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

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

  1. 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. 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)
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  4. 4. Why do we Fractionate Radiotherapy? 2012
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  8. 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. 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. 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. 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. 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. 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. 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. 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. 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
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  20. 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. 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. 22. PMH H&N Site Group (8 Radiation Oncologists with Agreed Policies)2012 Courtesy of Dr J Waldron
  23. 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
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  25. 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. 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. 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. 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
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  30. 30. IMRT in NPC •  Many of these patients were treated with concurrent chemotherapy2012 •  Need new approaches to improve systemic outcome
  31. 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. 32. Potentially the biggest hurdle in accomplishing2012 organ preservation.
  33. 33. 2012
  34. 34. Recurrence in Spared Parotid RegionPre-treatment MRI& Dose distributionRecurrence PET/CT 2012 Cannon & N Lee, IJROBP 2008
  35. 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. 36. 24% 20%2012
  37. 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. 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. 39. ECOG 1308 - The First HPV-Unique Trial2012 Courtesy of M. Gillison
  40. 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. 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. 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. 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. 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. 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. 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

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