Innovative Radiotherapy In Hnc

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Innovative Radiotherapy In Hnc

  1. 1. Innovative radiotherapy in HNC: IMRT and IGRT Dr Chris Nutting MD FRCP FRCR Consultant and Senior Lecturer in Clinical Oncology Head and Neck Unit, Royal Marsden Hospital & The Institute of Cancer Research, Fulham Road, London ESMO Stockholm 2008
  2. 2. Goals of Head and Neck IMRT 1. Reduce local failure by improved target volume localisation, and dose escalation Site: larynx and hypopharynx organ preserving chemoradiation protocols in Stage III and IV 2. Reduce toxicity by improved dose distributions to OAR Site: Oropharynx – Parotid gland sparing 3. Novel techniques Site: Unknown primary SCCHN
  3. 3. Phase I/II IMRT Trial Protocol Aim:To find a suitable dose escalation level for Phase III trial using IMRT Method: Single phase 63 Gy to to tumour and 51.8 Gy to lymph nodes in 28# with induction CF and concomitant cisplatin •Escalate to by 10% 67.2 Gy to larynx and 56 Gy to nodes in 28 # if late toxicity acceptable •To escalate further to 15-20% if possible Guerrero Urbano et al 2008
  4. 4. Demographics Table 1. Patient characteristics, larynx/ hypopharynx dose escalation study Cohort 63Gy Cohort 67.2 Gy Median follow up in weeks (range) 87 (55-162) 40 (9- 64) Median age (range) 57 (35-75) 66 (60-85) Gender Male 11 10 Female 4 5 Primary tumour site Larynx 7 7 : e mi t t n e m t a e r t n a e M Hypopharynx 8 8 T stage T1 0 1 ± s y a d 3 9 3 :tr o h o c y G 0. 3 6 • T2 3 3 syad 1 83 :trohoc yG2.76• ± T3 8 8 T4 4 3 N stage N0 4 8 SKAERB TNE MTAERT ON N1 4 2 N2a 1 0 %001 RAEN N2b 3 2 HTI W E C N AIL P M O C N2c 2 3 TNATIMOCMOC N3 1 0 YPAREHTO MEHC Neoadjuvant chemotherapy 15 13 Concomitant chemotherapy 15 14 Guerrero Urbano et al 2008
  5. 5. ACUTE RADIATION DERMATITIS 100.0% 75.0% G3 63.0Gy G3 67.2Gy 50.0% G2 63.0Gy G2 67.2Gy 25.0% 0.0% 1 2 3 4 5 6 7 8 9 10 14 •G3 peak prevalence: -63Gy cohort: 16.7%, week 1 post-RT -67.2Gy cohort: 21.4%, on the last week of RT. •No real difference between dose levels •Skin sparing effect of MV photons
  6. 6. ACUTE RADIATION-INDUCED DYSPHAGIA Prevalence of acute G3 dysphagia 100.0% 80.0% G3 dysphagia, % s’namraepS :trohoc yG0.36 60.0% 67.2Gy cohort tneiciffeoc noitalerroc knar 40.0% 63.0Gy cohort d n a si ti s o c u m n e e w t e b 20.0% ai g a h p s y d ) 2 0. 0 = p ( 6. 0 0.0% 1 2 3 4 5 6 7 8 9 10 14 Follow-up (weeks) •Peak prevalence of dysphagia in both cohorts occurred following completion of chemo-IMRT. -64.3% for the 63.0Gy cohort, on weeks 1 and 2 post-RT -83.3% on week 3 post-RT for the dose escalated cohort Guerrero Urbano et al 2008
  7. 7. ACUTE TOXICITY: NCI CTC v.2.0 scale Incidence of acute G2 and G3 toxicity 63.0Gy cohort 67.2Gy cohort G2 G3 G2 G3 Dermatitis 66.7% 20% 46.7% 20% Mucositis 33.3% 66.7% 46.7% 40% Dysphagia 20% 66.7% 13.3% 86.7% Pain 46.7% 26.7% 53.3% 40% Xerostomia 60% 0 73.3% 6.7% Guerrero Urbano et al 2008
  8. 8. Late Normal Tissue Toxicity at 1 year Dose Level I (63 Gy/28 #) Dose Level II (67.2 Gy/28 #) Organ Grade I Grade II Grade III Grade I Grade II Grade III Dysphagia 26% (4) 0% 0% 26% (4) 0% 6% (1) Xerostomia 60% (9) 12% (2) 0% 53% (8) 0% 0% Larynx 30% (5) 20% (3) 0% 46% (7) 6% (1) 0% Subcutaneous 43% (6) 0% 0% 6% (1) 12% (2) 0% Skin 20% (3) 20% (3) 0% 33% (5) 6% (1) 0% Mucosa 33% (5) 0% 0% 43%(6) 0% 0%
  9. 9. Outcome: Survival event_lr 100 Survival Function 90 1.0 80 Survival probability (%) 70 .8 60 group 50 0 1 40 .5 30 20 10 Cum Survival .3 0 0 10 20 30 40 50 60 70 Survival Function Time 0.0 Censored Number at risk 0 12 24 36 48 Group: 0 29 25 16 10 7 5 2 1 Time to death- months Group: 1 31 24 13 10 7 0 0 0 %09 lavivrus eerf ymotcegnyraL llarevO •Loco-regional 65% vs. 82% at 3 years •To detect this difference in a Phase III trial would require total of 320 patients (90% power 5% p)
  10. 10. Goals of Head and Neck IMRT 1. Reduce local failure by improved target volume localisation, and dose escalation Site: larynx and hypopharynx organ preserving chemoradiation protocols in Stage III and IV 2. Reduce toxicity by improved dose distributions to OAR Site: Oropharynx – Parotid gland sparing 3. Novel techniques Site: Unknown primary SCCHN
  11. 11. IMRT – Reducing the dose to the parotid gland in tonsil cancer
  12. 12. Head and neck IMRT: Xerostomia • Graff et al IJROBP 02/2007 • Matched case-control study of QoL after bilateral CRT/IMRT – IMRT improved dry mouth and sticky saliva (p= 0.0001) – Prevalence Odds Ratios were: Dry mouth 3.2, Sticky saliva 3.2, Oral pain 3.6, Trismus 2.6, Difficulty swallowing 2.8.
