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Radiation therapy for head and neck cancer by Brian O'Sullivan

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  • 1. The International Federation of Head and Neck Oncologic SocietiesCurrent Concepts in Head and Neck Surgery and Oncology 2012 Radiotherapy for Head and Neck Cancer Brian O Sullivan 1
  • 2. Outline / Scope •  Radiobiology of fractionation (normal tissue and tumor effects) –  Altered fractionation (MARCH meta-analysis) •  Precision radiotherapy –  IMRT etc –  Radiotherapy quality –  Late toxicity and strategies •  Interaction with other treatments –  Chemotherapy (sequential, concurrent)2012 –  Biotherapy (targeted agents)
  • 3. 2012
  • 4. Why do we Fractionate Radiotherapy? 2012
  • 5. 2012
  • 6. 2012
  • 7. 2012
  • 8. Altered Fractionation •  Accelerated Fractionation: –  Strategy: Shorter treatment time to combat tumor proliferation has an advantage if enough dose administered; intense proliferation during treatment commences in the 3rd week approximately (possibilities include finishing treatment close to this time or start accelerating at this time) –  Generally: •  More than once daily to reduce single dose exposure intensity - this often involves reducing fraction size •  Alternatively eliminate week-end breaks, or double up several day(s) per week, or give a concomitant ‘boost’ when proliferation starts •  Hyperfractionation:2012 –  Strategy: Use smaller dose per fraction more than once daily to ameliorate damage to late responding tissues.
  • 9. MARCH (Meta-analysis of Radiotherapy inCarcinoma of the Head and Neck) Bourhis et al 7 weeks Hyperfractionated 6 weeks 5 weeks Moderately accelerated 4 weeks 3 weeks Very 2 weeks accelerated 50 Gy 60 Gy 70 Gy 80 Gy2012 Altered Fractionation (BID) means different things
  • 10. MARCH Lancet   2006   MARCH: Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck (n= 6,515) à  Altered fractionation radiotherapy (RT) improved survival as compared to standard RT: Absolute benefit 3·4% à  8% using Hyperfractionated RT with augmented dose MACH  -­‐  NC:  Altered  the  landscape  in  head  and  neck  cancer                MACH-NC Lancet   2000   MACH-­‐NC:  Meta-­‐Analysis  of  Chemotherapy  in  Head  &  Neck  Cancer  (10,741)  2012 à  Chemotherapy  (CT)  added  to  RT,  improved  survival  by  5%     à  8%  using  concurrent  chemo-­‐RT      
  • 11. MARCH Lancet   2006   MARCH: Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck (n= 6,515) à  Altered fractionation radiotherapy (RT) improved survival as compared to standard RT: Absolute benefit 3·4% à  8% using Hyperfractionated RT with augmented dose - Under-emphasized MACH  -­‐  NC1  :  Altered  the  landscape  in  head  and  neck  cancer                 MACH-NCRadiotherOncology   24  addiLonal  trials  (85%  concurrent)   2009   ~  6000  addiLonal  paLents   MACH-­‐NC:  Meta-­‐Analysis  of  Chemotherapy  in  Head  &  Neck  Cancer  (17,346)  2012 à  Chemotherapy  (CT)  added  to  RT,  improved  survival  by  4.5%     à  6.5%  using  concurrent  chemo-­‐RT  -­‐  Evolving  nature  of  Head  and  Neck  Cancer    
  • 12. Loco-Regional Failure MARCHMeta-Analysis of Radiotherapyin Carcinomas of Head & neck 24% Meta- Analysis Hyperfractionation2012 Bourhis et al. Lancet 368: 843-54, 2006
  • 13. Loco-Regional Failure MARCHMeta-Analysis of Radiotherapyin Carcinomas of Head & neck Meta- 24% Analysis Hyperfractionation Cancer death Cancer death 22%2012 Bourhis et al. Lancet 368: 843-54, 2006
  • 14. 8.2 +/- 2.6 % Overall Survival Accelerated by Treatment Arm According fractionation w/o total Hyperfractionat ion dose reduction to the Type of Radiotherapy Accelerated fractionation All 3 groups with total dose reduction combined2012 Bourhis et al, Lancet 2006
