Multidisciplinary Management of Head and Neck Cancer I

Transcription

1 Multidisciplinary Management of Head and Neck Cancer I Min Yao, M.D., Ph.D. Department of Radiation Oncology University Hospitals Case Medical Center Case Western Reserve University

2 Nothing to disclose

3 Outline First Hour: Laryngeal and Hypopharyngeal Cancer Nasopharyngeal Cancer Second Hour: Oral Cavity Cancer Oropharyngeal Cancer

4 The Question: The best radiotherapy regimen for T2N0 glottic squamous cell carcinoma is: A. 1.8 Gy per fraction daily to 70.2 Gy B. 2.0 Gy per fraction daily to 70 Gy C Gy per fraction daily to Gy D. 1.2 Gy perfraction twice daily to 79.2 Gy

5 Treatment of Laryngeal Squamous Cell Carcinoma

6 The Larynx Objectives: Management of early stage cancer Management of locally advanced cancer 1. Laryngeal preservation trials with chemoxrt and patient selection 2. Altered fractionation 3. Radiation with concurrent cetuximab 4. Postoperative radiation

7 Early Stage of Glottic Cancer T1A T1B

8 Early Stage of Glottic Cancer (T2)

9 Risk of Lymph Node Metastasis Glottic Cancer T1 <2% T2 <5-8% T % T % CC Wang. Radiation Therapy for Head and Neck Neoplasms

10 Radiation Technique for Early Stage Glottic Cancer

11 Retrospective study of 315 T1 and 83 T2 patients

12 Local Control for T1 Disease by Fraction Size Le. IJROBP 1997

13 Local Control for T1 Disease by Overall Treatment Time Le. IJROBP 1997

14 Randomized Trial on T1 Glottic Cancer R A N D O M I Z E Conventional Fractionation 2 Gy/Fx Hypofractionation 2.25 Gy/Fx Tumor < 2/3 of glottis 60 Gy/30 Fx Tumor > 2/3 of glottis 66 Gy/33 Fx Tumor < 2/3 of glottis Gy/25 Fx Tumor < 2/3 of glottis 63 Gy/28 Fx Yamazaki. IJROBP 2006;64:77-82

15 Local Control Rate Between Arm A and Arm B 2.25 Gy/fx 2 Gy/fx Yamazaki. IJROBP 2006;64:77-82

16 Local Control for T2 Disease by Fraction Size Le. IJROBP 1997

17 Local Control for T2 Disease by Overall Treatment Time Le. IJROBP 1997

18 2006 ASTRO RTOG HYPERFRACTIONATION FOR T2 VOCAL CORD CA. S T R A T I F Y Stage 1. T2a 2. T2b R A N D O M I Z E 1. Conventional Fractionation: 2 Gy/fx/d to 70 Gy/35 fx/7 wks 2. Hyperfractionation: 1.2 Gy/fx BID to 79.2 Gy/66 fxs/6.5 wks No Difference between the 2 arms

19 228 patients, with median follow up of 20 months

20 Radiation Dose Fractions 83 pts (36%) treated BID, /fx, total dose, Gy. 147 pts (64%) tx QD. 89 with at least 2 Gy fx., 57 with Gy/fx, 1 with 1.8 Gy/fx. Total dose 65 to 75 Gy, median 70 Gy. Garden et.al. IJROBP 55:2:

21 Radiation Treatment Outcomes P=0.06 N=228 Garden et.al. IJROBP 55:2:

22 Radiation Treatment Outcomes Garden et.al. IJROBP 55:2:

23 Summary for XRT for Early Stage Glottic Cancer Radiation to the larynx only. No need to include lymph node Higher than 2 Gy daily fraction, preferable 2.25 Gy/fraction to 63 Gy for T1 disease and Gy for T2 disease. Limit treatment course < 43 days

24 Early Stage Supraglottic Cancer (Clinical Stage T1-2N0-1)

25 Risk of Lymph Node Metastasis Glottic Cancer Supraglottic Cancer T1 <2% 27 to 40% T2 <5-8% 27 to 40% T % 55 to 65% T % 55 to 65% CC Wang. Radiation Therapy for Head and Neck Neoplasms

26 Early Stage Supraglottic Cancer (Clinical Stage T1-2N0-1) Surgical approach Supraglottic laryngectomy and bilateral selective neck dissection (level II to IV) Definitive Radiation alone Tumor to 70 Gy, 2 Gy/fx, once daily Whole larynx and bilateral neck to Gy

27 Locally Advanced Laryngeal Cancer (T3-4, N2-3)

28 Locally Advanced Laryngeal Cancer (T3-4, N2-3) Surgical approach Total laryngectomy and selective neck dissection. Post-op XRT +/- chemo. Laryngeal Preservation with ChemoXRT Tumor and nodes to 70 Gy, 2 Gy/fx/day Whole larynx and bilateral neck to Gy

29 VA LARYNGEAL PRESERVATION TRIAL R A N D O M I Z E Surgery CR or PR (3rd Cycle of Chemo) Radiation Therapy Radiation Therapy PR Surgery CR Induction Chemotherapy (2 Cycles) < PR Surgery Radiation Therapy Induction Chemotherapy: Cisplatin and 5-FU

30 VA LARYNGEAL PRESERVATION TRIAL 2 yr overall survival of 68% in both arms NEJM 1991;324:

31 VA LARYNGEAL PRESERVATION TRIAL 64% patients (107) in the induction chemo arm preserved their larynx. NEJM 1991;324:

32 RTOG Laryngeal Preservation Trial R A N D O M I Z E CR/PR CDDP/5FU XRT CDDP/5FU No Response Surgery/XRT RT plus concurrent cisplatin RT alone

