ▸ Cisplatin 100mg/m2 D1, D22, D43 ▸ Primary outcome - Acute & late toxicity REGISTER HPV-Positive RT + Cetuximab RT + Cisplatin HPV p16 testing HPV-Negative RANDOMISE RT + Cisplatin
  16. 16. REPLACEMENT OF CISPLATIN WITH CETUXIMAB ▸ TROG 12.01 ▸ Phase III RCT ▸ Includes Stage III-IV Oropharyngeal Ca (Excluding T4 & N3) ▸ Utilizes Standard RT (70 Gy/ 6 wks) in both arms ▸ Standard Cetuximab dosing ▸ Cisplatin 40mg/m2 weekly ▸ Primary outcome - Acute toxicity REGISTER STRATIFY T1-2N1-2 or T3N0, PS, Smoking<10y RANDOMISE RT + Cetuximab RT + Cisplatin HPV p16 testing
  17. 17. SURGERY FOLLOWED BY ADJUVANT RADIOTHERAPY ▸ ADEPT ▸ Phase III RCT ▸ Includes HPV+, oropharyngeal Ca ▸ All patients undergo minimal access surgery+Neck dissection ▸ RT is delivered by IMRT to dose of 60 Gy/30 Fr in both arms ▸ Primary endpoint: 2yr LRC, DFS REGISTER Minimal Access Surgery R0 resection, ECE + RT alone RT + Weekly Cisplatin HPV p16 testing RANDOMISE
  18. 18. SURGERY FOLLOWED BY ADJUVANT RADIOTHERAPY ▸ ECOG 3311 ▸ Phase II RCT ▸ Includes HPV+, oropharyngeal Ca ▸ All patients undergo Trans-oral minimal access surgery+Neck dissection ▸ RT is delivered by IMRT to dose of 50 Gy/25 Fr in low-dose arm & 60 Gy/30 Fr is standard dose arm ▸ Chemo is delivered weekly, Cisplatin or Carboplatin ▸ Primary endpoint: 2yr PFS, Complication rates REGISTER Trans-Oral Surgery HPV p16 testing Low-dose RT Observe Standard- dose RT+ Chemo RANDOMISE Standard-dose RT Assess Risk Low HighI/M
  19. 19. SURGERY FOLLOWED BY ADJUVANT RADIOTHERAPY ▸ ECOG 3311 ▸ Low Risk - T1-2, N0-1 ▸ I/M Risk - Clear/close margins, <1mm of ECE, LVI or PNI+, 2-3 LN positive ▸ High risk - Margins positive, 4 or more LN positive, >1mm of ECE REGISTER Trans-Oral Surgery HPV p16 testing Low-dose RT Observe Standard- dose RT+ Chemo RANDOMISE Standard-dose RT Assess Risk Low HighI/M
  20. 20. SURGERY FOLLOWED BY ADJUVANT RADIOTHERAPY ▸ PATHOS ▸ Phase II/III RCT ▸ Includes HPV+, oropharyngeal Ca ▸ All patients undergo Trans-oral minimal access surgery+Neck dissection ▸ RT is delivered by IMRT to dose of 50 Gy/25 Fr in low-dose arm & 60 Gy/30 Fr is standard dose arm ▸ Chemo is delivered as weekly or q3week, Cisplatin ▸ Primary endpoint: Swallowing function REGISTER Trans-Oral Surgery HPV p16 testing Low-dose RT Observe Standard- dose RT RANDOMISE Standard-dose RT Assess Risk Low HighI/M RANDOMISE Standard- dose RT+ Chemo
  21. 21. SURGERY FOLLOWED BY ADJUVANT RADIOTHERAPY ▸ PATHOS ▸ Low Risk - No adverse features ▸ I/M Risk - T1-3, N2a-2b, Close margins, LVI or PNI present ▸ High risk - Margins positive, 4 or more LN positive, >1mm of ECE REGISTER Trans-Oral Surgery HPV p16 testing Low-dose RT Observe Standard- dose RT RANDOMISE Standard-dose RT Assess Risk Low HighI/M RANDOMISE Standard- dose RT+ Chemo
  22. 22. TIL - A NEW MOLECULAR MARKER FOR GOOD-PROGNOSIS HNSCC ▸ CD8+ Tumor infiltrating lymphocytes have recently been shown to influence outcomes of HNSCC patients irrespective of HPV status. ▸ Along with this, similar other molecular markers can form a molecular signature which can help to identify HPV positive patients who are a potential candidate for de-escalation or aggressive approaches, which will further strengthen risk models. Balermpas P et al, Int J Cancer 2015
  23. 23. SUMMARY: CHARACTERISTICS OF HPV+ SCCHN 1. Gillison ML et al, J Natl Cancer Inst 2008; 2. Chaturvedi AK et al, Head Neck Pathol 2012 3. Ragin CC et al, Int J Cancer 2007; 4. Chaturvedi AK et al, J Clin Oncol 2011 5. Licitra L et al, Hematol Oncol Clin N Am 2008 Growing incidence vs HPV– tumors in Europe and US High-risk sexual practices, marijuana use Lower mortality and risk of progression than HPV– (oropharyngeal SCCHN) Younger age (by 3–5 years) vs HPV– Risk factors1,2 Prognosis3 HPV+ Patient profile2 Incidence4,5 Risk factors for HPV– SCCHN include smoking, alcohol, and poor oral hygiene1
  24. 24. CONCLUSIONS ▸ HPV positive oropharyngeal Ca has a different ethology and better prognosis than other HNSCC. ▸ Its prevalence in India is expected to increase in the coming years. ▸ Due to its better prognosis, it gives us the opportunity to de-intensify treatment protocols to reduce late toxicities associated with CCRT. ▸ Results of ongoing trials will further clarify which protocol is the most effective in this setting. ▸ To avoid under treatment of patients, a new molecular marker, Tumor Infiltrating Lymphocytes (TIL) may be used to better select patients with improved outcomes irrespective of p16 status.
