Radiation therapy for laryngeal function preservation by Brian O'Sullivan

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Radiation therapy for laryngeal function preservation by Brian O'Sullivan

  1. 1. The International Federation of Head and Neck Oncologic SocietiesCurrent Concepts in Head and Neck Surgery and Oncology 2012 Radiation Therapy forLaryngeal Function Preservation Brian O Sullivan 1
  2. 2. Controversy has Characterised the Literature of Laryngeal Cancer for DecadesControversies even greater in early disease (endoscopic vs RT especially) Preference for Surgery in T3N0 Preference for Total Laryngectomy glottis 2012
  3. 3. Histology >95% SCC – Variations : •  verrucous carcinoma, spindle cell carcinoma, basaloid SCC, and papillary SCC •  hyperplasia, dysplasia, CIS2012
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  5. 5. Radiotherapy is a Staple among Organ-preservation strategies2012 Available online at http://www.asco.org/guidelines/larynx
  6. 6. Does Increasing Use of Radiotherapy Over 3Decades Worsen the Outcome for Laryngeal Cancer ? “A Population-Based Study of 13,808 US Patients”•  Radiotherapy with its advantage of organ preservation has been used to treat laryngeal cancer (LC) for several decades.•  Authors studied 3 periods: –  1988 - 1993, 1994 - 1999, 2000 – 2006•  Conclusion: No negative impact of radiotherapy on cancer survival of glottic or supraglottic larynx cancer2012 Zhang, H., Travis, L. B., Chen, R., et al Cancer 118 (5) 1276–1287, 1 March 2012
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  8. 8. General Philosophy of laryngeal preservation in management of laryngeal cancer •  Major local modalities: –  Surgery and/or radiotherapy •  Treatment choice depends on: –  stage, and tumor volume and extension –  laryngeal tumor location: anterior commissure and subglottic involvement –  Patient factors: co-morbidity, smoking, male gender, and anemia –  likelihood of functional preservation, –  patient preference2012
  9. 9. Regional Spread in Laryngeal Cancer •  Except for glottic T1, and some early T2s •  Regional lymph nodes must be accounted for: –  Midline nature – bilateral involvement is possible and treatment must address –  Levels II, III, IV are at risk –  Risk is increased by size, stage, supraglottic, tumor differentiation •  Influences the radiation volumes used •  Meticulous attention to post treatment imaging 8-12 weeks after completion of radiotherapy is essential to safeguard against uncontrolled disease that may be avoided by neck2012 dissection.
  10. 10. Distinct Issues About Radiotherapy for Laryngeal Cancer •  Bilateral radiotherapy for all except T1 Glottic •  Bulky T4b is generally best managed by surgery and post-operative RT +/- concurrent chemotherapy •  All other disease settings should be presented the option of organ preservation using a radiotherapy 2012 strategy (alone or with concurrent chemotherapy)
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  13. 13. Treatment – Early Stage (I/II) •  Current therapeutic options –  Laser microsurgery (transoral) –  Open partial laryngectomy –  Radiation therapy •  No RCT to compare surgery w/XRT •  Rate of local control similar between surgery and radiation •  Current recommendations: XRT with surgery reserved for salvage therapy with local2012 recurrence Mendenhall WM et al., Cancer. 2004 May 1;100(9)
  14. 14. Randomizedtrialsrecommended toresolve thesecontroversies:Need to considerthe challenges ina disease with sofew events. 2012
  15. 15. Radiotherapy of T1 Glottic Cancer (1) •  Traditionally one of the most straightforward techniques in radiation oncology –  Small volume –  Reproducible anatomy –  Regional nodes do not need to be considered •  Emerging evidence that IMRT with contralateral carotid preservation may be possible2012
  16. 16. Radiotherapy of T1 Glottic Cancer (2) •  Irrespective of the technique –  Movement of larynx (superior and inferior respiratory motion and internal vocal cord) warrant caution in changing targets –  Anterior commissure disease warrants attention to dosimetric coverage to minimize geographic miss (usually requires tissue isodense bolus placed) –  Dose needs to be adequate and of adequate fraction size (single daily fraction sizes of 1.8 should be avoided in favor2012 of larger dose per fraction, or altered fractionation)