33 Median F/U 3.8 years RTOG Induction CCRT RT 2 year Larynx preserved 75% 88% 70% 2 year LR control 61% 78% 56% 2 yr. DM 8% 9% 16% 5-yr. Survival 55% 54% 56% * Estimated from survival curves Forastiere et al, NEJM 2003; 349:

34 RTOG Laryngeal Preservation Trial 84% 72% 67% Median F/U 3.8 years Forastiere et al, NEJM 2003; 349:

35 Long Term Update of RTOG Forastiere et al, JCO 2013, March

36 Long Term Update of RTOG Forastiere et al, JCO 2013, March

37 Long Term Update of RTOG Forastiere et al, JCO 2013, March

38 Patient Factors Patient Selection for Laryngeal Preservation Patient preference Age, co-morbidity Patient social family support, compliance Disease Factors T stage Tumor volume Pretreatment laryngeal function

39 Patient Selection for Laryngeal Preservation Not Eligible for RTOG T4 with tumor extending through the thyroid cartilage into neck soft tissue Extending more than 1 cm into base of the tongue

40 Patient Selection for Laryngeal Preservation T4 with tumor extending through the thyroid cartilage into neck soft tissue Salvage Laryngectomy at the VA Trial < T4 28% T4 56% p = 0.001

41 Patient Selection for Laryngeal Preservation Bulky tumor tumor volume more than 3.5 cm 3 for glottic cancer and more than 6 cm 3 for supraglottic cancer

42 Patient Selection for Laryngeal Preservation Adequate baseline laryngeal function Tracheotomy PEG tube dependent Recurrent aspiration pneumonia

43 T4A: Thyroid Cartilage Invasion What to consider when patients refuse upfront surgery or medically inoperable?

44 Treatment Outcomes for T4 Laryngeal Cancer Institute No Treatment OS Larynx Preserved U Florida 1 43 XRT (bid) 37%(5y) 47% (5y) U Chicago 2 32 TFHX 53%(4y) 86% (med 43 mon followup) U Michigan 3 36 ind/conxrt 78%(3y) 67% (med 69 mon followup) Case 4 17 conxrt 64%(3y) 2 pt salvage laryngectomy 1. IJROBP 1998;40:549; 2. Ann Oncol 2008;19:1650; 3. Laryngoscope 2009;119: th International Head and Neck Symposium 2008

45 Treatment Outcomes for T4 Laryngeal Cancer About 20 to 25 % patients who did not need salvage surgery may need long term tracheostomy or PEG tube

46 T4A Laryngeal Cancer

47 T4A Laryngeal Cancer after ChemoXRT

48 Locally Advanced Laryngeal Cancer (T3-4, N2-3) What to consider for patients who are not candidates for chemoxrt and (refuse) surgery?

49 Radiation alone with altered fractionation Radiation with Cetuximab

50 RTOG PHASE III STUDY OF ALTERED FRACTIONATION VS. STANDARD FRACTIONATION S T R A T I F Y Site Oral Cavity Oropharynx Larynx Hypopharynx Stage N0 vs N+ KPS vs R A N D O M I Z E 1. Standard Fractionation 2. Hyperfractionation 3. Accelerated Fractionation (Split-Course) 4. Accelerated Fractionation (Concomitant Boost)

51 RTOG Standard fractionation Hyperfractionation Accelerated fractionation, split course 7000 cgy/35 fx 7 weeks 8160 cgy/68 fx 7 weeks (1.2 Gy Bid) Accelerated fractionation, concomitant boost 6720 cgy/42 fx 6 weeks (1.6 Gy Bid) 7200 cgy/42 fx 6 weeks

52 RTOG Results 2 yr LRC 2 yr DFS 2 yr OS Standard Fractionation Split-course Accelerated Concomitant Boost Hyperfractionated 46.0% 31.7% 46.1% 47.5% 33.2% 46.2% 54.5% 39.3% (p=0.05) (p=0.054) 50.9% 54.4% 37.6% 46.1% (p=0.045) (p=0.067) (p=0.13) Fu. IJROBP 2000;48:7-16

53 More than 1400 patients 6 fxs given either daily Monday to Saturday Or Bid one day in a week (Monday to Friday) Lancet 2003;362:

54 DAHANCA 6 & 7 Lancet 2003;362:

55 DAHANCA 6 & 7 Lancet 2003;362:

56 Radiation alone with altered fractionation Accelerated fractionation (Concomitant Boost) Six fractions per week (Bid one day per week, at least 6 hours apart between fractions)

57 Radiation plus Cetuximab vs. Radiation alone HNSCC stage III/IV, M0 R A N D O M I Z E Radiation alone Radiation plus weekly Cetuximab Bonner et al. NEJM 2006;354:

58 Kaplan-Meier Estimates of Local Regional Control Bonner et al. NEJM 2006;354:

59 Kaplan-Meier Estimates of Overall Survival Bonner et al. NEJM 2006;354:

60 Kaplan-Meier Estimates of Overall Survival 5 Year Update Bonner et al. Lancet Oncol 2010

61 Radiation technique in locally advanced laryngeal cancer

62 Conventional Radiation Techniques Initial setup 40 Gy, 2 Gy/fx/day 50 Gy, 2 Gy/fx/day

63 Conventional Radiation Techniques Off Cord electron Additional 14 Gy to 54 Gy

64 Conventional Radiation Techniques Final Boost Additional Gy to Gy

65 Intensity-Modulated Radiotherapy In the Treatment of Laryngeal Cancer

66 IMRT Results for Laryngeal Cancer Author No Locoregional Control Overall Survival Eisbruch 11 60% (3 y) NA Yao 33 85% (2 y) NA Lee 20 90% (2 y) 69% (2 y) Studer 58 65% (3 y) 78% (3 y) ultimate 82% (3 y) Daly 19 94% (3 y) 51% (3 y)

