Re-irradiation with or without chemotherapy. Jozsef Lövey National Institute of Oncology, Budapest, Hungary

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1 Re-irradiation with or without chemotherapy Jozsef Lövey National Institute of Oncology, Budapest, Hungary

2 Disclosures Occasional advisory board and educational activity to Merck, Roche, Nutricia, Takeda, and Fresenius I have no conflict of interest related to the topic of the presentation

3 Introduction After curative radiotherapy recurrence occur in 15-50% Second primary cancer develop in ~15% Best salvage is surgery in resectable cases Unresectable patients Reirradiation Palliative systemic therapy Incomplete biological information Lack of good quality data, reirradiation often regarded ineffective Number of publications and reported cases increases recently

4 Biology background normal tissues Tissues remember radiation effect that is fading by time Reirradiation capacity differs in various tissues and organs Serial (myelon) and parallel (salivary gland) organs Data comes from animal models and radiation side effects Linear quadratic (LQ) model and the Biological Effective Dose (BED) is used Not fully validated for large single dose such as used in SBRT During planning all possible normal tissue injury should be calculated

5 Jones & Hopewell, International Journal of Radiation Biology, September 2014; 90(9):

6 Biology background normal tissues Tissues remember radiation effect that is fading by time Reirradiation capacity differs in various tissues and organs Serial (myelon) and parallel (salivary gland) organs Data comes from animal models and radiation side effects Linear quadratic (LQ) model and the Biological Effective Dose (BED) is used Not fully validated for large single dose such as used in SBRT During planning all possible normal tissue injury should be calculated

7 Biology background recurrent tumor Second primary tumors usually have the usual radiosensitivity 1,2 Unless the microenvironment has negative impact e.g. hypoxia Recurrent tumors are more radioresistant than the originals In vitro recurrent clones are radioresistant 3 Microenvironment is worse (fibrosis, hypoxia) In clinical studies recurrent tumors have worse outcome Stronger effect is required Alternative fractionation with higher BED Concomitant treatment with chemo or biological therapy 1 Spencer et al. Head Neck 2008;30: Stevens et al. Int J Radiat Oncol Biol Phys 1994;29: Weichselbaum et al. Int J Radiat Oncol Biol Phys 1988;15:575-9.

8 New techniques of radiotherapy Advanced imaging in treatment planning Highly conformal techniques Intensity modulated radiotherapy (IMRT), Intensity modulated arc therapy (IMAT) Cyberknife, Tomotherapy Hadron (proton and heavy ions) Precise set up of the patient Image guided radiotherapy (IGRT) Cone beam CT LINAC MR (real time high resolution soft tissue imaging) Adaptive radiotherapy Adaptation of target volume according to the change of tumor during radiotherapy

9 Clinical experience Reirradiation after salvage surgery (postoperative reirradiation) Reirradiation with conventional fractionation / IMRT Special techniques Hadrons (proton and heavy ion) Brachytherapy Stereotactic body radiotherapy (SBRT) / Cyberknife Concomitant chemotherapy Concomitant biological therapy

10 Postoperative reirradiation GORTEC trial 130 pts randomized after salvage macroscopic complete surgery Chemoradiation 60 Gy + hydroxyurea-5fu vs observation Janot F et al. J Clin Oncol 26:

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12 Postoperative reirradiation GORTEC trial 130 pts randomized after salvage macroscopic complete surgery Chemoradiation 60 Gy + hydroxyurea-5fu vs observation Treatment related death: 8,3% Grad 3-4 side effects: 28% Janot F et al. J Clin Oncol 26:

13 Highly conformal conventional irradiation Study Pts No. 2y LC mos (months) 2yOS Gr 5. Duprez % 9,6 32% 4/60 (6,6%) McGill % 16 59% 2/27 (7,4%) Curtis % 22 18% 0/81 (0 %) Bots % 21 42% 3/137 (2,1%) Velez % 15 51% 0/76 (0%) Takian % 25 51% 3/173 (1,7%) ,4% 20,1 42,1% 2,1%

14 Study Pts No. 2y LC mos (months) 2yOS Gr 5. Stereotactic Body RadioTherapy (SBRT) Ozygit % NR 64% (CSS) 3 Voynov % 12 22% 0 Roh NR 16,2 30,9% 0 Heron % 12 41% 1 Siddiqui ,5% NR 14,3% 1 Rwigema ,7% 11,5 16,1% NR Cengiz ,8 11,9 22% 9 Kodani NR 23 50% 1 Kress % 8,6 24% 0 Lartigeau % 11,8 30,1 1 Comey NR 13,6 24% 0 Vargo 2015* 50 42% 10,4 12% 0 Yamazaki % 14,4 35% 9 Cvek NR 7 28% % 10,8 26,7% 25/615 (4%)