  17. 17. T1 and T2 Glottic University of Florida 5 Year Radiotherapy Results Initial Ultimate Ultimate Local Local LC + Larynx Stage N Control % Control % Preserved %T1a 230 94 98 95T1b 61 93 98 98T2a 146 80 96 82T2b 82 72 96 762012 Mendenhall WM et al JCO 2001: 19:4029-4036
  18. 18. T1 and T2 Glottic University of Florida 5 year Radiotherapy Results Absolute Cause specific Survival % Survival %T1a 230 82 98T1b 61 79 98T2a 146 77 95T2b 82 77 902012 Mendenhall WM et al JCO 2001: 19:4029-4036
  19. 19. Dose Fractionation in Early Disease •  Yu et al., 1997 [1] –  Retrospective study – 5 yr local ctr rate of XRT on T1 glottic CA –  Daily fx > 2 Gy (50 Gy/2.5Gy QD & 65.25Gy/2.25 Gy QD) had 5 yr local ctr rate of 84% –  Daily fx = 2 Gy had 5 yr local ctr 65.6% •  Yamazaki et al., 2006 [2] –  RTC – in T1 glottic CA addressing dose per fraction •  Andy Trotti et al, RTOG 95-12 – closed [3] –  Randomized pts with T2 glottic cancer to 70Gy/2Gy QD vs 79.2 Gy/1.2 Gy BID2012 1 Yu E. et al., Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):587-91 2 Yamazaki H et al., Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):77-82 3 Trotti A, IJRBOP Volume 66, Issue 3, Supplement 1, 1 November 2006, Page S15
  20. 20. Arm A Arm B Minimal tumors 60 Gy 30f 56.25 Gy in 25f <= 2/3 of vocal cord 6 weeks 5 weeks Larger tumors 66 Gy in 33f 63 Gy in 28f 6.6 weeks 5.6 weeks Use of 2.25-Gy f and shorter overall superior local control compared to 2-Gy fractions without adverse reactions from the greater fraction size2012
  21. 21. A randomized study of hyperfractionation versus conventional fractionation in T2 Squamous cell carcinoma of the vocal cord (RTOG 95-12) Study CLOSED following complete accrual STRATIFY: T2a R T2b A Arm 1: Standard fractionation (SF) N 70Gy / 35 f / 2 Gy daily / 7 wks ELIGIBILITY: D N category: N0 O M Age: >18. I Karnofsky >= Z Arm 2: Hyperfractionation (HF) 60 E 79.2Gy / 66 f / 1.2 Gy BID / 6.5 wks ACCRUAL: Primary Outcome: Local control 240 patients Secondary Outcomes: Toxicity, overall and 2012 disease free survival The trial was designed to detect a 55% reduction in the yearly hazard rate for local failure with 80% statistical power.
  22. 22. "A Randomized Trial of Hyperfractionation vs. Standard Fractionation In T2 Squamous Cell Carcinoma of the Vocal Cord" •  Local control was modestly higher with HFX compared to standard fractionation for T2 carcinoma of the vocal cord, but the difference did not reach statistical significance •  With only 58 local failures, the statistical power of detecting the observed 35% hazard reduction is only 36%. There was a trend for better disease free survival with HFX. •  Results are consistent with other studies showing a modest benefit 2012 for altered fractionation in cancers of the H&N. Trotti A, IJRBOP Volume 66, Issue 3, Supplement 1, 1 November 2006, Page S15
  23. 23. IMRT for Early Glottic Cancer •  Pros –  Potential normal tissue sparing: –  Carotid arteries –  Potential reduction in the incidence of CVA •  Cons –  Results with IMRT uncertain –  Good results with conventional planning –  Severe complications rare2012 –  Target miss with IMRT Albert Tiong, Waldron J, O Sullivan B et al
  24. 24. Parallel Opposed Pairs (POP) GTV2012 Albert Tiong, Waldron J, O Sullivan B et al
  25. 25. Radiotherapy Technique (IMRT) Cord PRV PTV CTV 2012
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  29. 29. Technical Issues in Radiotherapy of Advanced Laryngeal Cancer •  Target Volumes –  Larynx and entire neck are usually treated •  Primary –  GTV targeted with full dose (e.g. 70 Gy in 7 weeks) –  Elective dose to the surrounding volume (1.5 cm) –  Tracheostomy, if present, should be included in the elective dose target •  Neck –  Gross nodes targeted with full dose (e.g. 70 Gy in 7 weeks) –  elective irradiation of Levels II, III, and IV (e.g. 50 Gy in 25 fractions) –  Additional coverage of level V, high level II into the retro-styloid space, and retropharyngeal nodes if indicated by extent of nodal2012 disease