67 Target Delineation For Definitive IMRT CTV1 CTV2 GTV + 5 mm (tumor and involved nodes) CTV1 + high risk surrounding tissue (the whole larynx) High risk lymphatic areas CTV3 Intermediate risk lymphatic areas (lymphatic areas not included in CTV2)

68 Dose Fractionation in IMRT PTV1 PTV2 PTV3 70 Gy in 33 to 35 fractions 60 to 63 Gy in 33 to 35 fractions 50 to 56 Gy in 33 to 35 fractions PTV = CTV mm

69 Intensity-Modulated Radiotherapy T3N1 Laryngeal Cancer Red PTV1 70 Gy Purple PTV2 63 Gy Yellow PTV3 56 Gy

70 Intensity-Modulated Radiotherapy T3N2C Supraglottic cancer

71 Incorrect IMRT A patient with T3N0 larynx cancer, received definitive IMRT Only the larynx was included in IMRT

72 Incorrect IMRT Patient recurred just inferior to the radiation field

73 Postoperative Radiation in Laryngeal Cancer

74 Postoperative IMRT for Laryngeal Cancer Stoma > 60 Gy

75 Treatment of Hypopharyngeal Squamous Cell Carcinoma

76 Anatomy of Hypopharynx 3 parts - the 3 Ps Pyriform sinus Posterior pharyngeal wall Post-cricoid region

77 Anatomy of Hypopharynx Pyriform sinus Pyriform sinus

78 Pyriform Sinus Cancer

79 NC NP OC OP H L

80 EORTC LARYNX PRESERVATION FOR HYPOPHARYNGEAL CA. R A N D O M I Z E Induction Chemotherapy (3 Cycles) Surgery Radiation Therapy Complete Responders* Radiation Therapy Partial or Surgery XRT Non-Responders Induction Chemotherapy: Cisplatin and 5 FU J.L. Lefebvre et al, JNCI 88: , 1996

81 EORTC LARYNX PRESERVATION FOR HYPOPHARYNGEAL CA. S + RT CT+ RT+ S No. of patients yr. D-F Survival 27% 25% 5-yr. Survival 35% 30% Distant Mets. 36% 25% 5-yr. Alive with Larynx % J.L. Lefebvre et al, JNCI 88: , 1996

82 EORTC LARYNX PRESERVATION 10 year Results Median F/U: 10.5yrs S + RT CT+ RT+ S No. of patients yr. PFS 8.5% 10.5% 10-yr. Survival 13.8% 13.1% Distant Mets. 36% 25% 10 yr. Alive with functional Larynx 8.7% J.L. Lefebvre et al, Annals Oncology, 2012

83 IMRT for Hypopharyngeal Cancer Include bilateral retropharyngeal lymph node to skull base Include level V Pay attention to the lower edge of the hypopharynx

84 IMRT for Hypopharyngeal Cancer

85 IMRT for Hypopharyngeal Cancer

86 IMRT Results for Hypopharyngeal Cancer Author No Locoregional Control Overall Survival Eisbruch 12 75% (3 y) NA Lee 11 73% (2 y) 53% (2 y) Studer 65 80% (3 y) 80% (3 y) ultimate 89% (3 y) Daly 23 70% (3 y) 45% (3 y) Liu % (3y) 51.9% (3y) 63% (5y) 34.8% (5y)

87 NASOPHARYNGEAL CARCINOMA

88 INTERGROUP 99 (RTOG 88-17) Al-Sarraf et al, JCO, 1998 AJCC (1992) III or IV M0 R A N D O M I Z E RT alone (70 Gy) Conventional XRT RT (70 Gy) + CDDP x 3 CDDP + 5FU x 3

89 INTERGROUP 99 (RTOG 88-17) Minimal 5 year follow up for all patients CT/RT RT 5 yr progression-free survival 58% 29% (p<0.001) 5 yr disease-free survival 74% 46% (p<0.001) 5 yr overall survival 67% 37% (p<0.001)

90 INTERGROUP 99 (RTOG 88-17) Caucasian patients have more WHO type 1 histology, but Asian patients have more WHO type 3 histology.

91 National Cancer Center-Singapore Joseph Wee, JCO, 2005 AJCC (1997) III or IV M0 WHO II/III N = 221 R A N D O M I Z E RT (70 Gy) Conventional XRT RT (70 Gy) CDDP x 3 CDDP + 5 FU x 3

92 National Cancer Center-Singapore Joseph Wee, JCO, 2005 Median Follow up 37.8 months CT/RT RT 2 yr Disease Free Survival 76% 59% (p=0.027) 2 yr distant metastases-free rate 87% 70% (p=0.0007) 2 yr overall survival 84% 77% (p=0.006)

93 Can chemotherapy add any benefit beyond stage III/IV patients?

94 CCRT vs. RT alone for Stage II NPC Chen et al. JNCI 2011 Chinese stage II 230 Patients Med Follow-up 5 years R A N D O M I Z E RT (70 Gy) RT (70 Gy) Weekly CDDP (30mg/m2)

95 CCRT vs. RT alone for Stage II NPC Chinese stage II which is equivalent to AJCC II/III patients 78% received at least 6 cycles of CDDP and 26% received 7 cycles and 5% 8 cycles No difference in LRC (93% vs. 91%) Chen et al. JNCI 2011

96 CCRT vs. RT alone for Stage II NPC 5 year OS: 94.5% vs. 85.8%, p= year PFS: 87.9% vs. 77.8%, p= year DMFS: 94.8% vs. 83.9%, p=0.007 MVA showed the # of chemotherapy cycles was the only independent factor associated with better OS, PFS, Distant control Chen et al. JNCI 2011

97 NCCN Guidelines (V2.2011) T1N0M0 T1,N1-3, M0 T2-4, Any N Definitive XRT to Nasopharynx and Elective XRT to neck Concurrent ChemoXRT Followed by adjuvant chemo

