Future Rt Cco (0sullivan)

How would we practice today using optimal human resources, technology and techniques ? “Achieving the Achievable” HEAD AND NECK CANCER Radiation Treatment Program Symposium “The Future of Radiation Treatment in the 21st Century” 2 – 3 March, Toronto Brian O’Sullivan MD, FRCPC Department of Radiation Oncology University of Toronto

Overview / Objectives • What is optimal practice and how do we deliver it in the present human and technology resource environment ? • Is their a rationale for using approaches requiring more expertise and intensive resources ? • How difficult is it to implement comprehensive IMRT for head and neck ? • Some problems in delivering very precise treatment techniques • Some non-traditional examples of the use of precision radiotherapy techniques (eg IMRT) • Additional barriers to practice today that conflict with available options

Treatment Options in HN SCC Early stage disease (T1 and small T2) – Single modality treatment (RT vs surgery) – Usually conservative RT regimens 50/20 f – 66/33 f Intermediate stage disease (large T2; small T3 ‘exophytic’; N1 some N2s) – Most usual: Radiotherapy +/- chemotherapy or Cetuximab – RT alone is intensified altered fractionation – If surgery performed the majority also need post-op RT (margins, # nodes, ECE) Advanced stage disease (large T3; T4; Some N2s and N3) – Most usual: concurrent Chemo-Radiotherapy or RT-Cetuximab – May use composite primary surgery with neck dissection. And post-op RT (margins, # nodes, ECE) and often Chemo (margins and ECE) – Functional and cosmetic deficits should be considered

Approaches to locally advanced Head and Neck Cancer • MARCH: Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck (n= 6,515 patients) Altered fractionation radiotherapy (RT) improved survival as compared to standard RT: Absolute benefit 3·4% 8% using Hyperfractionated RT with augmented dose Bourhis et al Lancet 2006 • MACH-NC: Meta-Analysis of Chemotherapy in Head & Neck Cancer (n=17,858) Chemotherapy (CT) added to RT, improved survival by 5% 8% using concurrent chemo-RT Bourhis et al ASCO 2004

Post-operative Adjuvant Treatment of head and neck Cancer Postop Radiation +/- Cisplatinum Postop Radiation +/- Cisplatinum NEJM 2004 Head and Neck 2005

Examples of Schedules with or without chemotherapy Challenge Multi-phased Single Phase IMRT is the (2Gy / fraction) (variable target fractions) Radiobiology 7 wk course 7 wk course 6 wk course PTV1 50 Gy in 25 f 56 Gy in 35 f 54 Gy in 30 f ‘Microscopic’ (Cord shield 40 Gy) (No cord shield) PTV2 70 Gy in 35 f 70 Gy in 35 f 66 Gy in 30 f ‘Gross’ PTV3 60 Gy in 30 f 63 Gy in 35 f 60 Gy in 30f <2 cm node ** *Requires cord shielding, electrons, low neck matching (3 or 4 ‘phases’) **Intermediate dose (PTV3) especially useful for small nodes at the level of the brachial plexus, or for dubious small nodes in the radiology report

What is optimal ? • Potential to include the Target Objects properly • Spare as much normal tissue as possible, and especially normal tissues where function is compromised – Critical neurological tissues – Salivary function – Swallowing mechanism – Mandible • Options for augmentation (combined modality) are numerous (available skills and resources affect choice) • Several balances in decision-making re: technique – Balance against resources to accomplish – What drives the decision ? • Inclusion of the target • Avoidance of normal tissues • Accomplish both: “Include and avoid”

Prescribed Median Minimum % Intended Dose (Gy) Dose to GTV Dose Phase I 40 38.4 96% Phase II 10 7.3 73% (cord and brain stem shield) Phase III 10 6.5 65% (chiasm shield) Phase IV 6 4.0 67% (High Energy GTV with dose template boost) (outlined using archived MRI restored from DAT )

Dose coverage issues: T4 disease with bulk and normal • Surprisingly good outcome historically with RT alone and 2D planning despite tissue inadequate coverage - about 70-75% constraints control in major centres • Landmark Intergroup 0099 Chemo-RT had very poor control in the control arm • May have shown us that concurrent chemotherapy can compensate for inadequate coverage in multicentre setting • Also potentially cure could be higher if local control more optimal; alternatively some of the effect of chemo may disappear

IMRT in NPC • Many of these patients were treated with concurrent chemotherapy • Need new approaches to improve systemic outcome

25% recovery of IMRT significantly pre-RT stimulated better than CRT parotid flow in terms of parotid sparing, and improved QOL (SF36, EORTC)

• 70-Gy isodose confomed around the PTV for the gross tumor and 59.4 Gy to the ipsilateral neck • 54 Gy to contralateral neck PTV • Simultaneously

Lee at al 2006

3-yr actuarial CBRT IMRT P-value Local progression free 85% 95% 0.17 Regional PF 95% 94% 0.90 Locoregional PF 82% 92% 0.18 Distant–free 85% 86% 0.78 Disease-free 76% 82% 0.57 Overall survival 81% 91% 0.10 Treatment-related death 3 0 Tube dependent (2yr) 21% 4% 0.02 Lee at al 2006

Technical delivery Tissue sparing potential of IMRT Conventional conformal plan in 2/3 phases Improved target coverage in numerous sites

• Without mucosal dose objective IMRT will treat a larger amount of mucosa with clinically relevant doses compared to conventional RT • With dose objectives, the reverse is true up to 30% reduction in the mucosal volume in the high-dose region compared with conventional RT (p < 0.01).

