An Introduction to Head & Neck Radiotherapy. Vincent GREGOIRE, M.D., Ph.D. Head and Neck Oncology Program, Radiation Oncology Dept. & Center for Molecular Imaging and Experimental Radiotherapy, Université Catholique de Louvain, St-Luc University Hospital, Brussels, Belgium Myths and facts in Oncology: the challenge of local therapies not cure (distal recurrence) not cure (local recurrence) 18% 37% 12% Radiotherapy Chemotherapy 5% 6% 22% Surgery + radiotherapy Surgery Myths and facts in Oncology: the challenge of local therapies in HNSCC Tumor Control Probability (TCP) Dose-response curve for neck nodes 3 cm not cure (distal recurrence) 25-35% 1-15% >>12% Chemotherapy % 22% Surgery >6% Tumor control (%) 12 1 8 6 4 not cure (local recurrence) Radiotherapy Surgery + radiotherapy ± chemo/biological ± chemo/biological modifiers modifiers 2 45, 55 65 75 85 95 T o t a l d o s e ( G y ) Bataini et al, 1982 Normal Tissue Control Probability (NTCP) Uncomplicated tumor control: Therapeutic Ratio Tumour control Human Monkey Effect Unacceptable normal tissue damage Uncomplicated tumour control Dose Baumann et al., Strahlenther Onkol 17: 131-139, 1994
Uncomplicated tumor control: Therapeutic Ratio Uncomplicated tumor control: Therapeutic Ratio Effect Tumour control Unacceptable normal tissue damage Effect Tumour control Unacceptable normal tissue damage Uncomplicated tumour control Uncomplicated tumour control Dose Dose Less effect per gray at low doses/# Fractionation sensitivity n N = 1 2 5 1 2 Typical dose per fraction 1.8-2 Gy for standard fractionation 1.1-1.3 Gy for hyperfractionation Late effects Acute effects + tumor response Total dose (Gy) Withers et al, 1983 Hyperfractionation Decreased dose per fraction EORTC Hyperfractionation trial in oropharynx cancer Oropharyngeal Ca T2-3, N-1 Conventional fractionation Hyperfractionation ( pure, MFD) 2. Gy/ f, 1x/ d 6 weeks= 6 Gy 1. Gy/ f, 2x/ d 6 weeks= 6 Gy 8.5 Gy - 7 fx - 7 wks vs 7 Gy - 35-4 fx - 7-8 wks p =.2 p =.8 LOCAL CONTROL SURVIVAL Hyperfractionation ( dose escalated, MFD) 1.2 Gy/ f, 2x/ d 6 weeks= 72 Gy Hyperfractionation ( pure, SFD) 1.5 Gy/ f, 1x/ d 6 weeks= 6 Gy Years Years Horiot 1992
EGFR and repopulation during RT FaDu hscc EGF-Receptor Radiobiological and clinical issues in IMRT for HNSCC Influence of overall treatment time on HNSCC local control 12 TCD 5 (Gy) 6 T clon = 9.8d [;21] T clon = 3.4d [1.7;5] Day 22 [13;3] RDI pab Radiobiological hypoxia 1 2 3 Tage nach 1. RT Petersen et al., IJRB 79: 469-477, 23 Withers et al, 1988 Accelerated fractionation (AF) Shortened overall treatment time, dose per week > 1 Gy IIIII IIIII IIIII IIIII IIIII IIIII IIII 64-68 Gy/ 2. Gy/ 6.5w DAHANCA 6&7 - H&N SCC - stage II-IV (n=1476) IIIIII IIIIII IIIIII IIIIII IIIIII IIIIII 64-68 Gy/ 2. Gy/ 5.5w CF 7Gy/ 2. Gy/ 7w CB 7Gy/ 2. Gy/ 5w AF/HF 54Gy/ 3x1.5Gy/ ti=6h/ 12d Expectations: Increased tumor control Increased early reactions Unchanged or decreased late damage (AF/HF and/or reduced total dose) Overgaard et al. Lancet, 23 H&N SCC: MACH-NC C225 anti EGFR Ab; A 431 tumours: c 1x 3x SD18Gy 18Gy + 1x 18Gy + 3x RT SD/1xC225 SD/3xC225 Milas et al. Clin Cancer Res 6: 71-78, 2 Nasu et al., IJROBP 51: 474-477, 21 Pignon, Lancet, 2