98 Radiotherapy Advances Intensity Modulated Radiotherapy

99 IMRT for NPC:UCSF Lee et al, IJROBP 2002;53:1:12-21 N = 87 T3/T4: 45% III/IV: 74% N+: 79% Chemotherapy: 85%

100 4 Year Local Progression-free 97% N=87 Median F/U=30 months Lee et al, IJROBP 2002;53:1:12-21

101 4 Year Distant Metastases-Free 66% N=87 Median F/U=30 months Lee et al, IJROBP 2002;53:1:12-21

102 4 year Overall Survival 73% N=87 Median F/U=30 months Lee et al, IJROBP 2002;53:1:12-21

103 IMRT(15 studies) vs. Conventional Local Progression-Free Rate % 74%-93% Distant Mets-Free Rate 66%-91% 67%-84%

104 RTOG 0225 IMRT in NPC Stage: I-IVb Histology: WHO I-III R E G I S T E R 70 Gy to gross disease concurrently 59.4 Gy to microscopic disease Over 33 days CT:( T2b and/or + LN)

105 RTOG PROTOCOL 0225 Lee et al, JCO, 2009

106 Late complications of Radiation Xerostomia Temporal Lobe Necrosis Oral and dental complications Hearing loss (more with CCRT) Pituitary hypofunction Neural complications Soft and hard tissue necrosis

107 Two randomized trials for early-staged NPC showed IMRT to be superior to Conventional radiotherapy in terms Improving salivary function. Pow EH et al. IJROBP 66: , 2006 Kam MK et al. JCO 25: , 2007

108 IMRT in Nasopharyngeal Cancer Target Delineation Dose Prescription Treatment Planning

109

110 Initial stage T1N0 Nasopharyngeal cancer

111 PET upstaging to T1N1

112 There appears to be extension into the medial aspect of the left pterygopalatine fissure and extension into the left-sided vidian's nerve into the skull base.

113 Target Volumes in NPC CTV1 CTV2 CTV3 GTV-P and GTV-LN plus margins (5 mm bone and air) High-risk areas with microscopic disease Lower risk lymphatic regions

114 Target Volumes in NPC CTV2 CTV2: CTV2-Primary CTV2-Node

115 CTV1 CTV2-P CTV2-P Entire nasopharynx, posterior 4th or 3rd nasal cavity and maxillary sinus, anterior ½ to 2/3 clivus, laterally, parapharyngeal space.

116 CTV2-P CTV2-P skull base, and inferior sphenoid sinus (entire sphenoid sinus in T3/4 disease)

117

118 CTV2-Node Bilateral Upper deep jugular (junctional, parapharyngeal), Bilateral Level II, and level VA, Bilateral retropharyngeal nodes.

119 CTV2-Node And also the lymphatic region adjacent to involved nodes

120 Dose Prescription PTV 1 PTV2 PTV3 70 Gy/33 to 35 fractions Gy/33 to 35 fractions Gy/33 to 35 fractions

121 Radiation Dose Escalation? Altered Fractionation; Brachytherapy; SRS, accelerated fractionation in 2D and IMRT era. None of the trials showed benefit in terms of tumor control in the setting of chemoradiation. Late toxicities observed: temporal lobe necrosis, massive epistaxis, cranial neuropathies.

122 IMRT in Nasopharyngeal Cancer

123 Mean Parotid dose < 26 Gy; 50% of parotid dose < 30 Gy 70% larynx, hypopharynx, cervical esophagus < 45 Gy Or Use split-field IMRT if lower neck is not involved

124 Max optic nerves 50 Gy Max BS Dose: 50 Gy Mean Oral Cavity 40 Gy

125 NPC: 2013 and Beyond Since Intergroup 0099 from 15 years ago, despite multiple randomized trials, CCRT followed by adjuvant chemotherapy remains the standard. Stage II patients should be offered chemotherapy. Patients should be offered IMRT to maximize target coverage and spare normal tissues.

126 NPC: 2013 and Beyond Distant failure is main issue with this disease. More effective and less toxic systemic therapy is needed. Patient selection will be key for all future studies (EBV DNA).

127 NPC: 2013 and Beyond RTOG Developing Protocol T>2 or N+ WHO I-III R E G I S T E R IMRT (70 Gy) Plus CDDP X3 Low EBV High EBV R A N D O M I Z E R A N D O M I Z E Observe CDDP + 5FU X 3 New chemo Regimen (Gemcitabine)

128 Multidisciplinary Management of Head and Neck Cancer II Min Yao, M.D., Ph.D. Department of Radiation Oncology University Hospitals Case Medical Center Case Western Reserve University

129 Treatment of Oral Cavity Squamous Cell Carcinoma

130 Oral Cavity

131 Treatment Paradigm Oral Cavity Cancer Upfront surgical resection Adjuvant treatment based on risk factors from pathology

132 General Indications for Post-operative Radiation in Head and Neck Cancers Advanced stage Multiple lymph nodes involved Extracapsular extension (ECE) Positive/close surgical margins Perineural invasion Lymphovascular invasion Oral tongue cancer with deep invasion

133 General Principles in Post-operative Radiation in Head and Neck Cancers Delivered as soon as the wound is healed Hopefully within 4 to 6 weeks after surgery Radiation finished within 100 days after surgery (package time, Rosenthal. Head Neck 2002) At least 60 Gy Concurrent chemotherapy in high risk patients

134 Risk Adaptive Adjuvant Radiation Depending on Pathology Features

135 PORT in Head and Neck Cancer Phase III Randomized Study to Determine the Optimal Dose Pathology adverse Features ECE Margin + >2 N+ T stage PNI Oral cavity primary R A N D O M I Z E Low Risk High Risk Dose A 57.6 Gy/32 fx Dose B 63 Gy/35 fx Dose C 68.4 Gy/38 fx Peters, et al. IJROBP 1993;26:3

