Oropharyngeal carcinoma State of the Art

Oropharyngeal carcinoma State of the Art Pr. Jean Bourhis Institute Gustave Roussy Ville juif, France - Among HNSCC what are the specificities of the oropharyngeal sub site? - Frequent among HNSCC - More HPV related carcinomas (up to 5-75%) - Importance of IMRT for parotid sparing - Are the results obtained in the orophaynx different from the rest of HNSCC? - Relative consensus on «general treatment guidelines» Multidisciplinary approach in oropharynx carcinomas T1-T2 T3-T4* Surgery (IM)RT (Uvula-tonsil) Surgery Inoperable (brachy) or non infiltrating (IM)RT-CT or HPV) (IM)RT-erbitux Post-op RT +/- CDDP * induction chemo revisited 1

How different are the oropharyngeal carcinomas as compared to the other HNSCC? How different are the oropharyngeal carcinomas as compared to the other HNSCC? For altered fractionation Is the effect of altered fractionated RT any different in oropharynx sub site? MARCH database of randomized trials (197-1999) Hyperfractionated or accelerated RT Conventional RT 2

MACH-NC Meta-Analysis of Chemotherapy in 1 Head & Neck Cancer Overall results (all sites) Loco regional control 1 Risk of recurrence (%) 8 6 4 2 Hyperfractionation 57.9% 48.5% Risk of recurrence (%) 8 6 4 2 Acceleration w / o total dose reduction 47.5% 4.2% 1 2 3 4 5 6 7 Time from randomisation (Years) 1 1 2 3 4 5 6 7 Time from randomisation (Years) 1 Alt. fractionated RT Conventional RT Risk of recurrence (%) 8 6 4 2 IGR, June 24 59.8% 57.5% 1 2 3 4 5 6 Time from randomisation (Years) Acceleration with total dose reduction 7 Risk of recurrence (%) 8 Absolute difference at 5 years: 6.4 ± 1.3% 6 52.9% 4 46.5% 2 All the 3 groups together 1 2 3 4 5 6 7 Time from randomisation (Years) Altered fractionated RT database (N > 65 patients randomized) Characteristics Altered fractionated RT (n=3,65) Conventional RT (n=3,423) Site of tumour - Oral cavity 13% 13% - Oropharynx 44% 44% - Larynx 34% 33% - Hypopharynx 8% 8% - Others 2% 2% Stage - I 9% 9% - II 18% 16% - III 28% 29% - IV 46% 45% Altered fractionated versus conventional RT : survival by site Category No. Deaths / No. Entered Alt. fractionated RT Control O-E Variance Hazard Ratio Interaction test Age 5 or less 374/68 394/631-45.6 184.5 51-6 736/1172 719/1128-19.4 355.5 61-7 785/1221 736/1125-29.3 371.4 71 or over 48/561 376/524 14.2 191. Sex Male 1916/35 1839/2777-93.6 924.9 Female 388/63 387/632-6. 187.1 p =.2 p =.39 Performance status 117/1878 13/182-64.2 57. 1 959/1348 9/1235-8.4 454.6 2 or 3 297/367 269/326-14. 124.2 Stage I-II 397/95 355/862-2.8 184.2 III 639/124 681/1-62.4 321.8 p =.23 p =.1 IV 1265/1655 1189/1542-43.4 62.4 Site Oral 282/37 278/346-15.7 134.9 cavity Oropharynx 115/1673 1127/1576-53.9 561.2 Larynx 586/1231 553/1142-19.9 276.8 p =.2 Hypopharynx 235/297 227/282-12.3 11.7 Others 52/69 45/72 8.9 19.6..5 1. 1.5 2. fractionated better Control better Alt. RT 3

