Radio(chemo)therapy for head and neck cancer HNSCC: indications and modalities Prof. dr. Sandra Nuyts Radiotherapy-Oncology

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1 Radio(chemo)therapy for head and neck cancer HNSCC: indications and modalities Prof. dr. Sandra Nuyts Radiotherapy-Oncology March 2018

2 > Half million new cases HNC/year in world 50-60% cured not cured local failure Less side effects More organ and function preservation More effective local and systemic treatment distant failure More effective systemic treatment

3 Therapy of Head and Neck Cancer Multidisciplinary! Head and neck surgeon Maxillofacial surgeon Reconstructive surgeon Dietician Speak and language therapist Maxillofacial prosthodontists Nurses Dentist Medical oncologist Radiation-oncologist Radiologist/ nuclear medicine Pathologist Tabacologist Social nurses

4 Current standard treatment for early HNC: radiotherapy or surgery Surgery (organ sparing) Radiotherapy alone Often altered fractionation schedules

5 Current standard treatment for locally advanced HNC: chemoradiotherapy or surgery Inoperabele locally advanced HNC: CRT Operabele locally advanced HNC CRT: Organ and function preservation Surgery + postoperative (C)RT

6 CANCER TREATMENT surgery chemotherapy radiotherapy hormonal therapy immunotherapy

7 linear accelerator Impacting intra-cellular mechanism Damaging molecular structure of DNA Ionizing atoms Cellular level Ion Photon Impacting processes in the human body Molecular level Atomic level Free electrons

8 Increasing the therapeutic ratio in radiotherapy 1.0 Probability of Tumor Control Probability of Normal Tissue Damage Therapeutic Effect (A) 0 Dose (Gy)

9 Advances in radiotherapy for HNC 1. Lessons from randomized trials 2. IMRT: beyond parotid sparing? Tumorbiology Fractionation schedules 3. New approaches Optimise radiotherapy Concomitant Chemo/biotherapy Technological improvement

10 Radiotherapy for HNC Primary setting Chemoradiotherapy Bioradiotherapy Altered fractionation Postoperative setting Chemoradiotherapy Ionising radiation

11 Current standard treatment for locally advanced HNSCC: chemoradiotherapy 1.Primary setting Inoperable locally advanced HNSCC Operable locally advanced HNSCC Organ and function preservation Tumorbiology Fractionation schedules Optimise radiotherapy Concomitant Chemo/biotherapy Technological improvement

12 Concurrent therapy At current: 2 options Chemoradiotherapy (CRT): based on data from thousands of patients Bio radiotherapy (BRT): based on 1 trial

13 Intergroup trial RTOG Larynx stadium III-IV, resecabel, exclusie T4 Primair eindpunt larynx preservatie Standaard RT (n=170) Inductie CH+ RT of S (n=171) Conc CH-RT (n=169) 70 Gy 2Gy/fr 7 weken CDDP 100mg/m 2, d1 5FU 1g/m 2, d1-5 X2-3 >= PR: 70Gy <PR: chirurgie 70 Gy,2Gy/fr,7w CDDP 100mg/m 2, d1,22,43 Forastiere, NEJM 2003

14 Intergroup trial RTOG % 0% Years from randomization

15 Intergroup trial RTOG % 88% 74% 85% 71% 69% 64% 59% 54% 53% 0% Years from randomization

16 chemoradiotherapy 4% pts 63 trials Pignon, Lancet 2000

17 Chemoradiotherapy meta-analysis pts 87 trials Pignon et al, R&O 2009

18 Radiochemotherapy Radiotherapy Concomitant Radiotherapy + Chemotherapy pts 87 trials Pignon, Radiother Oncol 2009

19 chemoradiotherapy: which chemotherapy? Only 2 combinations based on randomised studies: Carbo (70mg/m 2 )-5FU (600mg/m 2 x4d) 3 weekly Calais et al JNCI 1999 CDDP 100mg/m 2 3 weekly Bernier et al EORTC NEJM 2004 Cooper et al RTOG NEJM 2004 Forastiere et al Intergroup RTOG91-11 NEJM 2003

20 1373 patients Szturz Oral Oncology 2018

21 CRT results in significant increase in acute toxicity Grade 3+: 77% with CRT vs 34% with RT alone (p<0.001) RCT RT CT Cooper NEJM 2004