Caveats about IMRT for Head and Neck Cancer Preliminary Results: Extraneous and unusual/unexpected dose deposition: “Nausea, Vomiting, and Other Unanticipated Toxicities During IMRT for Head and Neck Squamous Cell Carcinoma” • Headache • Nausea and vomiting • Hair • Eyes and lacrimal glands • Lips • Larynx • Skin • Mucosa JW Fan, DI Rosenthal et al 2007: ASTRO / ASCO / AHNS Palm Spring

“Labored swallowing, prolonged eating times, and the limited range of foods that can be swallowed lead to disruption of relationships and social isolation.”

50 Gy Pretreatment 3 months post XRT/chemo 50 Gy Eisbruch et al IJROBP 60(5) 1425,2004 Standard IMRT Sparing IMRT

N = 142 • Saliva flow rates +/- stimulation • 18 months after radiation therapy • mean doses of 0, 20, 30, and 40 Gy, respectively. Conclusions: • Saliva production is affected significantly by radiation, • but with doses <25–30 Gy, recovery is substantial and returns to pretreatment levels 2 years after RT.

3 Eras of IMRT Provision at PMH (Full inverse planning) Hesitation Implementation 600 / yr Accomplisment 300 250 Number of patients 200 150 100 50 0 Jan-01 Jan-02 Jan-03 Jan-04 Jan-05 Jan-06

Building an IMRT Factory, Courtesy of Stephen Breen • ICRU 62 • Descriptive • General •R2CTV56 • Documented • Retrospective • Adapted by audit planners Experience-driven •Contours (all) •Plan (Physics) Product: •Daily Imaging High-volume •(RT unit) Head & Neck IMRT Programme

Quality Assurance Steps Volumes Appropriate CT Sim Nomenclature Consistent Contours Protocols Planning Coverage Doses Patient acceptable Positioning Delivery Acceptable (measurement or Treatment secondary calculation)

This H&N structure nomenclature, contouring guidelines and terminology system was implemented to: • facilitate multidisciplinary communication between radiation oncologists, planners and physicists • facilitate quality assurance review of H&N planning • enable the automation of complex programming tasks within our planning system • facilitate audit of outcomes Slide: courtesy John Kim

The Primary – the Radiation Oncologist’s Role is to Contour the Gross Objects and the Putative microscopic risk area and label appropriartely GTV CTV70 CTV56 Corresponding PTVs PTV70 PTV56 (Planners role) T4a N2c M0 Tongue Base Cancer Slide: courtesy John Kim

The Neck Right neck shown only Rretro RretroCTV70 RCTV56 R2A3 R2A3CTV70 Corresponding PTVs RretroPTV70 RPTV56 R2A3PTV70 T4a N2c M0 Tongue Base Cancer Slide: courtesy John Kim

Daily Online Setup Correction

Cone-beam CT Images of the Head & Neck Cone-beam CT datasets fully 3D. Permit arbitrary reformatting for interpretation. Well-suited to image-guidance applications. Exquisite anatomical detail possible

Random Uncertainty: weekly cone beam studies

NCI – All Ireland - Nov 2006 Daily Cone beam images can: 1. TrackCT sim Planning response Day 1 Day 7 2. Determine dose received 3. Guide adaptation 4. Determine PTVs Data from David Hwang Similar data on spinal cord Mehrdad Vakilha Day 14 Day 21 Day 35

Evaluation of a Semi-Automated Segmentation Method for Delineation of Organs at Risk and Lymph Node Target Volumes in Head and Neck Radiotherapy Planning Michael Kaus Philips Radiation Oncology Systems, Madison, WI J. Kim, B. O'Sullivan, A. Mansouri, S. Breen, L. A. Dawson, D. A. Jaffray Radiation Medicine Program, Princess Margaret Hospital, University Health Network University of Toronto, Toronto, ON, Canada ASTRO 2006

The potential clinical benefits A population-based semi-automated segmentation – assist physician contouring of complex H&N cases – improve efficiency of contouring tasks – facilitate implementation of image- guided and adaptive RT

Is treating T1 Larynx with IMRT reasonable ? • Ultrasonography used to measure difference (R vs L) in carotid wall thickness (intima-media thickness) in 42 unilaterally irradiated parotid cancer patients. • 5 had a vascular ischaemic event (3 TIA, 2 infarction) at a median of 11 years (range 5.9–13.1 years) following RT. • In 4 of these 5, it occurred in the area of the irradiated carotid artery. The mean difference in IMT was 1.1 mm. • One patient developed cerebral infarction contra-lateral to the side of RT and showed no difference in IMT (0 mm).