MARCH: Overall survival by age (incl. oropharynx) Hazard ratio Category No. Events / No. Entered (Alt. fractionated RT/Control) HR [95% CI] 5 or less 768 / 1 311 51-6 1 455 / 2 3 61-7 1521 / 2 346 71 + 784 / 1 85.78 [.65 -.94].95 [.83-1.9].92 [.81-1.6] 1.8 [.89-1.3] Total 4 528 / 7 42.92 [.86 -.97] Test of interaction: p =.2..5 1. 1.5 2. Alt. Frac. RT better Control better Test for trend: p =.7 Alt. fractionated RT effect p=.2 How different are the oropharyngeal carcinomas as compared to the other HNSCC? For Chemo-RT A few pure oropharynx randomized trials 4

Example of specific trial : RT-CT 94-1 trial 7 Gy / 7 weeks N = 226 T3-T4 oropharynx Non operated 7 Gy / 7 weeks + Carbo-5FU 1 GORTEC 94-1 : oropharynx 9 8 LR 7 control rate (%) 6 5 48% 4 LOCO-REGIONAL CONTROL p =,2 > concomitant t RT - CT 25% 3 2 > RT alone 1 months after randomization 1 2 3 4 5 6 7 8 1 9 GORTEC 94-1 : oropharynx 8 7 Overall 6 survival rate (%) 5 OVERALL SURVIVAL 7% 4 3 23% 2 16% 1 > RT / CT > RT months after randomization 1 2 3 4 5 6 7 8 p (Mantel-Cox Logrank) =,6 5

Concomitant chemo : the price to pay? GORTEC 94-1 : oropharynx : Acute toxicity RT RT+CT P value Mucositis Patchy 32 57.5 Confluent 7 14 Skin Erythema. Dry desquamation 47 44.2 Moist desquamation 12 23 Nutritional status Weight loss >1% of body mass 6 14.4 Feeding tube 15 36.2 Haematology Neutrophils <.9 4.4 Platelets < 5 1 6.4 Hemoglobin < 8 g/1ml 3.5 Toxic death 1 GORTEC 94-1 : oropharynx : Late toxicity 6

Is the effect of adding chemotherapy to RT any different in oropharynx sub site? MACH-NC database of randomized trials (1965-2) RT-CT RT MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer PERCENT 19 Chemotherapy data base ( N=9615 pts randomized ) 15 1 5 Oral cav. Orop. Larynx Hypop. Others Site of Primary Treatment: Chemotherapy No Chemotherapy MACH-NC Effect of concomitant CT-RT versus RT (survival by site) Meta-Analysis of Chemotherapy in Head & Neck Cancer 17% + 5 23% + 4 22% + 6 16% + 6-3% + 11 7

MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Chemotherapy is more beneficial in younger patients (N = 9615 pts randomized) Age Absolute survival benefit at 5 years < 5 12% 51-6 9% p<.1 61-7 4% > 71 1.5% IGR, June 24 MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Platin-5FU : concomitant versus induction 1 Chemotherapy Control 8 of recurrence (%) Risk o 6 4 2 Local failure 63.2 % 49.7 % Distant failure 18.9 % 16 % 1 2 3 4 5 6 7 8 Time from randomisation (Years) of recurrence (%) 1 Chemotherapy Control 8 Local failure 6 5.9 % 49.1 % 4 Risk o Distant failure 2 15.6 % 12.1 % 1 2 3 4 5 6 7 8 Time from randomisation (Years) Concomitant Absolute difference at 5 years: Local failure: -13.5 ± 2.8 % Distant failure: -2.9 ± 2.7% Neoadjuvant Absolute difference at 5 years: Local failure: 1.8 ± 2.3 % Distant failure: -3.5 ± 2. % MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Concomitant PF > induction PF ; but TPF > PF 1 Chemotherapy Control 8 of recurrence (%) Risk o 6 4 2 Local failure 63.2 % 49.7 % Distant failure 18.9 % 16 % 1 2 3 4 5 6 7 8 Time from randomisation (Years) of recurrence (%) 1 Chemotherapy Control 8 Local failure 6 5.9 % 49.1 % 4 Risk o Distant failure 2 Taxotere-PF 15.6 % versus PF, Vermorken 24 12.1 % 1 2 3 4 5 6 7 8 Time from randomisation (Years) Concomitant Absolute difference at 5 years: Local failure: -13.5 ± 2.8 % Distant failure: -2.9 ± 2.7% Neoadjuvant Absolute difference at 5 years: Local failure: 1.8 ± 2.3 % Distant failure: -3.5 ± 2. % 8