  25. 25. MCQs
  26. 26. QUESTION 1 ‣ YOU CANNOT GET HPV FROM SWIMMING POOL OR POOR PERSONAL HYGIENE…. IS IT A FACT OR A MYTH
  27. 27. ‣ YOU CANNOT GET HPV FROM ‣ TOILET SEATS ‣ POOR PERSONAL HYGIENE ‣ HUGGING ‣ SHARING UTENSILS ‣ SWIMMING POOLS
  28. 28. QUESTION 2 ‣ WHICH IS THE MOST COMMON HPV SUBTYPE IN HEAD AND NECK CANCERS IN HUMANS? ‣ A) 6 ‣ B) 11 ‣ C) 16 ‣ D) 18
  29. 29. ‣ E6 PROTEIN DESTRUCTS? ‣ A: p53 GENE ‣ B: Rb GENE
  30. 30. ‣ E6 PROTEIN DESTRUCTS? ‣ A: p53 GENE ‣ B: Rb GENE
  31. 31. QUESTION 3 ‣ LATENCY PERIOD FOR HPV TO CONVERT INTO MALIGNANCY? ‣ 5 YEARS ‣ 10 YEARS ‣ 15 YEARS ‣ 20 YEARS
  32. 32. ‣ LATENCY PERIOD FOR HPV TO CONVERT INTO MALIGNANCY? ‣ 5 YEARS ‣ 10 YEARS ‣ 15 YEARS ‣ 20 YEARS
  33. 33. QUESTION 4 ‣ MOST COMMON SITE? ‣ LARYNX ‣ HYPOPHARYNX ‣ ORAL CAVITY ‣ OROPHARYNX
  34. 34. ‣ MOST COMMON SITE? ‣ LARYNX ‣ HYPOPHARYNX ‣ ORAL CAVITY ‣ OROPHARYNX
  35. 35. QUESTION 5 ‣ HPV+ PATIENTS ARE 5-10 YEARS YOUNGER IN AGE AS COMPARED TO HPV NEGATIVE PATIENTS? ‣ FACT OR MYTH?
  36. 36. ‣ HPV+ PATIENTS ARE 5-10 YEARS YOUNGER IN AGE AS COMPARED TO HPV NEGATIVE PATIENTS? ‣ FACT OR MYTH?
  37. 37. QUESTION 6 ‣ IN A PATIENT CLUP, FNAC FROM NODE IS SUGGESTIVE OF HPV POSITIVITY. IT CAN BE TREATED ON THE LINES OF OROPHARYNX? ‣ TRUE OR FALSE?
  38. 38. ‣ IN A PATIENT CLUP, FNAC FROM NODE IS SUGGESTIVE OF HPV POSITIVITY. IT CAN BE TREATED ON THE LINES OF OROPHARYNX? TRUE
  39. 39. QUESTION 8 ‣ A PATIENT PRESENTS WITH 2cm p16+ TONSIL CANCER AND 2 POSITIVE LYMPH NODES IN THE SAME SIDE OF THE NECK. WHAT IS THE STAGE OF THE PATIENT? ‣ STAGE I ‣ STAGE II ‣ STAGE III ‣ STAGE IV
  40. 40. ‣ A PATIENT PRESENTS WITH 2cm p16+ TONSIL CANCER AND 2 POSITIVE LYMPH NODES IN THE SAME SIDE OF THE NECK. WHAT IS THE STAGE OF THE PATIENT? ‣ STAGE I ‣ ACCORDING TO 7th EDITION IT WILL BE STAGED AS STAGE IV BUT IT BECOMES STAGE I IN 8th EDITION
  41. 41. THANK YOU

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