  13. 13. Head and neck IMRT: Xerostomia • Fang et al Cancer Jan 2007 • 237 Nasopharynx carcinoma patients • Non-randomised allocation: Conv (152) vs Conformal (CFRT – 33 IMRT 52) • Conformal group showed improved QoL scores, and multiple functional scores including xerostomia, eating, speech, senses etc • OR for xerostomia was 0.37 (CI 0.2-0.66) • OR for global QoL was 2.0 (CI 1.2-3.7)
  14. 14. Head and neck IMRT: Xerostomia • Pow et al IJROBP 2006 • Small randomised trial of 51 patients with T2 N0/1 M0 nasopharynx cancer • CRT vs IMRT • Recovery of parotid flow to at least 25% of pre- treatment levels was 83% with IMRT, and 10% with CRT • IMRT patients had improved dry mouth and sticky saliva
  15. 15. TROPSRAP Study Design Head and neck cancer patients at high risk of radiation induced xerostomia Randomisation Conventional Parotid-sparing radiotherapy IMRT 1:1 randomisation
  16. 16. TROPSRAP Current status PARSPORT closed to recruitment in Dec 2007 96 patients were randomised from 6 UK centers Data collection rates ~80% 10% of trial participants died before reaching the primary endpoint (usually of non-HNC) Primary endpoint data collection should be completed Dec 2008
  17. 17. IMRT – New tumour types Expansion of indications into midline tumours: tongue base, nasopharynx PARSPORT II to investigate feasibility of bilateral parotid gland sparing
  18. 18. vs Mean doses to total combined parotid salivary tissue is the same with each approach This would predict that saliva flow will be equivalent in each approach if gland is homogeneous
  19. 19. vs Initial clinical results (n=60) suggest that the two approaches are not equivalent, and that a higher rate of G0 xerostomia is seen in patients treated with bilateral sparing of the superficial lobes. This is an unexpected finding and may support the findings from rat models that parotid tissue is not homogeneous in its saliva production, or radiosensitivity.
  20. 20. Goals of Head and Neck IMRT 1. Reduce local failure by improved target volume localisation, and dose escalation Site: larynx and hypopharynx organ preserving chemoradiation protocols in Stage III and IV 2. Reduce toxicity by improved dose distributions to OAR Site: Oropharynx – Parotid gland sparing 3. Novel techniques Site: Unknown primary SCCHN
  21. 21. IMRT for unknown primary site • Patients presenting with cervical lymph node metastases and no mucosal tumour • Post-operative options of hemi-neck RT or TMI issues of local control vs survival • Target volumes for post-op and potential microscopic disease can be defined • Hypothesis: Can TM-IMRT offer the advantages of local control without the high levels of toxicity?
  22. 22. Basic principles of TM-IMRT PTV1 (post-op) 60 Gy in 30# PTV2 elective (microscopic disease) 50 Gy in 25# Bhide et al 2008
  23. 23. Currently recruiting Phase II protocol at RMH to assess local control and toxicity issues Bhide et al 2008
  24. 24. IGRT in Head and Neck Cancer 1. Optimise conventional anatomic imaging Site specific protocols e.g. skull base/BOT Image registration 2. Add functional/biological information FDG PET/CT, dceMRI, dynamic CT 3. Image areas of potential radioresistance Hypoxia tracers, proliferation markers
  25. 25. Adjuvant MRI for GTV definition •CT-GTV (red), MR-GTV (blue) and combined-GTV (pink). •Part of the GTV is identified only on CT, part on MRI only onabrU orerreuG .T.M rD fo ysetruoC
  26. 26. onabrU orerreuG .T.M rD fo ysetruoC Adjuvant MRI for OAR definition
  27. 27. RMH Experience With PET/CT For RT Planning • Two groups of patients: 9 with known primary site and 9 unknown • RT planning performed with or without PET/CT data • Unknown primary planned for ipsilateral neck irradiation only 8002 la te dlobweN
  28. 28. Known primaries: Change in CTV 900 800 700 600 500 400 300 200 100 0 Co nventio nal P ET/CT Median increase 11cm3 (1, 65.8) p=0.012 8002 la te dlobweN
  29. 29. % change in target volumes in Unknown primaries: CT to PET/CT 250 200 1 50 1 00 50 0 CT P E T / CT M odal i ty 8002 la te dlobweN
  30. 30. Imaging of hypoxia in head and neck cancer Probability of normal tissue damage Probability of tumour control Normoxia Hypoxia Radiation dose (Gy)
  31. 31. DCE-MRI Pimonidazole Source image ROIs Enhancement vs time CA9 Wash-in rate Newbold in press IJROBP
  32. 32. Conclusions • We have attempted to design clinical trials with clear questions to test IMRT in HNC • Phase I and II results support dose escalation strategies in SCCHN • Parotid sparing IMRT: Randomised trial data now available • Novel IMRT techniques can be formulated and tested to expand indications • IGRT potentially offers new RT targets • More clinical research in this area is required

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