TAX324 : Survival 1 9 8 Log-Rank P =.5 Hazard Ratio =.7 Survival Probability (%) 7 6 5 4 3 TPF PF 2 1 TPF (n=255) PF (n=246) 6 12 18 24 3 36 42 48 54 6 66 72 Survival Time (months) Number of patients at risk TPF: 255 234 196 176 163 136 15 72 52 45 37 2 11 PF: 246 223 169 146 13 17 85 57 36 32 28 1 7 Posner M, et al. N Engl J Med 27;357:21-31. MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer 1 of recurrence (%) Risk o 8 6 4 2 Chemotherapy Control TPF : a new standard for induction CT in HNSCC Local failure 63.2 % 49.7 % Distant failure 18.9 % 16 % 1 2 3 4 5 6 7 8 Time from randomisation (Years) of recurrence (%) Risk o 1 8 6 4 2 Chemotherapy Control TPF TPF Local failure 5.9 % 49.1 % 15.6 % Distant failure 12.1 % 1 2 3 4 5 6 7 8 Time from randomisation (Years) Concomitant Absolute difference at 5 years: Local failure: -13.5 ± 2.8 % Distant failure: -2.9 ± 2.7% Neoadjuvant Absolute difference at 5 years: Local failure: 1.8 ± 2.3 % Distant failure: -3.5 ± 2. % With no significant difference in toxicity MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Combining TPF induction + concomitant? 1 Chemotherapy Control 1 Chemotherapy Control 8 Local failure 8 63.2 % 6 Local failure 6 TPF 5.9 % 49.7 % 4 49.1 % 4 Distant failure? TPF Distant failure 18.9 % 2 2 15.6 % 16 % 12.1 % 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 Time from randomisation (Years) Time from randomisation (Years) of recurrence (%) Risk o of recurrence (%) Risk o Concomitant Absolute difference at 5 years: Local failure: -13.5 ± 2.8 % Distant failure: -2.9 ± 2.7% Efficacy? / toxicity? Neoadjuvant Absolute difference at 5 years: Local failure: 1.8 ± 2.3 % Distant failure: -3.5 ± 2. % 9

How different are the oropharyngeal carcinomas as compared to the other HNSCC? For erbitux Erbitux + Radiotherapy : a good ratio efficacy / toxicity in locally advanced HNSCC ERBITUX + RT in locally advanced HNSCC : a phase III randomized study (the most important sub site was oropharyngeal cancer) stage III and IV non metastatic HNSCC R RT (n=213) ERBITUX + RT (n=211) Primary endpoint: Locoregional control Bonner J, et al. N Eng J Med 26;354:567 578 1

RT + cetuximab : local-regional control (more effect was seen in oropharynx (subgroup?) P =.2 31 ival probability Survi 1..9.8.7.6.5 Benefit also found with Erbitux + chemo in relapse / metastatic patients : Extreme randomized study :.4.3 Cetuximab + CTX.2.1 Log-rank : p =.3 CTX only. 3 6 9 12 15 18 21 24 Patients at risk Survival time (months) 222 184 153 118 82 57 3 15 3 22 173 127 83 65 47 19 8 1 Vermorken JB, et al. ASCO 27 (Abstract No. 691; updated information presented) Oropharyngeal carcinomas : Importance of IMRT 11

IMRT, intensity modulated RT IMRT in Oropharyngeal carcinoma 1) Better normal tissue protection (parotid) 2) Dose escalation to the tumor Potentially Interesting since : - Most relapses in the GTV - Dose effect relationship IMRT : increased dose conformality clinical benefit? IMRT in oropharynx carcinomas : carcinological results Mendenhall W. JCO 26 12