  • 15. MARCH Lancet   2006   MARCH: Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck (n= 6,515) à  Altered fractionation radiotherapy (RT) improved survival as compared to standard RT: Absolute benefit 3·4% à  8% using Hyperfractionated RT with augmented dose - Under-emphasized2012
  • 16. IMRT for Head and Neck Cancer •  Technologically robust means of improved dose delivery: –  Exquisite sharp dose gradients especially in areas of crucial interphase (Tumor vs Normal tissue) –  Delivers optimized non-uniform beam intensities to precisely delineated target volumes –  Improved outcomes (especially normal tissues) •  Requires specific approach: –  Immobilization and set-up issues and knowledge of uncertainties –  Optimal imaging modality acquisition and registration –  Clearly identified dose specification and prescription regarding dose-volume constraints –  Quality control on the whole procedure from Object delineation to delivery –  Knowledge of the pitfalls that exist (poor delineation, dose dumping, erratic planning, tumor or normal tissue deformation and set up uncertainties emerging throughout treatment)2012
  • 17. 2012
  • 18. 2012
  • 19. 2012
  • 20. IMRT requires formalized Policies and ProceduresTreatment plan as a Treatment plan as an unique event instance in a process •  Specific •  General •  Neglect history •  Monitor processes •  Make up rules as needed •  Establish guidelines based on information •  Anecdotal learning •  Demonstrated good practices •  Novel •  Innovative and nimble •  Oral history •  Shared protocols •  Skills limited to few staff •  Widely used tools2012 Courtesy of Dr S Breen, Medical Physics
  • 21. Theodore S. Hong, Wolfgang A. Tomé, Richard J. Chappell, Paul M. Harari, Univ of Wisconsin H&N IMRT Practice HeterogeneityVariations in TargetDelineation for Headand Neck IMRT:International Survey 2012 Courtesy of Dr P Harari
  • 22. PMH H&N Site Group (8 Radiation Oncologists with Agreed Policies)2012 Courtesy of Dr J Waldron
  • 23. Summary of evidence for IMRT in head and neck cancer•  Amelioration of normal tissue effect: –  Xerostomia and QOL (3 RCTs and numerous cohort studies) –  Blindness and ORN•  Improvement: –  Dramatic for loco-regional control (NPC)•  Comments: –  In some situations cannot perform trials due to normal tissue sequelae (e.g. advanced NPC) –  Strong support for NPC and Paranasal (efficicacy and morbidity) –  Other cancers: efficacy data weaker, but tissue protection is strong2012
  • 24. 2012
  • 25. Late toxicity: Late toxicity greatest score at =/ >6 months after Day 1 of RT In 74 patients, none developed IMRT-related blindness (Grade 4 ocular toxicity).2012
  • 26. N = 176 patients, 75% and 50% had received >65 Gy and >70 Gy to >1%of the mandibular volume, respectivelyAt a median follow-up of 34 months no cases of osteoradionecrosis havetaken place 2012
  • 27. et tolf U, tz K, Lu ofile P , Gra risk pr ug uenin nimized T ). ults: len R, H : mi apy (IMR ible lar res , Zwah e mand ion ther Simi der S is of th t radia 3 - 8. G, Stu ro s ted St uder radionec -modula 2(5):28 teo ity ;18 a l. Os g intens ol. 2006 n llowi th 75% kN = 176opatients, er On and 50% had received >65 Gy and >70 Gy to >1% f en S trahlof the mandibular volume, respectivelyAt a median follow-up of 34 months no cases of osteoradionecrosis havetaken place 2012
  • 28. NPC IMRT: Parotid Sparing Randomized trials of IMRT vs 2D-RT 51 pt (T2N0-1M0) 60 pt (T1-2N0-1M0) Pow, IJROBP 2004 Kam, JCO 2007Significantly better recovery of salivary flow 2012
  • 29. 2012
  • 30. IMRT in NPC •  Many of these patients were treated with concurrent chemotherapy2012 •  Need new approaches to improve systemic outcome
  • 31. NPC IMRT: Tumor Control Author Rate Local Nodal Distant Survival Bucci 4-y 96% 98% 72% 74% Wolden 3-y 91% 93% 78% 83% Kam 3-y 92% 98% 79% 90% Kwong1 2-y 100% 94% 94% NR Kwong2 2-y 96% - 94% 92% Chong 3-y 99% 99% 88% 86% SW Lee 2-y 88% 88% 90% NR2012
  • 32. Potentially the biggest hurdle in accomplishing2012 organ preservation.
