Head & Neck Cancer: When to Irradiate
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- Beatrice Burke
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2 Head & Neck Cancer: When to Irradiate ESO-ESMO Latin-America 2018 Talented students colleagues 1
3 > 15 different diseases for RT strategies NC NP OC OP H L 2
4 HPV Prognostic Marker >2010 Trial Cases Marker Survival First author RTOG 323 HPV 82% vs. 57% (3-year) TROG 185 p16 INK4A 91% vs. 74% (2-year) DAHANCA 794 p16 INK4A 66% vs. 28% (5-year) TAX HPV 82% vs. 35% (5-year) Ang, 2010 Rischin, 2010 Lassen, 2011 Posner, 2011
5 No data yet
6 T AFRT vs CFRT no diferences in outcome
7 HPV p16 + vs - Never smokers
8 Selected topics for talented When RT? Locally advanced stages Nasopharynx Postoperative RT Laryngeal preservation Oligo-recurrence New concepts, new trials How? and what? (to expect) 7
9 Highest level of clinical evidence Australian National Health and Medical Research Council 48% all cancer pts indication of RT 73% chemoradiation level I-II 34% curative 14% palliative Radiation type LC 5y OS 5y RT 10 % all pts 2,4% all pts CRT 0,6% all pts 0,3% all pts Head & Neck CRT 32% 16% Cervix CRT 33% 18%
10 Principles of RT technique/target delineation Simulation Head extended Supine Arms down IV contrast 5-pt mask Thin cut (2-3 mm) Technique: IMRT (except for early stage glottic cancer)
11 Target delineation (elective nodes) Primary echelon Location/drainage of primary Lateralized (ipsilateral) vs. midline» (bilateral) Secondary echelon At risk if primary echelon contains bulky or high-volume disease Dose-Volume Histograms DVH
12 PARSPORT Nutting. Lancet Oncol 2011;12:127-36
13 H&N IMRT Practice Heterogeneity T2 N1 M0 Tonsil Cancer P. Harari: Radiotherapy & Oncology 2012 Courtesy of Dr. Harari
14 Isodoses or Heterodoses: 3D!
15 IMRT: decisions boost & fractionation: sequential vs SIB Gross Disease High-Risk Risk 70 Gy in daily fractions Gy in daily fractions Gy in daily fractions Macro micro nano level of risk
16 3DCRT IMRT IMRT
17 Selected topics for talented When RT? Locally advanced stages Nasopharynx Postoperative RT New concepts, new trials How? and what? (to expect) 16
18 Loco-regional Advanced when, how and what to expect - Unresectable: radical chemoradiation - Consolidation: post-induction CT - Oligo-recurrent: radical rescue
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21 Selected topics for talented Locally advanced stages: randomized trials RT FRACTIONATION altered vs standard 20
22 RTOG Standard fractionation Hyperfractionation Accelerated fractionation, split course Accelerated fractionation, concomitant boost 7000 cgy/35 fx 7 weeks 8160 cgy/68 fx 7 weeks (1.2 Gy Bid) 6720 cgy/42 fx 6 weeks (1.6 Gy Bid) 7200 cgy/42 fx 6 weeks
23 33 trials and 11,423 patients Any Hiperfractionation Overall survival Moderately accelerated Very accelerated Fractionation RT 5y 10 y Hiperfractionation 8,1% 3,9% Very accelerated 1,3% 0,4%
24 Any Hiperfractionation Moderately accelerated Very accelerated Progression-free survival
25 Selected topics for talented FRACTIONATION +/- CRT 24
26 Clin Oncol (R Coll Radiol) ;28: Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell Carcinoma. Gupta T 1, Kannan S 2, Ghosh-Laskar S 3, Agarwal JP 3 No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
27 Chemoradiotherapy updated meta-analysis, Jan 1, 2009, and July 15, 2015 conventional fractionation RT vs altered fractionation radiotherapy conventional fractionation CRT vs altered fractionation radiotherapy alone 33 trials and 11,423 patients Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010
28 OS LR failures New England Journal of Medicine, 2006;354:567-78
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30 LRC OS HPV + HPV - OS The addition of an anti-egfr agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC. Except for patients with coexisting medical conditions or decreased performance status, concurrent CRT should remain the standard of care for patients with LA-HNSCC.
31 Loco-regional Advanced when, how and what to expect - Unresectable: radical chemoradiation - Consolidation: post-induction CT - Oligo-recurrent: radical rescue
32 Why to Still Consider Induction Chemotherapy Pros: Salvage subclinical M1 disease and OS benefit Assessment of response Reduce dose/volume of RT Cons: Prolongs treatment time/cost Increases toxicity No clinical benefit
33 N2 / N3
34 Responders
35 HPV Oroph Non-Oroph N2 N3
36 Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol Mar;14(3): Study terminated early due to poor accrual (145 enrolled) Median f/u 49 mos 3-yr OS: (73% ICT vs 78% CRT, NS) Febrile neutropenia (23% ICT vs 1% CRT) Haddad, Lancet Oncol. 2013; 14: 257.
