Re-irradiation with or without chemotherapy Jozsef Lövey National Institute of Oncology, Budapest, Hungary
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
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
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
Jones & Hopewell, International Journal of Radiation Biology, September 2014; 90(9): 731 741
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
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;30:281-82. 2. Stevens et al. Int J Radiat Oncol Biol Phys 1994;29:687-98. 3. Weichselbaum et al. Int J Radiat Oncol Biol Phys 1988;15:575-9.
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
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
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 26:5518-5523.
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 26:5518-5523.
Highly conformal conventional irradiation Study Pts No. 2y LC mos (months) 2yOS Gr 5. Duprez 2015 60 52% 9,6 32% 4/60 (6,6%) McGill 2015 27 52% 16 59% 2/27 (7,4%) Curtis 2016 81 50% 22 18% 0/81 (0 %) Bots 2016 137 46% 21 42% 3/137 (2,1%) Velez 2017 76 38% 15 51% 0/76 (0%) Takian 2016 173 59% 25 51% 3/173 (1,7%) 554 50,4% 20,1 42,1% 2,1%
Study Pts No. 2y LC mos (months) 2yOS Gr 5. Stereotactic Body RadioTherapy (SBRT) Ozygit 2011 23 82% NR 64% (CSS) 3 Voynov 2006 22 26% 12 22% 0 Roh 2009 36 NR 16,2 30,9% 0 Heron 2009 25 30% 12 41% 1 Siddiqui 2009 21 38,5% NR 14,3% 1 Rwigema 2010 85 30,7% 11,5 16,1% NR Cengiz 2011 46 83,8 11,9 22% 9 Kodani 2011 21 NR 23 50% 1 Kress 2011 85 28% 8,6 24% 0 Lartigeau 2013 60 20% 11,8 30,1 1 Comey 2012 40 NR 13,6 24% 0 Vargo 2015* 50 42% 10,4 12% 0 Yamazaki 2016 107 63% 14,4 35% 9 Cvek 2016 40 NR 7 28% 0 661 45% 10,8 26,7% 25/615 (4%)
Hadron therapy (proton @ heavy ion) Study Pts No. 2y LC mos (months) 2yOS Gr 5. Romesser 2010 91 60% 20 40% 2 Hayashi 2016 46 70% 12 46% 5 Phan 2016 60 72% 20 69% 3 McDonald 2016 61 80,3% 16,5 32,7% 3 Yamazaki 2017 26 66,9% (1y) 24,5 52,2% 2 284 68,4% 18,2 46,2% 15/284 (5,3%)
Brachytherapy Study Pts No. 2y LC mos (months) Hepel 2004 30 69% 13 37% 0 Narayala 2007 30 71% 29 63% 0 Tselis 2011 74 67% 10 37% 0 Strnad 2015 104 92,5% NR 21% (5y) 0 Teudt 2016 (p.op) 9 50% 60 78% 0 Rudzainskas 2016 30 47% (p.op. 74%) 10 47% 0 Martinez- Rodriguez 2017 63 60% 23 47% 5 2yOS Gr 5. 304 68% 21,4 54% 5/304 (1,6%)
Chemoradiation Study Bergen 2010 Pts No. 2y LC mos (months) 2yOS Chemo Gr 5. 30 NR 13,4 24% docetaxel 0 Choe 2011 166 50,7% 24,8 23,8% 5FU HU 33 Kharofa 2012 Vormittag 2012 Rades 2016 38 34% 16 44% Carbo-paclitaxel 0 31 7% 8 12% Capecitabine 0 4 20% 14,5 10% Paclitaxel 0 269 39% 20 24,8% 33/269 (12%)
Bioradiotherapy (cetuximab) Study Pts No. 2y LC mos (months) 2yOS Gr 5. Zwicker 2011 10 50% 15 19% 0 Balermpas 2012 18 20% 8,38 18,3% 0 Jensen 2011 22 28% 8 28% 0 Heron 2011 35 52% 24,5 53,3% 0 Lartigeau 2013 56 20% 11 13% 1 Dornoff 2016 33 30% 10 12% 0 Vargo 2015 50 42% 10,4 12% 0 Milnonvic 2013 23 NR 9 17% 1 247 32,5% 12 20,4 2/247 (0,8%)
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%
Comparison with old and Extreme data Treatment 2y LC mos (months) 2yOS Gr 5. Modern reirradiation 32-68% 12-21 20-54% 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%
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
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:?
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
Carotid blowout syndrome (CBOS) Yamazaki et al. 2015 Carotid Blowout Score (CBS score) Carotis invasion >180 Ulceration LN region irradiation
Quality of life Few data Chen et al. 2014 : no deterioration of QOL in 17 patients Vargo et al. 2012 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
Prediction of survival / patient selection Ward et al. IJROBP 2017 412 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
Riaz et al. Radiother Oncol 2014
Strojan et al Head Neck 2015 Patient selection algorithm
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
Thank you for your attention!