  • 33. 2012
  • 34. Recurrence in Spared Parotid RegionPre-treatment MRI& Dose distributionRecurrence PET/CT 2012 Cannon & N Lee, IJROBP 2008
  • 35. For deficient versus compliant radiotherapy Large variation in the percent of plans with majorrespectively: adverse impact was noted according to country. Even more striking:•  The 2 year overall survival:50% versus70% (hazard ratio 1.99; P < .001) •  Correlation between the number of patients Ø  20% difference entered and the probability of receiving unsatisfactory radiotherapy. •  The 2 year freedom from locoregional •  Centers enrolling < 5 patients, 29.8% had a failure was 54% versus 78% (hazard major adverse impact ratio 2.37; P < .001) •  Centers enrolling > 20 patients had 5.4% Ø  24% difference2012
  • 36. 24% 20%2012
  • 37. •  Cetuximab + radiation versus radiation alone –  Efficacious •  Locoregional disease: HR=0.68 (p=0.005) •  PFS: HR=0.70 (p=0.006) OS: HR=0.74 (p=0.03) •  Subset analysis: Best results for altered fractionation radiation regimen (OS: HR=0.64) and in oropharynx2012 •  No increase in in field toxicity Bonner 2006 NEJM
  • 38. Unusual Skin Toxicity – Even in Low Dose Radiotherapy Regions n=13 Cetux abgebrochen bei n=92012 Pryor et al., Radiother. Oncol. 90, 2009,
  • 39. ECOG 1308 - The First HPV-Unique Trial2012 Courtesy of M. Gillison
  • 40. 40Forest Plot of the Hazard Ratios (95% Confidence Intervals) by Pre-Treatment Characteristics – Five-year Update Improvement with Cetuximab 2012 Bonner et al 2010
  • 41. Elderly patients with malignant disease will progressively constitute the majority of patients in oncological practice Catherine Terret, Centre Leon Berard, Lyon2012 Terret. Expert Rev Anticancer Ther 4(3) 469-475 (2004)
  • 42. •  Physiological changes associated with ageing •  Declining renal function and decreasing reserve in multiple organ systems predispose to unpredictable toxicities •  Rapidly increasing population •  Laden with problems of multiple organ systems, comorbidities (esp.2012 vascular pathologies) •  Polypharmacy complicates situation
  • 43. Disease Response Pignon T et al Eur Journal of Cancer, Vol 32A, 12, 2075-81, 1996 •  1589 patient with head and neck cancer enrolled in 5 EORTC trials (Feb 1980 – March 1995) •  20% were >65 years •  No difference survival, loco-regional control, Acute Toxicity, Weight loss, or Late Toxicity •  Older patients had more severe subjective symptoms (Functional acute2012 toxicity, Grade 3 and 4, P<0.0001) •  Conclusion: chronological age is irrelevant – at least 11 years ago.
  • 44. Elderly defined as >/= 75 years •  2312 patients: 425 elderly (20%); 1860 Cause-specific survival in patients who received definitive younger (80%) radiotherapy (n=1487) (p<0.01) •  F vs. M: 36% vs. 27%, p<0.01 •  Other cancer: 23% (elderly) vs. 13%, p<0.01 •  Curative treatment; 79% (elderly) vs. 93%, p<0.01 •  760 received intensified treatment (concurrent chemoradiotherapy or hyperfractionated accelerated RT) (elderly = 46) and (younger n = 714) •  No difference in tolerance to treatment2012
  • 45. rospective ed for pCause-specific survival in Elderly defined as >/= 75 years e ei s an urgent n adapted (n=1487)definitive •  2312 patients: 425 elderly (20%); 1860 nd patients who received nd Theryounger (80%) fs tandard a head a (p<0.01) radiotherapy o th aluation tients wi •  F vs. M: 36% vs. 27%, p<0.01 ev a elderly p •  Other cancer: 23% (elderly) vs. 13%, sch edules in p<0.01 cancer. •  Curative treatment; 79% (elderly) vs. neck 93%, p<0.01 •  760 received intensified treatment (concurrent chemoradiotherapy or hyperfractionated accelerated RT) (elderly = 46) and (younger n = 714) •  No difference in tolerance to treatment2012
  • 46. Summary •  We have many radiotherapy options (technical, biological, scheduling, prescriptive, combinations with other agents and other treatments) •  We must refine approaches, combine modalities more conservatively with potential equal or greater efficacy •  Molecular biology of tumors and of radiation interaction with tissues and in combination with systemic agents and surgery is essential •  We need especially to focus on management approaches that meet the needs of our aging population •  Quality assurance must become an accepted part of the delivery of high quality radiotherapy •  Clinical trials that address all domains of the practice of radiation medicine remain the cornerstone of progress2012