22 CRT: late toxicity! Analysis 3 RTOG trials on CRT 230 eligible patients: 43% late toxicity Machtay JCO 2008

23 Newer agents molecular targeting: EGFR Overexpression in % HNC Poor prognostic factor Reduced response to XRT and CT Ang Int J Radiat Oncol Biol Phys 2004

24 Phase III studie: Radiotherapie +/- Cetuximab Phase III randomised study Stage III-IV oropharynx, larynx and hypopharynx R A N D O M I S A T I O N Arm 1: XRT (n=213) conventional BID hyperfractionation concom boost Arm 2: XRT + weekly Cetuximab (n=211) NEJM 2006 Lancet Oncol 2010

25 Results: locoregional control RT RT+ C225 P-value Median duration (months) Locoregional control rates 1 year 55% 63% 2 year 41% 50% 3 year 34% 47% <0.01 Bonner, NEJM 2006

26 Results: Survival Median overall survival (months) RT RT+ C225 P-value Survival rates 3 year 45% 55% year 36% 45.6% 0.02

27 Toxicity?

28 16 Correlation of rash and survival after treatment with EGFR targets Survival (months) CRC CRC CRC CRC Pancreatic SCCHN Study: BOND Saltz (2001) 1 Saltz (2004) 2 Cunningham Van Cutsem Xiong (2004) 5 Kies (2002) 6 (2004) 3 (2004) 4 No reaction Grade 1 Grade 2 Grade 3 1 Saltz et al. Proc ASCO Saltz et al. J Clin Oncol Cunningham D Van Cutsem E. N Engl J Med Van Cutsem et al. EORTC/NCI Geneva Xiong H et al. J Clin Oncol Kies et al. Proc ASCO 2002.

29 Update Bonner trial Lancet Oncol 2009

30 Take home message 1: Golden standard locally advanced HNSCC: Radiotherapy+ high dose cisplatin If patient not eligible cisplatin: cetuximab What about early stage disease? Use of altered fractionation

31 altered fractionation Standard fractionation Hyperfractionation scheme Higher total dose Dose/fraction lower Accelerated radiotherapy Total treatment shorter Combination schedules

32 fractionation meta-analysis MARCH group 6515 ptn, 15 trials All fractionationschedules together: 6.4% gain 5yr locoregional control Hyperfractionation schedules: largest benefit: 9.4% Bourhis, Lancet 2006

33 Take home message 2: 70 Gy in 7 weeks alone= perhaps the worst we can do! RT-CT Altered fractionation Induction chemotherapy Cetuximab+ RT +13% +10% +10% +???

34 postoperative XRT 2.Postop setting Reduces locoregional recurrence rates by at least factor 2 Cohort studies Small randomized trials Kokal WA, J Surg Oncol 1988; 38(2): Marcial VA, Semin Oncol 1988; 15(1): Sadeghi A, Otolaryngol Head Neck Surg 1986; 94(5): Huang DT, Int J Radiat Oncol Biol Phys. 1992;23(4): Reduced locoregional control translates in survival benefit

35 Oral cavity: timing PORT In general: within 6 weeks postop

36 postop XRT vs preop XRT? RTOG 73-03: LAHNCC: supraglottic larynx, hypopharynx, oral cavity, oropharynx Preop (50Gy) versus postop (60Gy) OC/OP also had definitive RT arm (65-70Gy) followed by surgery if residual disease 277 patients, 10 yr follow up Improved LRC in postop arm (65%) vs preop (48%, P=0,04) Trend toward improved survival: 38 vs 33% (p=0,1) Surgical and RT complications similar RTOG established 60Gy as postop RT dose Kramer et al, Head Neck Surg 1987;10:19-30 Tupchong et al, IJROBP 1991;20:21-28

37 radiation dose based on risk MDAnderson prospective randomized trial 240 pts resected stage III/IV OC, OP, HP, L

38 radiation dose Locoregional control by risk factors: Peters et al IJROBP 1993;26:3-11