136 Local Regional Control by Risk Factors ECE >4 Peters, et al. IJROBP 1993;26:3

137 Low Risk Intermediate Risk High Risk Ang et al. IJROBP 2001;51:

138 Local Regional Control and Survival by Risk Factors Ang et al. IJROBP 2001;51:

139 RTOG 9501/EORTC Surgery Patients with high risk pathology features R A N D O M I Z E Arm 1 : Gy Arm 2: Gy plus Cisplatin X3

140 Results of EORTC Trial and RTOG 9501 (PORT vs PORT PLUS CHEMO) EORTC 22931(60 mo) End Point RT RT+CT p value RTOG 9501(45.9 mo) RT RT+CT p value 5 yr DFS 36% 47%.04 61% 78%.04 LR Control 69% 82% % 82%.01 5 yr OS 40% 53%.02 57% 63%.19 Bernier. NEJM 2004; 350:1945 Cooper. NEJM 2004; 350:1937

141 Overall Survival Results EORTC RTOG 9501 Bernier. NEJM 2004; 350:1945 Cooper. NEJM 2004; 350:1937

142 Combined RTOG/EORTC Analysis Bernier, Cooper. Head Neck 2005;27:843

143 Combined RTOG/EORTC Analysis Overall Survival for Patients WITH Positive Margin and/or ECE Bernier, Cooper. Head Neck 2005;27:843

144 Combined RTOG/EORTC Analysis Overall Survival for Patients WITHOUT Positive Margin and/or ECE Bernier, Cooper. Head Neck 2005;27:843

145 Long Term Follow Up of RTOG 9501 Patients with Positive Margin and/or ECE Cooper et al. IJROBP 2012

146 Risk Adaptive PORT depending on Pathology Risk Features Low Risk Intermediate Risk (neg margin, no ECE) High Risk (pos margin and/or ECE) Management No Radiation Radiation alone to 60 Gy Radiation to Gy with concurrent cisplatin

147 RTOG 0920 Phase III Intermediate Risk PORT Eligibility Perineural invasion; Lymphovascular invasion; T1, N1-2 or T2-4a, N0-2, no extracapsular extension Close margin (< 5 mm) T2 oral cavity cancer with > 5 mm depth of invasion. R A N D O M I Z E Arm 1 : 60 Gy Arm 2: 60 Gy plus Cetuximab X 11

148 RTOG 1216 Phase II/III High Risk PORT Eligibility Stage III or IV HNSCC Extracapsular extension < 3 mm surgical margin R A N D O M I Z E Arm 1 : Gy cisplatin X 6 Arm 2: Gy docetaxel X 6 Arm 2: Gy docetaxel and Cetuximab

149 Radiation Technique for Oral Cavity Cancer

150 General Principles in Target Delineation in Postoperative Radiation in HNC Review pre-operative information including physical exam and images to understand the extent of the disease Read operation note and talk to surgeon to find out the areas of concern Read pathology report and talk to pathologist Deformed registration of pre-operative images to post-operative simulation CT If still not sure, ask the surgeon to come to the planning room when you delineate targets

151 Target Delineation For Postoperative IMRT CTV1 CTV2 Tumor bed (tumor and involved nodes) CTV1 + high risk surrounding tissue High risk lymphatic areas (hemi-neck) CTV3 Intermediate risk lymphatic areas (lymphatic areas not included in CTV2)

152 Dose Fractionation in IMRT Intermediate Risk High Risk PTV1 PTV2 PTV3 60 Gy (30 fx) 66 Gy (30-33 fx) 60 Gy (30 fx) 60 Gy (30-33 fx) 54 to 56 Gy (30 fx) 54 to 56 Gy (30 fx) PTV = CTV mm

153 Published Series in Postoperative IMRT in Oral Cavity Cancer Chan et al Chan et al. Oral Oncology 2013;49:

154 Failure Patterns after Postoperative IMRT in Oral Cavity Cancer Primary tumor bed Infratemporal fossa/skull base Pterygoid muscle involvement Extensive perineural involvement Contralateral Neck Area between primary tumor and first echelon lymphatic region Yao, et al. IJROBP 2007;67:

155 IMRT Treatment Plan PET at Recurrence Yao, et al. IJROBP 2007;67:

156 Anatomy of Inferior Alveolar Nerve and Mental Nerve Yao, et al. IJROBP 2007;67:

157 Failure Patterns after Postoperative IMRT in Oral Cavity Cancer CT at Treatment Planning CT at Recurrence Yao, et al. IJROBP 2007;67:

158 Failure Patterns after Postoperative IMRT in Oral Cavity Cancer Primary tumor bed High level II/Skull base Contralateral Neck 1/3 failures were marginal and out-of-field Contralateral neck failures in patients received ipsilateral XRT or primary site XRT only Failures in high level II/skull base in the node positive neck Chan et al. Oral Oncology 2013;49: patients treated at Princess Margaret Hospital

159 Contralateral Level 1A and 2 Failure T3N1 oral tongue cancer. Post-op IMRT included only ipsilateral oral cavity and ipsilateral upper neck

160

161 Contralateral Level 2 Failure T2N1 oral tongue cancer, postoperative radiation Courtesy of Dr. Nancy Lee Damast, et al. Head Neck 2012;34:

162 Ipsilateral Level 3 Failure T2N1 oral tongue cancer, postoperative radiation Courtesy of Dr. Nancy Lee Damast, et al. Head Neck 2012;34:

163 Contralateral Level 2 Failure T4AN1 oral tongue cancer, postoperative radiation Courtesy of Dr. Nancy Lee Damast, et al. Head Neck 2012;34:

164 Submental Failure Patient with T4AN3 oral tongue cancer with FOM involvement. Level 1A was not included in the IMRT treatment Courtesy of Dr. Nancy Lee Damast, et al. Head Neck 2012;34:

165 Conclusions regarding treatment planning 1. Postoperative IMRT requires careful and comprehensive target volume delineation, and larger volumes may be needed than the primary RT setting. 2. Nearly a third of LRFs occurred in marginal or out-of-field locations, suggesting that more comprehensive radiotherapy volumes are needed. 3. Bilateral neck irradiation in patients with N2b disease (I say all oral tongue cancer) and inclusion of high level II (to the jugular foramen) in the presence of extensive nodal involvement are recommended. Chan et al. Oral Oncology 2013;49:

166 Oral Tongue Target Summary Oral tongue: pay attention to the depth of invasion Cover the entire tongue Cover the entire flap Bilateral neck included Include level 1b to level IV Cover high level II in the ipsilateral positive neck

167 Oral Tongue Target Summary Constrictor T4AN0 Oral Tongue SCC

168 FOM Make sure to cover level 1A and the submental skin well. Placement of Bolus in your planning Constrictor SCC of FOM extending into mandible

169 T4AN2C Buccal Mucosa Cancer, Recurred at skull base before PORT

170 Oral Tongue Cancer with Extensive Perineural Involvement and Skull Base Extension

171 Oral Tongue Cancer with Extensive Perineural Involvement and Skull Base Extension

172 perineural spread Make sure V3 is covered to the Base of Skull 35 F with recurrent SCC of gingivobuccal sulcus. R chin numbness

173 Conclusions Adjuvant treatment based on pathology features risk adaptive Careful attention to target delineation should be done for all cases. Comprehensive radiation needed

174 Treatment of Oropharyngeal Squamous Cell Carcinoma

175 Oropharynx Anatomy Base of the tongue Tonsils Anterior and posterior tonsillar pillars Tonsillar fossa Soft palate Posterior and lateral pharyngeal wall

176 Incidence of Oropharyngeal Cancer SEER data from 1973 to 2004 Oropharynx (HPVrelated Oral SCC) 17,625 Oral cavity (HPVunrelated Oral SCC) 28,144 Chaturvedi A K et al. JCO 2008;26:

177 Incidence of Oropharyngeal Cancer Oropharynx HPV-related Oral Cavity HPV-unrelated Chaturvedi A K et al. JCO 2008;26:

178 Incidence of Oropharyngeal Cancer 271 OPC collected in SEER from Overall incidence of OPSCC increased by 28% HPV- positive OPSCC increased by 225% HPV- negative OPSCC decreased by 50% Chaturvedi A K et al. JCO 2011;29:

179 Incidence Rates for Oropharyngeal Cancer Chaturvedi A K et al. JCO 2011;29:

180 Human Papillomavirus (HPV) DNA virus >100 different sub-types Infects skin and mucosa Asymptomatic Benign growths warts Oncogenic (cancer causing) types are mostly 16 and 18

181 HPV Virus Transforms Normal Cell Into Cancer Cell Nucleus Viral DNA integrates into normal cell DNA Viral DNA enters nucleus Virus uncoats viral proteins E6 and E7 Disables Tumor Suppressor Proteins Uncontrolled cell growth CA

182 HPV Biology E6 protein mediates p53 degradation. E7 protein binds to prb protein releases E2F => cell cycle progression to S phase

183 Presentation HPV-Positive HPV-Negative Anatomic Site Tonsil/BOT All sites Histology Basaloid Keratinized Age Younger Older Gender (M:F) 3:1 3:1 SE Status High Low Risk Factors Sexual behavior Tobacco/alcohol Incidence Increasing Decreasing Survival Improved Worse

184 Presentation HPV positive tumors tend to present with smaller primary disease T1-2 : T3-4 3:2 Most patients (especially HPV +ve) are node positive 80-90%

185 HPV and survival Trial Cases Marker Survival Rates First author, year RTOG HPV 82% vs. 57% (3- year) Ang, 2010 TROG p16 INK4A 91% vs. 74% (2- year) Rischin, 2010 DAHANC A 6/7 794 p16 INK4A 66% vs. 28% (5- year) Lassen, 2011 TAX HPV 82% vs. 35% (5- year) Posner, 2011

186 Risk Grouping for Overall survival from RTOG 0129 Ang et al NEJM 2010 Oropharyngeal Carcinoma (N=260) p16-positive (N=187) p16-negative (N=73) 10 pack-years (94) >10 pack-years (93) 10 pack-years (16) >10 pack-years (57) N0-2a (29) N2b-3 (64) T2-3 (9) T4 (7) Low-risk (N=123 or 47%) 3-Y OS: 94% Intermediate-risk (N=73 or 28%) 3-Y OS: 67% High-risk (N=64 or 25%) 3-Y OS: 42%

187 Risk Classification for Overall survival by p-16, Smoking, & T-N Category Ang et al NEJM 2010

188 Management Strategies in Oropharyngeal Cancer

189 NCCN grouping T1 2 N0-1 T3 4A N0-1 unresectable T1 4A N2-3

190 NCCN guidelines 3 basic recommendations for all groups Radiation (+/- concurrent chemotherapy) Surgery (+/- postoperative radiation/ chemoradiation) (except for unresectable disease) Induction chemotherapy followed by RT or CRT (except for early stage disease)

191 What is the optimal therapy for oropharynx cancer? No randomized trials (between Surgery vs XRT) MEDLINE search studies, ~ 6400 pts Parsons et al (2002) Marked similarities in all disease and survival outcomes Marked disparity with higher complication rates in Surgery +/- RT vs RT +/- ND Comparative functional outcomes poorly studied Parsons. Cancer 2002, 94:

192 Trends in treatment for advanced stage oropharyngeal cancers, 1985 to 2001, National Cancer Database data, N = 42,688. Surgery 2013 Changes in Treatment of Advanced Oropharyngeal Cancer, Chen, Amy, et al. Laryngoscope. 117(1):16-21, January 2007.