Efficacy EGF-R inhibitor and RxTh in HNSCC Phase III Study Design Erbitux + RT Stratify by Karnofsky score: 9-1 vs. 6-8 Regional Nodes: Negative vs. Positive Tumor stage: AJCC T1-3 vs. T4 RT fractionation: Concomitant boost vs. Once daily vs. Twice daily Arm 1 (RT) R A N D O M I Z E RT Radiation therapy Locoregional Control Erbitux + RT Arm 2 (RT+E) RT Radiation therapy + Cetuximab, weekly Bonner, 24 Log-rank p Image-Guided Radiation Therapy in HNSCC 1963 Overall Survival Bonner, 24 Image-Guided Radiation Therapy in HNSCC 1937 19 Intensity Modulated Radiation Therapy (IMRT) 2 1976
Clinical outcome of IMRT in head and neck cancer GUH (3) Nasal cavity Paranasal sinus UCSF (2) Nasopharynx WU (4) All sites CUP U-M (1) Oral cavity Oro- hypopharynx Larynx (1) Eisbruch 1999, Dawson 2: University of Michigan (U-M) (2) Lee 22: University of California at San Francisco (UCSF) (3) Claus 22, Duthoy 23: Ghent University Hospital (GUH) (4) Chao 23: Washington University, St. Louis (WU) Cumulative incidence Cumulative incidence 1..9.8.7.6.5.4.3.2.1. 1..9.8.7.6.5.4.3.2.1. Head (3-5 FP) 1 2 3 4 5 6 7 8 9 1 Deviation from the isocenter (mm) Neck (3-5 FP) 1 2 3 4 5 6 7 8 9 1 Deviation from the isocenter (mm) Cumulative incidence 1.9.8.7.6.5.4.3.2.1 Shoulder (4 & 5 FP) 1 2 3 4 5 6 7 8 9 111121314 Deviation of the isocenter (mm) Image acquisition Dual detector spiral CT 2.7 mm collimation, pitch.7, reconstruction of 2-2.5 mm Display matrix of 512 x 512 pixels Contrast enhancement (interstitial and blood vessel contrast) Conformal radiotherapy: 3D reconstruction Conformal radiotherapy: image display
Target volumes in Radiation Oncology: ICRU definition Conformal radiotherapy and IMRT in Head and Neck Tumors Gross Tumor Volume: GTV Clinical Target Volume: CTV Planning Target Volume: PTV Organs at Risk: OAR Planning Organ at Risk Volume: PRV ICRU report 62, 1999 Definition of the extend of the CTV in the neck Incidence of pathologic lymph node metastasis in oropharyngeal tumors State of the art Predictive pattern of lymph node involvement in HNSCC Selective neck treatment (irradiation or dissection) for selected N stage Clinically N neck (n=48) 2% 25% 19% 2% 8% Clinically N + neck (n=165) 15% 71% 42% 9% 27% From Candela, 199 Oropharyngeal Carcinoma Conformal radiotherapy and IMRT in Head and Neck Tumors Stage Ipsilateral neck Controlateral neck N-N1 (Ib 1 )-II-III-IV + RP for post. II-III-IV + RP for post. pharyngeal wall tumor pharyngeal wall tumor N2a-N2b Ib-II-III-IV-V +RP II-III-IV + RP for post. pharyngeal wall tumor N2c According to N stage on According to N stage on each side of the neck each side of the neck N3 I-II-III-IV-V +RP ± adjacent II-III-IV + RP for post. structures according to clinical pharyngeal wall tumor and radiological data 1 Ib only if extension to oral cavity Grégoire et al., 2 DAHANCA: http://www.dshho.suite.dk/dahanca/guidelines.html EORTC: http://www.eortc.be/home/ Radio/EDUCATION.htm RTOG: http://www.rtog.org/hnatlas/main.htm