37 LRC DFS Induction CT Surgery +/- RT OS
38 5 randomized trials 1022 patients TPF induction CT Pt / Tx CRT
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40 LRR Distant faliure
41 ECOG 1308: Phase II trial of IC followed by cetuximab + 54 Gy vs 69 Gy IMRT in HPV-associated resectable oropharyngeal SCCA
42 Loco-regional Advanced when, how and what to expect - Unresectable: radical chemoradiation - Consolidation: post-induction CT - Oligo-recurrent: radical rescue
43 bio-guided IMRT for oligo-recurrences
44 22 articles 1105 patients published 1976 and 2014 The 5-year OS improved over time: 18% pre % mixed pre-2000 and post % in the post-2000 (p <.001).
45 Re-RT after salvage surgery, 16 publications 919 patients 522 patients POreRT to highly selected patients with high-risk features (R+) Re-irradiation with highly conformal techniques and only when a dose > 50 Gy can be delivered LC from 21% to 100% 2-years-OS of 48% (range, 24 81%); mucositis and/or dyspha-gia/pharyngitis (11 52%) late fibrosis (range, 2 44%) pharynx dysfunction (range, 2 70%). death up to 6,8%
46 Selected topics for talented When RT? Locally advanced stages Nasopharynx Postoperative RT New concepts, new trials How? and what? (to expect) 45
47 Nasopharynx: Anatomy Nasal choanae Clivus Soft Palate
48 Treatment Approach Stage I RT alone (10 yr LC and DSS > 90%) Stage II-IVb Concurrent chemoradiation + adjuvant chemotherapy Stage IVc (M1 disease) Chemotherapy RT for symptom palliation
49 RT Treatment planning IMRT LC > 90% Gross disease (primary + nodes): ~70 Gy High-risk CTV (bilateral RP, II-V, subclinical nasopharynx): Gy Low-risk CTV: Gy
50 NPC: Imaging
51 Induction Adjuvant Experimental arm all combinations Concomitant CRT + adjuvant
52 EBV: Prognostic Marker Pre-RT 1 wk post-rt Lin N Engl J Med 2004; 350: 2461
53 Rmyistwr
54 Nasopharynx: Summary RT is the curative modality RT alone: stage I CRT: stage II-IVb IMRT: standard of care High rates of local control (> 90%) Failures predominantly systemic Approaches to address to systemic relapse warranted Role of adjuvant chemotherapy? Risk stratification via EBV
55 Selected topics for talented When RT? Locally advanced stages Nasopharynx Postoperative RT New concepts, new trials How? and what? (to expect) 54
56 Poor / Imposible Volume Definition
57 Ipsilateral Level 3 Failure T2N1 oral tongue cancer, postoperative radiation Damast, et al. Head Neck 2012;34:
58 Submental Failure Damast, et al. Head Neck 2012;34:
59 Postoperative IMRT for Laryngeal Cancer Stoma > 60 Gy
60 Postop RT: Indications Multiple lymph nodes involved Extracapsular extension (ECE) Positive/close surgical margins Perineural invasion Lymphovascular invasion Deep (>5mm) invasion
61 Postop RT: Treatment Decisions May deliver RT as soon as the wound is healed Ideally initiate within 6 weeks after surgery Intermediate Risk: 60 Gy / 30 fractions High Risk (Positive margin / ECE): 66 Gy / 33 fx Concurrent systemic therapy in high risk patients
62 Combined RTOG/EORTC Analysis Bernier, Cooper. Head Neck 2005;27:843
63 Long Term Follow Up of RTOG 9501 Patients with Positive Margin and/or ECE Cooper et al. IJROBP 2012
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68 CRT vs RT alone: postoperative Loco-regional Disease free Survival
69 Selected topics for talented When RT? Locally advanced stages Nasopharynx Postoperative RT Laryngeal preservation New concepts, new trials How? and what? (to expect) 68
70 Anatomy Supraglottis Epiglottis Arytenoids AE folds False cords Ventricles Glottis True vocal cords Subglottis 5mm below glottis to bottom of cricoid