193 GORTEC French Trial: Oropharyngeal CA Stage III/IV Oropharynx N=226 R A N D O M I Z E Arm 1 : 5 FU + Carbo 70 Gy (QD) Arm 2: 70 Gy RT (QD) Denis et al. JCO, 2004

194 GORTEC French Trial: Oropharyngeal CA Chemo + RT RT Alone 5 yr LRC 48% 25% p= yr DFS 27% 15% p= yr OS 22% 16% p=0.05 Denis et al. JCO, 2004

195 MACH meta-analysis Set the Stage for concurrent chemoradiation Individual patient data trials;10,741 pts Absolute benefit of chemotherapy 4% Pignon et al. Lancet, 2000

196 Meta-analysis of locoregional treatment with and without chemotherapy: absolute effect on survival Pignon et al. Lancet, 2000

197 MACH updated (2007) Through 2000 (including 1965 to 2000); total 87 trials; 16,485 patients Still 4% survival benefit with chemo adding to radiation; 8% with concurrent chemoradiation Magnitude of benefit higher with platinum (p < 0.01); No difference between concurrent poly-chemo and mono-chemo Benefit consistent over all tumor locations (Blanchard, Radiotherapy Oncol 2011) Pignon et al, Radiotherapy Oncol 2009

198 MACH updated (2007) 5 year overall survival increased from 27.4% to 32.7% Significant benefits from studies with concurrent chemotherapy and from studies using cisplatin Blanchard. Radiotherapy Oncol 2011

199 Cisplatin Traditional cycles - RTOG - 100mg/m2 X 3 cycles (NPC +ve trial, larynx preservation, and EORTC postop trials, INTERgroup unresectable trial) Weekly - ECOG - weekly 20mg/m2 was ve; now common to see 30 (-40) mg/m2 little HN data, though cervical (GYN) data. Daily - Jeremic pts - randomize 6mg/m2/day CDDP + 70 Gy / > survival and LRC

200 Is the more the better? Is accelerated radiation with concurrent chemotherapy better than conventional fractionation radiation with concurrent chemotherapy?

201 GORTEC trial Stage III or IV of sq cell ca R A N D O M I Z E QD RT: 70 Gy / 7 weeks Carbo/5FU (n=279) Acc RT: 70 Gy / 6 weeks Carbo/5FU (n=280) Acc RT : 64.8 Gy/3.5 wks (n=281) Median F/U=5.2 years

202 GORTEC Bourhis et al. Lancet Oncology, 2012

203 RTOG 0129 S T R A T I F Y Zubrod PS 0 or 1 Site : larynx vs none Nodal Status : N0 N1 or N2a-b N2c-N3 R A N D O M I Z E Arm 1: AFX-CB/6 weeks 72 Gy/42 FXS/6 wks Cisplatin 100 mg/m2 days 1 and 22 Arm 2: 70 Gy in 7 weeks Cisplatin 100 mg/m 2 days 1, 22, 43.

204 RTOG 0129: Trial Endpoints Primary Endpoint

205 Is the more the better? Can cetuximab add any benefit to concurrent chemoradiation?

206 RTOG 0522 S T R A T I F Y Zubrod PS 0 or 1 Site : larynx vs none Nodal Status : N0 N1 or N2a-b N2c-N3 R A N D O M I Z E Arm 1: AFX-CB or IMRT plus CDDP 100 mg/m2 days 1 and 22 Plus cetuximab Arm 2 :AFX-CB or IMRT plus CDDP 100 mg/m2 days 1 and 22

207 RTOG patients were enrolled Median follow-up 2.4 years 2 year progression-free survival: 63% vs. 64%. p= year overall survival: 83% vs. 80%, p = 0.17 Arm A had higher rates of grade 3-4 mucositis (45% vs. 35%, P=0.003) and skin reactions (40% vs. 17%, P<0.0001) Ang ASCO 2011

208 Is the more the better? The More is NOT the better

209 Sequential Combined Modality Therapy A Phase III Study: TAX 324 TPF vs PF Followed by Chemoradiotherapy R A N D O M I Z E T P F P F Carboplatinum - AUC 1.5 Weekly EUA Daily Radiotherapy Surgery TPF: Docetaxel 75 D1 + Cisplatin 100 D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 Posner et al, NEJM 2007

210 TAX324 Posner et al, NEJM 2007

211 TAX 323. NEJM 2007

212 TAX324 The control arm PF induction chemo not standard treatment 83% of patients on TPF had grade 3-4 neutropenia and 65% grade 3-4 nonhematologic effects Only 73% completed treatment per protocol Posner et al, NEJM 2007

213 The Paradigm Study: Sequential Therapy vs. Chemoradiotherapy A Phase III Study of TPF/C-XRT vs P-ACBXRT R A N D O M I Z E T P F P Q 3 Weeks XRT 3 Cycles of Chemotherapy NR PR,CR T* C ACB Daily Radiotherapy Surgery Surgery ACB Radiotherapy *T + ACB for Non-Responders

214 Phase III Sequential Trial: University of Chicago DeCIDE Trial R A N D O M I Z E T P F T H F 2 Cycles of Chemotherapy * 6 Cycles of Every Other Week Chemoradiotherapy * T H F X 6 Cycles of Every Other Week Chemoradiotherapy * X * Cisplatinum (P); Docetaxel (T); Hydoxyurea (H); 5-Fuorouracil (F); BID Radiotherapy (X)

215 Randomized Induction Trials PARADIGM Terminated due to slow accrual Analyzed 145 of planned 300 pts 3y overall survival 73% induction v 78% upfront CRT (p=.77) DeCIDE 280 pts 3y overall survival 75% induction v 73% upfront CRT (p=.70) Lower rates of DF (10% v 19%, p=.025) did not translate into survival benefit ASCO 2012