IMRT in oropharyngeal carcinomas : a multicentric prospective study of patients necessitating a bilateral IMRT (M Lapeyre) GORTEC : Loco-regional & survival (N= 93) 1,75,5 Contrôle loco-régional,25 Survie globale Recul moyen : 14 mois (3-37) 6 12 18 24 3 36 42 Late xerostomia (N =93) (RTOG-EORTC scoring system) 1,,8,6,4 grade -1 grade 2-3,2, 3 mois 6 mois 12 mois 18 mois 13

Salivary toxcity at 1 year Grade 2-3 Controlateral lparotid : Dose moy < 3 Gy Dose moy > 3 Gy 16 % 43 % p=,5 QOL : 7 scores in favor of IMRT Scoring of symptoms Dolor (HN) Deglutition Eating in public Dental Pbs Opening mouth Mouth dryness Stick saliva RTE conv IMRT p 33,5 [28,5] 35,1 [26,2] 38,2 [31,8] 34,9 [4,] 48,3 [37,7] 83,1 [25,5] 76,6 [3,1] 21,5 [25,] 23, [25,6] 26,9 [3,3] 19,5 [3,6] 28,8 [31,9] 57,2 [33,2] 47,1 [34,7],1,1,3,2,1 <,1 <,1 Graff P et al Int J Radiat Oncol Biol Phys. 27 Apr 1;67(5):139-17 Dose escalation with IMRT in oropharyngeal carcinomas? An ongoing randomized study with / wo IMRT (GORTEC 24-1) Oropharynx + OC Stage II-IV with R 7 Gy + CDDP IMRT 75 Gy + CDDP Hypothesis = IMRT 75 Gy more efficient & less toxic? N = 67 pts 14

IMRT in oropharynx carcinomas : summary - Better conformality / 3D, & one of the tumor sites where it is increasingly used +++ - Steep dose gradient : need for clinical validation in locally advanced ddisease - Promizing & converging results (EBM 2-3) : - Few LR recurrence - Less late toxicity - Learning curve / Re-inforced QA needed ++ Radiotherapy for oropharyngeal carcinoma : Importance of the RT-QA Radiotherapy for oropharyngeal carcinoma : Importance of the RT-QA contouring 15

Importance of RT-QA : contouring ; international survey : T2 Tonsil Primary Tumor Neck Node Harari 24 Samples : Elective CTV Designs Harari 24 Radiotherapy for oropharyngeal carcinomas : Importance of the RT-QA RT plan verification 16

LR Failure according to RT plan deviations yes / no (N= 82) (Rishin, ASCO 28) 1 nal failure-free Estimated percentage locoregio 8 6 4 2 2P <.1 compliant plan by TMC no adv impact adv impact No deviation Deviation 1 2 3 4 Years following end of radiotherapy IMRT : what s next? New tools for radiation delivery : Image guided RT Adaptive RT Dose Guided RT Adaptive Radiotherapy - Anatomic and set-up Changes 19 CT Scans over 47 Days Elapsed Days Patient Immobilized with Acquaplast Mask Barker et al. IJROBP 59:96-97, 24 (MDACC); Lei Dong et al. (MDACC) 17

Dose distribution in Superior Constrictor Muscle from Brachytherapy in Tonsillar Fossa (< 5%) mcs Brachytherapy Boost 1% TF Peter Levendag et al EORTC H&N35 Swallowing / Dose swallowing muscles % Probability severe dysphagia.5.4.3.2.1 MCM ---- -----MCS Cyberknife boost. 2 4 6 8 Dose Constrictor Muscles(Gy) CBK patients EORTC H&N35 Swallowing / Dose swallowing muscles % Probability severe dysphagia.5.4.3.2.1 MCM ---- -----MCS Brachytherapy boost. 2 4 6 8 Dose Constrictor Muscles(Gy) BT patients Peter Levendag et al New generation of trials in locally advanced oropharyngeal carcinomas? Most of them do integrate concomitant CT-RT (CDDP-RT) 18