Is treating T1 Larynx with IMRT reasonable ? 50 Gy 50 Gy Traditional Volume (IMRT planned) Optimal Volume (IMRT planned) • Where the target is not compromised • Where normal tissues can be spared • Why not place the dose where you want it ? • Potential gains: carotid protection; arytenoid protection

Is treating BCC with IMRT reasonable ? • Where the target is not compromised • Where normal tissues can be spared • Why not place the dose where you want it ? • Potential gains: Eye preservation

Is treating BCC with IMRT reasonable ? Patient is ANED at 5 years. Has a small cataract

The Role of PET: • Staging / assessment • 8 wks post • Prediction (probably chemo-RT need more than FDG) • Determination of • Anatomic Response imaging negative • Neck Pre-chemo RT dissection positive in 4 nodes • ANED 3 years later

Observer variability CT, CECT, PETCET • Do observers draw the same volumes on CT and CT-PET? – 8 observers (6 RO, 2 NR) – 10 H&N patients – GTVs on CECT, CT-PET, CT CECT PETCT – Involved nodes Findings: • Specialty makes no difference • We cannot confirm the perception that FDG-PET reduces uncertainty in primary tumor target volume delineation • Differences are small, overwhelmed by inter-observer differences • Lymph node delineation may be facilitated • Suspicion – PET aids concurrence De Silva S et al ASTRO 2005 and 2006

A Phase III Study of Radiotherapy ± Cetuximab (C225) in Patients with Locally Advanced HNSCC Local-Regional Control Survival Probability Probability RT + C RT + C RT RT+C RT RT+C Patients 213 211 Patients 213 211 Events 105 90 RT Events 117 93 Median 19 m 36 m Median 28 m 54 m RT 1-Year 59% 69% 2-Year 55% 62% 2-Year 48% 56% 3-Year 44% 57% Log rank p 0.02 Log rank p 0.02 Months Months RT RT-E Any Gd 3-4 Any Gd 3-4 Subgroup analyses (HR): • 26% rc’d once-daily fractionation = 1.01 Skin 91 18 97 34 Mucositis 93 52 91 54 • 18% twice-daily fractionation = 0.74 Dysphagia 63 30 64 25 • 56% concomitant boost radiotherapy = 0.64. Bonner et al NEJM 2006

How should we practice ? • Use Level 1 evidence based ev evidence for dose fractionation regimen • Concerning Technique – Do not compromise on the targets – Spare the normal tissues when this is possible • Place the dose where you want it and where it needs to go • Often that means IMRT in complex Head and Neck cancers

Planning & Treatment Team • Radiation Oncology – A. Bayley, B. Cummings, L Dawson, J. Kim, B. O’Sullivan, J. Ringash, J. Waldron • Physicists – S. Breen, J. Borg, A. Damyanovich, B. Zhang • Team 1 Planners – J.Roussos, M.Ryan, D.Sajac, I Kaminsky, S.Pillay, S.Pizzale, C.Rocca, L.Chau, P. Rakaric, S.Singh, M.Glinnyi, J.Giovinazzo • Therapists (33) – S.Singh, S. Pizzale, I.Kaminsky, C. Rocca, L.Chau, P. Rakaric C.Bradley, E.Borodina, C.Cerase, C.Chow, C.Dupuis, M.Engel, C.Field, A.Fung, J.Giovinazzo, M.Glinnyi, B.Guibord,, S.Hua, S.Huang, J.Loudon, L.Johnson, K.Man, D.Marshall, , E.Mettrick, G.Parlan, S.Pillay, F.Sie , W.So, A.Sperdutti, M.Tamerou, W.Tang, V.Truong, G.Wu

Additional Key Team Members Medical Imaging Head and Neck Surgery Image Management Translational Science Pat Gullane David Jaffray Fei-Fei Liu Ann Keller Ralph Gilbert Michael Sharpe Carlo Bastianutto Eugene Yu Angelo Hui Jon Irish Jeff Siewerdsen Dale Brown Bern Norrlinger Sizanne Kame-Reid RMP IT Infrastructure Ting Jun Zhang Ian Witterick Doug Moseley Pathology Jerry Freeman Terry Michaelson Anna Kirilova Peter Neligan Bayardo Perez- Stuart Rose Kristy Brock and team Ordonez Medical Oncology Lillian Siu Nursing, Nutrition, Psycho-social Eric Chen The Susan Grange Family Bartley-Smith/Wharton Fund of the PMH Foundation CARO/ACURA Fellowship Program Elekta Oncology Systems Varian Medical Systems

Future Rt Cco (0sullivan)

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