39 radiation dose Patients receiving <54 Gy had significantly higher failure rate. No dose response beyond 57.6 Gy except for patients with extracapsular nodal spread. +ECE needed at least 63 Gy Clusters of two or more of the following also predicted increased risk of failure and need for 63 Gy: oral cavity primary, positive/close margins, nerve invasion, >2 positive nodes, largest node >3 cm, treatment delay >6weeks, Zubrod performance status>2 Moderate to severe complications seen in 7.1%; more if RT dose >63 Gy Dose escalation above 63 Gy does not appear to improve the therapeutic ratio. Peters et al IJROBP 1993;26:3-11

40 radiation dose based on risk Risk factors: > 1 nodal group >= 2 nodes Nodes >3cm Microscopic + margins PNI+ OC ECE -Low risk: no features -Intermediate risk: 1 risk factor (no ECE) -High risk: ECE or >= 2 risk factors Ang et al IJROBP 2001; 51:

41 Locoregional control and survival by risk factors 5 yr LRC and OS : Low risk: 90% and 83% Intermediate risk: 94% and 66% High risk: 68% and 42% Ang et al IJROBP 2001; 51:

42 Indication PORT Risk features: Microscopically positive surgical margins ECE LVI PNI Close margins (0,01-5mm) >= 2 involved neck nodes >1 positive nodal group Oral cavity primary site Nodal diameter>3cm >6 week interval between surgery and XRT Advanced T stage Recurrent disease Tumor spillage Multicentricity Invasion of bone/cartilage/skin or soft tissue of the neck Depth of tumor invasion >3mm (An 2008), >4mm (Fakih 1989, O Brien 2003), >5mm (Fukano 1997) (Tumors 3-9 mm: 44% node+, 7% local recurrence; >9 mm: 53% subclinical node+, 24% local recurrence Head Neck 2002: 24:513-20)

43 PORT- risk group definition RPA (recursive partitioning analysis) 801 patients Class I-intermediate risk (5Y LRC 88%) No N3 nodes Negative margins (>5mm) No extranodal spread (ENS) Class II-high risk (5Y LRC 73%) pn1 ENS Or pt1, pt2 or pt4 with close or + margins Langendijk et al Cancer 2005; 104:

44 PORT- risk group definition RPA (recursive partitioning analysis) Class III-very high risk (5Y LRC 58%) N3 node >= 2 positive lymph nodes with ENS pt3 with close or positive margins No extranodal spread (ENS) Langendijk et al Cancer 2005; 104:

45 Model based on 979 patients OCSCC Validation on 431 patients

46 Postoperative RT: role chemo? 2 important studies NEJM 2004 high risk group:

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49 Overall survival

50 Combined EORTC/RTOG analysis Bernier, Cooper Head Neck 2005;27:843

51 OS for patients WITH positive margin and/or ECE CRT CRT RT RT

52 OS for patients WITHOUT positive margin and/or ECE CRT RT

53 Update: long term follow up RTOG9501 patients WITH positive margin and/or ECE Cooper et al IJROBP 2012

54 Postoperative RT: role chemo? Differences in selection criteria explain variation in impact of chemo 26-27% of population had OC primaries Adjuvant chemo is indicated in Positive margins +ECE Head Neck 2005; 27:

55 Postoperative RT: role chemo? Words of caution: Important increase acute toxicity: doubling acute mucositis gr III/IV (21% vs 41%) 3 toxic deaths in study Only 61% pts received 3 cycles chemo EORTC no pts > 70j, in RTOG trial only 5% of pts > 70j No reduction in distant metastasis in both trials DFS for pts with ECE and/or positive margins still remains poor: 45.2% at 3 yrs and at 35.7% at 5 yrs (Meta-analysis of EORTC and RTOG trial)

56 Take home message 3: Risk Adaptive PORT depending on pathology Risk Features Management Low risk No radiation Intermediate risk (neg margin, no ECE) Radiation alone to 60Gy High risk (pos margin, and/or ECE) Radiation to 60-66Gy with concurrent cisplatin

57 PORT: altered fractionation? Accelerated fractionation in adjuvant setting: no advantage shown Ang et al IJROBP 2001 Suwinkski et al R&O 2008 Hyperfractionated XRT: not systematically investigated in postop setting