15 Hadron therapy heavy ion) Study Pts No. 2y LC mos (months) 2yOS Gr 5. Romesser % 20 40% 2 Hayashi % 12 46% 5 Phan % 20 69% 3 McDonald ,3% 16,5 32,7% 3 Yamazaki ,9% (1y) 24,5 52,2% ,4% 18,2 46,2% 15/284 (5,3%)

16 Brachytherapy Study Pts No. 2y LC mos (months) Hepel % 13 37% 0 Narayala % 29 63% 0 Tselis % 10 37% 0 Strnad ,5% NR 21% (5y) 0 Teudt 2016 (p.op) 9 50% 60 78% 0 Rudzainskas % (p.op. 74%) 10 47% 0 Martinez- Rodriguez % 23 47% 5 2yOS Gr % 21,4 54% 5/304 (1,6%)

17 Chemoradiation Study Bergen 2010 Pts No. 2y LC mos (months) 2yOS Chemo Gr NR 13,4 24% docetaxel 0 Choe ,7% 24,8 23,8% 5FU HU 33 Kharofa 2012 Vormittag 2012 Rades % 16 44% Carbo-paclitaxel % 8 12% Capecitabine % 14,5 10% Paclitaxel % 20 24,8% 33/269 (12%)

18 Bioradiotherapy (cetuximab) Study Pts No. 2y LC mos (months) 2yOS Gr 5. Zwicker % 15 19% 0 Balermpas % 8,38 18,3% 0 Jensen % 8 28% 0 Heron % 24,5 53,3% 0 Lartigeau % 11 13% 1 Dornoff % 10 12% 0 Vargo % 10,4 12% 0 Milnonvic NR 9 17% ,5% 12 20,4 2/247 (0,8%)

19 Comparison with old and Extreme data Treatment 2y LC mos (months) 2yOS Gr 5. IMRT 50,4% 20,1 42,1% 2,1% SBRT 45% 10,8 26,7% 4% Hadron 68,4% 18,2 46,2% 5,3% Brachytherapy 68% 21,4 54% 1,6% CRT 39% 20 24,8% 1,6 Cetuximab 32,5% 12 20,4 0,8%

20 Comparison with old and Extreme data Treatment 2y LC mos (months) 2yOS Gr 5. Modern reirradiation 32-68% % 0,4-5,3% RTOG 9610 NR 8,8 16,9% 7,8% RTOG 9011 ~15% 12,1 25,9 8% Extreme NR 10,1 18% 2,2%

21 Prediction of side effects Severe early toxicity Aspiration Tracheostomy (new) Feeding tube (new) Soft tissue / skin necrosis Treatment related mortality Severe late toxicity Aspiration pneumonia Pharyngeal esophageal sricture Feeding tube dependence Osteoradionecrosis Carotid blowout Fistula / necrosis

22 Prediction of side effects Main predictors (MVA) Time from previous irradiation Irradiated volume Possible predictors (UVA) Age Gender Organ dysfucntion Flap reconstruction surgery before reirradiation Grade 3-4 early toxicity: 18-36% Grade 5 early toxicity: 0-5,4% Grade 3-4 late toxcitiy: 15-30% (lower with competeing risk analysis) Late grade 5:?

23 Carotid blowout syndrome (CBOS) McDonald 2012, 1554 patients 2,6 %, but 76% fatal Group CBOS % Continuous convnetional fractionatioin 1,3 Split course conventional fractionation 1,8 Hyperfractionated accelerated 4,5 Chemotherapy yes 3,3 Chemotherpay no 1,5 Surgery yes 2 Surgery no 3,3

24 Carotid blowout syndrome (CBOS) Yamazaki et al Carotid Blowout Score (CBS score) Carotis invasion >180 Ulceration LN region irradiation

25 Quality of life Few data Chen et al : no deterioration of QOL in 17 patients Vargo et al Patient reported outcomes 150 patients Validated QoL methods Decrease until 1 month after radiation then improves The longer the patient lives the higher the QoL increases Not influenced by age, cetuximab, interval between radiation courses, treatment volume

26 Prediction of survival / patient selection Ward et al. IJROBP patients, Multi Institutional Cohort analysis Multivariable analysis, and Recursive Partition Analysis (RPA) Significant factors on MVA Site of disease (nasopharynx better) KPS (70) Organ disfunction Time between radiation courses Surgery

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29 Riaz et al. Radiother Oncol 2014

30 Strojan et al Head Neck 2015 Patient selection algorithm

31 Conclusions / Recommendations Reirradiation is a well-established treatment choice in rhnscc Multidisciplinary approach is a must Always consider surgery first if feasible In high risk postoperative situation adjuvant reirradation is effective Careful patient selection is a key issue Always use the best available tools in target volume delineation, treatment planning, treatment delivery Without well organized supportive care reirradiation dangerous Consider to perform reirradiation in clinical trial setting With good patient selection, advanced technique and good support reirradiation is safe and effective

32 Thank you for your attention!