  30. 30. Landmark Studies: Laryngeal Preservation in Locally Advanced Laryngeal Cancer •  The Department of Veterans Affairs Laryngeal Cancer Study Group (1991) •  The European Organization for Research and Treatment of Cancer (1996) •  Radiation Therapy Oncology Group 91-11 (2003) 2012 Evaluation of place of standard radiotherapy with several strategies
  31. 31. VA Larynx Trial •  85% of patients had at least a PR with induction PF •  31% of patients in the induction arm had a CR at the primary site after 2 cycles of chemotherapy and 49% had a CR after 3 cycles •  15% of patients did not have at least a PR to 2 cycles of PF and thus required a laryngectomy •  64% of the patients in the chemotherapy and radiation arm were able to preserve their larynx •  Overall survival was equivalent between the surgery arm and the larynx preserving arm2012 NEJM 1991
  32. 32. Intergroup 91-11 •  Built on questions raised by the VA study •  We can preserve the larynx but is chemotherapy plus radiation better than radiation alone? •  What about concurrent chemoradiation?2012
  33. 33. RTOG 91-11: Larynx Preservation TrialPhase III larynx preservation trial: induction chemotherapy and radiation therapy vsconcomitant chemotherapy and radiation therapy vs radiation therapy alone CR, PR x 3 d cycle RT Location R S 1. Glottic A 2. Supraglottic Arm 1: CDDP/5-FU x 2 cycles T N R T Stage D A 1. T2 O NR surgery RT 2. T3, fixed cord T 3. T3, no cord fixation M I 4. T4, with base of tongue ≤ 1 cm I Arm 2: Radiation therapy + CDDP F Z Y N Stage E Arm 3: Radiation therapy alone 1. N0, N1 2. N2, N3 Radiotherapy: 70 Gy in 35 f in 7 weeks Chemotherapy 2012 Arm 1: cisplatin 100 mg/m2/5-FU 1 gm/m2/24 hrs CVI x 120o q3wks x 3 Arm 2: cisplatin 100 mg/m2 Days 1, 22, 43 of RT Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098
  34. 34. Intergroup 91-112012
  35. 35. RTOG 91-11: Larynx Preservation Trial•  The median follow-up among surviving patients: 3.8 years•  Demographics: median age 59 yrs; 94% KPS ≥ 80; 50% N0; 68% SGL; 28% N2-3 Arm cDDP/5-FU → RT/cDDP RT RT Enrolled, n (evaluable) 180 (173) 182 (172) 185 (173) 2-yr laryngectomy FS, % 59 66 53 5-yr DMFS, % 85 88 78 5-yr DFS, % 38 36 27 5-yr OS,% 55 54 56•  Conclusions –  RT/cDDP: stat signif ↑ in LFS (P = .01) –  No SS diff in survival 2012 Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098
  36. 36. Intergroup 91-11 •  The rate of distant metastasis was the same between the induction group and the concurrent chemoradiotherapy group •  Overall Survival was the same between the 3 groups approximately 55% at 5 years •  This trial made concurrent chemo-RT the standard of care for larynx preserving therapy. •  Notably, the comparison was to standard fractionation radiotherapy (70 Gy in 7 weeks), known to be inferior to altered fractionation (e.g. RTOG 9003 and MARCH2012 meta-analysis etc)
  37. 37. Has Induction Done its Job ?After paving the way for Organ Preservation •  MACH-NC meta-analysis: –  > 10,000 patients in 63 trials –  Significant survival benefit for concurrent chemotherapy –  but not for neoadjuvant chemotherapy added to radiation (minimal effect)2012 New Strategies are emerging: TPF +/- Cetuximab Pignon et al 2000 Lancet Pignon et al 2009 Radiat Oncol
  38. 38. Adverse Effects of XRT in the Treatment of Laryngeal Cancer •  Acute (during treatment) –  Mucositis –  Odynophagia –  Skin reaction •  Intermediate –  Laryngeal edema –  Xerostomia –  Taste dysfunction •  Late (should be uncommon) –  Stricture and fibrosis –  Radionecrosis2012 –  Hypothyroidism (10-20%)
  39. 39. Conclusions about the use of Radiotherapy for Laryngeal Function Preservation •  Treatment of laryngeal cancer remains controversial, especially in early disease –  Modality based controversies predominate •  Radiotherapy underpins function preservation strategies in all stages of the disease •  In advanced disease, laryngeal preservation is accepted as an appropriate goal in a functioning larynx –  How to accomplish remains controversial –  Multiple options exist, including surgery –  Concurrent chemo-RT remains the goal standard •  Research should focus on survival, function, choice of patients for trials, translational research 2012 •  We should not forget the elderly patients from the standpoint of clinical trials

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