CT-based delineation of lymph node levels in the neck: Brussels- Rotterdam consensus guidelines LIa LIb RP LII CT-based delineation of lymph node levels in the neck: Brussels- Rotterdam consensus guidelines Level Ia and Ib Level III symphysis menti / platysma hyoid bone / submandibular gland Lat. ant. belly of digastric m. (Ia) mandible / platysma (Ib) Med. ant. belly of digastric m. (Ib) Cra. geniohyoid m./mandible (Ia) mylohyoid m, submandibular gland (Ib) Cau. hyoid bone Ant. sternohyoid m./ sternocleidomastoid m. Post. sternocleidomastoid m. Lat. sternocleidomastoid m. Med. paraspinal m. int. carotid artery Cra. hyoid bone Cau. cricoid cartilage Ant. Post. LIII LV Mr H. D. (77 years): T3-N-M base of tongue (ICD-1: C1) Antique (7 fields) Rx 6 MV 4 Gy Elect 8 MeV 1 Gy Rx 6 MV 3 Gy Rx 6 MV 5 Gy Art nouveau (1 fields, 12 segments ) SRAO SLAO Post. Seg. 1 Art nouveau (11 fields, 12 segments ) Ant. Post. Seg. 2 RAO Rx 6 MV 5 Gy RPO LPO Ant. LPO Rx 6 MV 2 Gy LAO1 LAO2
Forward planning IMRT «human optimization» Inverse planning IMRT Spare cord Spare left parotid 15 segments 1 levels Cummulative % of MUs Segment # 1 6. Dose-volume constraints & weights for PTV and OARs optimization algorithms Penalty function Courtesy of C. Field Left parotid ADC Dose: 3 x 2. Gy Spinal cord Left parotid Right parotid PTVs Hypopharyngeal SCC T4-N-M Dose: 25 x 1.8 Gy bid Right parotid Spinal cord Inner ear PTV
Objective assessment Subjective assessment Maximum secretion (%) 1 9 8 7 6 5 4 3 2 1 Bilateral irradiation Unilateral irradiation R=,77 SOMA scale (arbitrary units) 12 1 8 6 4 2 Bilateral irradiation Unilateral irradiation R=,63 1 2 3 4 5 6 7 Mean parotid dose (Gy) 1 2 3 4 5 6 7 Mean parotid dose (Gy) Oral cavity, oro- hypopharynx, larynx parotid-sparing 3D-CRT Nasopharynx 88 patients irradiated with parotid sparing saliva flow rates for 152 parotid glands dose / volume / function relationships parotid mean dose < 26 Gy is planning goal Lyman NTCP: n = 1, m =.18, TD5=28.4 Gy 67 patients treated April 1995-October 2 Stages I (n=8); II (n=12); III (n=22); IV (n=25) Non-keratinizing (n=34); undifferentiated (n=33) IMRT by compensators, MLC or MIMiC Conventional fields to treat the neck 12/58 patients developed recurrences: 1 in GTV region 2 in elective region (1 st echelon) Limits: local control in GTV area 4-year actuarial distant metastasis-free rate: 66% Limits: distant metastasis rate Lee et al. IJROBP 53: 12-22, 22 Paranasal sinus -Number of patients 44 -R surgery 44 - Male/female ratio 9/1 - Median age at diagnosis 6 years [3-76] - Subsite Ethmoid sinus 33 (75%) Maxillary sinus 6 (14%) Nasal cavity 5 (11%) Complications of postoperative radiation therapy for ethmoid sinus tumors period 1985-1994 1995-1998 1999-22 RT 2D 3D IMRT PTS 19 11 33 Optic neuropathy 2 Dry eye syndrome 5 2 Limits: local control in T4(b) W. Duthoy, 23
Duration of treatment planning procedure 2D planning Forward planning Inverse planning (St-Luc) (Edmonton Cancer center) Volume delineation -.25h 2-3h 1-1.5h Planning.25h 2-8h 1-2h Individualized QC h.25h 1h Treatment (per session) 1-15 min 2-25 min 15 min Activity-Based Costing (ABC) in radiotherapy Type of treatment Cost (EURO) Palliative irradiation (1 fractions) 1,686 Breast irradiation (25 fractions) 2,71 H&N irradiation (35 fractions) 4,724 From Azoury, 2 CT MRI (T2) FDG-PET PRE-R/ (Week 2) WEEK 3 (Week 4) WEEK 5