71 Treatment Approach Glottic, early stage: single modality RT: limited field Surgery: partial laryngectomy, cordectomy, laser Supraglottic, early stage: single modality RT: include regional nodes (bilateral levels II-IV) Surgery: partial laryngectomy + neck dissection Advanced stage: combined modality Organ preservation (concurrent chemoradiation): VA larynx, RTOG Surgery + adjuvant RT (+/- chemo) Selection: need to consider disease and patient characteristics
72 Dose and fractionation: T1 glottis (Yamazaki et al. IJROBP 2006) Prospective, Randomized Trial, pts with T1N0 Glottic Cancers Randomized to A)2.00 Gy/fraction 1)60 Gy in 30 fractions (<2/3 VC) 2)66 Gy in 33 fractions (>2/3 VC) B)2.25 Gy/fraction 1)56.25 Gy in 25 fractions (<2/3 VC) 2)63 Gy in 28 fractions (>2/3 VC) No significant increase in acute or chronic toxicity Conclusion: Use 225 cgy per fraction to 63 Gy for T1 Glottic Ca
73 RTOG LARYNX TRIAL 84% 72% 67% Median F/U 3.8 years Forastiere et al, NEJM 2003; 349:
74 Long Term Update of RTOG LARYNGEAL PRESERVATION OVERALL SURVIVAL Forastiere et al, JCO 2013
75 EORTC Laryngeal Preservation Trial R A N D O M I Z E Surgery Induction Chemotherapy (3 Cycles) RT Complete Responders* RT PR/NR Surgery XRT Induction Chemotherapy: Cisplatin and 5 FU J.L. Lefebvre et al, JNCI 88: , 1996
76 EORTC Laryngeal Preservation Trial Median F/U: 10.5yrs S + RT CT+ RT+ S No. of patients yr. PFS 8.5% 10.5% 10-yr. Survival 13.8% 13.1% Distant Mets. 36% 25% 10 yr. Alive w/larynx 8.7% J.L. Lefebvre et al, JNCI 88: , 1996; Annals Oncology, 2012
77 T4a Laryngeal Cancer
78 Patient selection/patterns of care/t4a (Grover et al. IJROBP 2015) NCDB 969 pts RT for T4a larynx cancer from Patterns of care/survival Results 2/3 treated with OP, 1/3 with initial TL
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80 Selected topics for talented When RT? Locally advanced stages Nasopharynx Postoperative RT Laryngeal preservation Re-irradiation New concepts, new trials How? and what? (to expect) 79
81 22 retrospective studies >550 pts 14% - 54% 5y 51% post y 5y Time recruitment Surgery RT
82 FDG-PET/CT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients) Sensitivity 83%, specificity 91% HPV positive tumors were associated with lower sensitivity(75%vs89%;p=0.01) specificity (87% vs 95%; p <0.005). FDG-PET/CT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residual/recurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined.
83 Ongoing RT practice oriented research 7 ECOG 1308: HPV + Induction CT + Cetuximab +IMRT/Cetuximab RTOG 1016: HPV + IMRT/CDDP vs IMRT/Cetuximab RTOG 1216: > 60 Gy + CDDP vs Docetaxel vs Docetaxel/Cetuximab ECOG 3311: HPV + risk adapted IMRT 50 vs 60 vs 66 Gy/CDDP RTOG 1221: HPV + IMRT 70 Gy vs surgery (PORT) RTOG 1305: IMRT 70 Gy/CDDP plasma EBV +/- Chemo/adjuvant 82
84 MOLECULAR IMAGE GUIDED RT (M-IGRT) GTV s aller Nodes ore Mis- atch GTV 20-40% 83
85 5 cm Macroscópic 5 cm TAC 5 cm 18 F-FDG PET Daisne et al, 2004
86 T3 N2c oropharynx: target adapted to M-IGRT 85
87 DOSE-ESCALATION BASED ON HIPOXIA M-IGRT A: GTV Hipoxia B: STANDARD PLAN C: Dose-escalation based on HIPOXIA gradients D: Dose-escalation based on HIPOXIA presence 86
88 TIME-IMAGE GUIDED RT (T-IGRT) 4D = time = movement = changes = adaptation = ART 87
89 Potential Target Deformations during Tx T-IGRT implications 88
90 Potential Dosimetric Changes Hansen et al Int. J. Radiation Oncology Biol. Phys. 2006;64:
91 4.2 mm INCREASED MEAN DOSE TO PAROTID 5 Gy Nishi et al, Radiother and Oncol 106 (2013)
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94 Selected topics for talented when, how and what HPV a d RT! De-escalatio? Not et but Locall ad a ced stages CRT + dose-escalation + AFX? induction CT? Nasophar CRT tailored volume Larynx preservation: CRT supra-tailored strategy Postoperati e RT risk adapted CRT Oligo-recurrent: 50% OS radical rescue ( 40% 2y OS re-rt) Ne co cepts M-IGRT / T-IGRT Ne trials Induction CT, viral status tailoring 93
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