New generation of trials for oropharynx carcinomas : concomitant CT-RT & modifying the radiotherapy GORTEC 99-2 randomized trial Conventional RT + Carbo/5FU Stage III/IV Accelerated RT + Carbo/5FU Very accelerated RT N = 84 pts randomized, 2/3 of oropharynx GORTEC-992 - Progression free survival 1..9.8 RTconv-CT Arm A.7 Arm B.6 RTacc-CT.5 Very-Acc-RT Arm C 33.4%.4.3 A vs B vs C p=.7 A vs B p=.61.2.1 32.9% 31.7% A vs C p=.3 *. 1 2 3 4 5 At risk Years 279 162 12 64 45 29 28 151 99 7 54 35 281 129 81 64 47 31 * Ajusté sur T, N et localisation 19

New generation of trials in locally advanced oropharyngeal carcinomas? concomitant CDDP-RT & adding a new drug RTOG H5-22 : Phase III Stage III-IV HNSCC R A N D O M I Z E Accelerated FX CDDP Accelerated FX CDDP Erbitux Future directions : multiple targeting? Example : ZD6474 : a Dual EGFR-VEGFR TKI EGFR TGFα ZD6474 Cancer cell ras MEK VEGF Endothelial cell KDR Cyclin D1 Endothelial cell proliferation Proliferation Wedge SR, et al. Cancer Res 22;62:4645 4655 2

Multiple- better than single-targeting? several ongoing trials in HNSCC Phase I (Localy advanced HNC) Brizel, 27 RT- CDDP + Erlotinib R RT- CDDP + Avastin RT-CDDP + Erlotinib + Avastin New GORTEC trial (> 2/3 oropharynx) Erbitux - RT R T2-T4 N-N1 Erbitux - RT + Carbo-5FU (best arm 99-2) New generation of trials in localy advanced oropharyngeal carcinomas? concomitant CT-RT & testing induction CT 21

6 ongoing randomized trials (Decide, Paradigm, Paccagnella etc ) R RT-CT TPF RT-CT Other Strategy tested : a new GORTEC trial TPF Erbitux - RT R T2-T4 N2b-N3 RT-CT (best arm 99-2) New generation of trials in localy advanced oropharyngeal carcinomas? Replacing CDDP concomitant to RT by a molecular targeted drug (erbitux)? 22

Replacing chemo by a molecular targeted drug? larynx preservation randomized trial (GORTEC-GETTEC) TPF CDDP-RT R TPF + Erbitux-RT Decreasing the dose intensity of the treatment : a relevant question for HPV+ oropharyngeal carcinomas? Other directions in oropharyngeal carcinoma specific treatments for HPV related tumors? - HPV found in 2-25% of HNSCC (and 3% benign biopsies of oropharynx) - Up to 5% in oropharynx carcinomas (some series : 9%) : - 85-9% HPV16 (De Souza, NEJM 27) - HPV+ tumors associated with : - Better survival (Richties 23) - Better survival in surgically treated tumors (Licitra JCO 26) - More radiosensitivity (Lindel 27) - More response to induction chemo (Worden JCO 28) - Cellular marker of prognostic value : p16 (Lassen JCO 29 survival 62% versus 26% with conventional RT) 23

Do we need different therapeutic approaches for HPV associated oropharyngeal tumors? - De-escalation? - Value of EGFr targeting instead of concomitant chemo? - Other specific anti-viral strategies? Antiviral agent Cidofovir + irradiation in HPV+ SC carcinoma xenografts (ongoing phase I) HPV+ xenografts 6 Control r volume Fractional tumor 5 4 3 2 1 Cidofovir IR Cidofovir +IR 1 4 8 12 16 2 24 28 32 36 Days Oropharyngeal carcinoma - Conclusions - - High proportion of HNSCC (about 5%) - The effect of chemotherapy and/or altered fractionation or EGFr targeting = not different from the other HNSCC EBM level 1a - Importance of IMRT / IGRT / RT-QA for normal tissue sparing in this particular sub-site - Question : more HPV related carcinomas (specific targeting? Treatment Desescaltion)? 24

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