58 role OTT

59 Advances in radiotherapy for HNC 1. Lessons from randomized trials 2. IMRT: beyond parotid sparing? 3. New approaches

60 old school

61 current

62 Evolution in RT techniques Technology 2D-RT D-RT 2000 IMRT 2010 Arc 2D-RT 3D-RT IMRT Arc

63 Technological improvement Technology Introduction conformal radiotherapy-imrt

64 Classic Radiotherapy Highly conformal Radiotherapy

65 What is IMRT?

66 CONFORMAL RADIOTHERAPY LINEAR accelerator COLLIMATOR Different angles MULTI-LEAF COLLIMATOR

67 IMRT

68 Xerostomia is one of the most common complications of RT for HNC. Technology Dirix P., Nuyts S. Cancer 2006

69 Head and Neck Cancer: IMRT is golden standard Phase III Multi-Centre Randomised Controlled Trial of Intensity Modulated vs Conventional Radiotherapy in Head and Neck Cancer: PARSPORT Conventional radiotherapy parallel opposed fields IMRT sparing left parotid C. Nutting, et al Lancet Oncology febr 2011

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71 Evolution in RT techniques 2D-RT 3D-RT IMRT Arc Reduction xerostomia

72 Evolution in RT techniques 2D-RT 3D-RT IMRT Arc Reduction dysphagia superior pharyngeal constrictor muscle middle pcm inferior pcm upper esophageal sphincter esophagus base of tongue supraglottic larynx glottic larynx

73 Intensity modulated arc therapy (VMAT)

74 Radiotherapy for head and neck cancer: past-present-future 2D-RT 3D-CRT IMRT proton Anno 1970 Anno 1990 Anno 2000 Anno 2020

75 Take home message 4: Current radiotherapy techniques offer possibilities to spare critical organs Like parotids, swallowing structures To reduce acute and long term toxicity Quality of radiotherapy is becoming more crucial!

76 Complexity RT increases We are at increased risk of missing very precisely (J. Rosenman)

77 Wuthrick E et al JCO 2014

78 6212 treated patients IMRT treated pats: increased survival if treated by higher volume radiation oncologists For each 5 patients more treated per year: 21 % reduction in all cause mortality

79 Advances in radiotherapy for HNC 1. Lessons from randomized trials 2. IMRT: beyond parotid sparing? 3. New approaches

80 Increase dose to parts of the tumor: Dose-painting on the biological target volume (BTV) Biology CT PET Fusion Galvin J. et al. J Clin Oncol 2007.

81 Molecular imaging-based dose escalation in HPV negative patients with locally advanced squamous cell carcinoma of the oropharynx Biology

82 Adaptive (Biological) Image-guided Radiotherapy Treatment planning Treatment delivery Linac-integrated kv Cone-beam CT technology Correction : Patient positioning Anatomy changes Biology changes Planning biology anatomy Treatment biology anatomy Image registration

83 Use of Hypoxic Radiosensitizers Biology

84 Biologie Radiation resistance: the oxygen fixation hypothesis FMISO-1 FMISO-2 Brown J. & Wilson W. Nat Rev Cancer 2004.

85 Immunotherapy: PD-1/PD-L1 inhibitors

86 protontherapy Robert. R. Wilson ( ) 1946: good things can come from the tragedy of war

87 Physical Aspects Proton Charged particles (+e) Mass: 1,67 x10-27 kg =1836 times the mass m e of an electron Photon Quantum of electromagnetic radiation No charge No mass Energy ~ frequency ~ wavelength Interaction with matter Newhauser et al. Phys. Med. Biol. 60 (2015)

88 Proton Beam Bragg peak Protons stop in solid or liquid matter. Beyond the stopping point the dose is negligible dose Entrance plateau Protons loose kinetic energy gradually when travelling through matter, through multiple collisions with atomic electrons depth The rate at which protons loose energy increases as the proton is slowing down The rate of energy loss or stopping power depends on the energy itself and on the stopping material Pencil beam High ionization density at the end of their range Weak scattering => Low entrance dose plateau followed by the sharp Bragg peak at the end of the proton range

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90 Proton vs. photontherapy Photon Proton No dose H&N case Medulloblastoma case

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92 Leeman et al Lancet Oncol 2014

93 Ongoing studies

94 Conclusion: Radiotherapy for HNC : Enormous progress made Tumorbiology Fractionation schedules Optimise radiotherapy Concomitant Chemo/biotherapy Technological improvement

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