216 Conclusion for Induction Chemotherapy Induction chemotherapy with TPF should NOT be considered as standard treatment. It may compromise patients to receive concurrent chemoxrt due to delay and side effects. Use only in patients who may have delay in definitive concurrent chemoxrt, could not tolerate radiation, or in clinical trial settings

217 Radiation Treatment Technique IMRT

218 T2 N1 M0 Tonsil Cancer Primary Tumor Neck Node Twenty centers from U.S., Europe and Asia with known H&N IMRT expertise Courtesy of Dr. Harari

219 H&N IMRT Practice Heterogeneity T2 N1 M0 Tonsil Cancer P. Harari: Radiotherapy & Oncology 2012 Courtesy of Dr. Harari

220 RTOG Guidelines RTOG 0022 (T1-2, N0-1) CTV1 GTV + areas considered to contain potential microscopic disease; typically 1-2 cm; minimum 5 mm except if GTV adj to areas known to be uninvolved CTV2 optional high risk subclinical disease (first echelon nodes) CTV3 - lymph node groups at risk RTOG 1016 (HPV pos.) CTV1 GTV cm CTV2 High risk subclinical disease possible local subclinical infiltration of the primary site, and first echelon lymph nodes CTV3 remaining neck nodal levels at risk (nodal levels not first echelon nodes and not adjacent to levels containing grossly involved nodes)

221 Target Delineation For Definitive IMRT CTV1 CTV2 GTV mm (tumor and involved nodes) minus bone and air CTV2-P CTV1 + high risk adj. tissue CTV2-N High risk lymphatic areas CTV3 Intermediate risk lymphatic areas (lymphatic areas not included in CTV2)

222 RTOG Dosing Guidelines RTOG 0022 (T1-2, N0-1) RTOG 1016 (HPV positive) PTV1 66 Gy/30 fx PTV1 70 Gy/35 fx 2.2 Gy/fx 2.0 Gy/fx PTV2 60 Gy/30fx PTV2 56 Gy/35 fx 2.0 Gy/fx 1.6 Gy/fx PTV3 54 Gy/30fx PTV Gy/35 fx 1.8 Gy/fx Gy/fx

223 Dose Fractionation in IMRT/Chemo PTV1 PTV2 PTV3 70 Gy in 33 to 35 fractions 60 to 63 Gy in 33 to 35 fractions 50 to 56 Gy in 33 to 35 fractions PTV = CTV mm

224 Base of Tongue Target Delineation CTV 1 (Red)

225 Base of Tongue Target Delineation CTV2 (Blue) CTV 3 (Yellow)

226 Base of Tongue Isodoses

227 Tonsil Target Delineation CTV 1 (Red) Courtesy of Dr. Garden

228 Tonsil Target Delineation CTV 1 (Red) CTV2 (Blue) CTV 3 (Yellow) Courtesy of Dr. Garden

229 Tonsil planning 3-D view CTV 1 (Red) CTV2 (Blue) CTV 3 (Yellow) Courtesy of Dr. Garden

230 Tonsil isodoses

231 RTOG Dosing Guidelines 95% of the high dose PTV covered with prescription No more than 20% to receive >110% dose No more than 1% to receive < 93% No more than 1% (or 1 cc) outside PTV should receive >110%

232 IMRT for Oropharynx First Author, year Patient number Median follow up (months) Disease control Feng, % (LRC, crude) Studer, % (LC, 2y) Mendenhall, % (LRC, 5y) Daly, % (LRC, 3y) Setton, % (LC, 3y) Sher, % (LRC, 3y) Garden, % (LRC, 5y) Clavel, % (LRC, 3y) Courtesy of Dr. Garden

233 Ipsilateral Radiation in Lateralized Tonsil Cancer T1-T2, N0-N1 tumor Less than 1.0 cm extension to soft palate No base of tongue involvement ACR Appropriateness Criteria. Head Neck 2012;34:

234 Stage T2N0 Tonsil Cancer

235 Ipsilateral Radiation in Tonsil Cancer

236 Ipsilateral tonsil radiation First author, year Patient number % N0-1 % T1-2 Contralateral neck failure Jackson, % 65% 3% (N0-1) Kagei, % 56% 0% O Sullivan, % 84% 3% Rusthoven, % 90% 0% Chronowski, % 100% 2% Courtesy of Dr. Garden

237 26 patients treated with IMRT versus 27 with conventional XRT.

238 QOL for IMRT in Oropharynheal Cancer Main HNCI domain scores at 12 months after treatment Yao. IJROBP 2007;69:

239 QOL for IMRT in Oropharynheal Cancer Types of diet at 12 months Yao. IJROBP 2007;69:

240 QOL for IMRT in Oropharynheal Cancer Mean eating scores across the first year Yao. IJROBP 2007;69:

241 QOL for IMRT in Oropharynheal Cancer Nutting. Lancet Oncol 2011;12:127-36

242 QOL for IMRT in Oropharynheal Cancer Mean EORTC HN35 dry mouth score Nutting. Lancet Oncol 2011;12:127-36

243 Future Prospective Management of HPV-related Oropharyngeal Cancer De-escalation Regimens

244 RTOG Cetuximab-RT vs ChemoRT Eligibility Oropharynx P16 pos T1-2, N2a-3 T3-4 any N S T R A T I F Y T-stage T 1,2 T 3,4 N-stage N0-2A N2B-C Smoking <10 PY >10 PY R A N D O M I Z E IMRT 70 Gy in 6 wks cisplatin x 2 IMRT 70 Gy in 6 wks cetuximab for 8 wks N= yrs to enroll ~8 yr to analysis Zubrod 1 2 IMRT 6 fractions per week

245 ECOG 1308: HPV-specific Trial Chemotherapy to Select Patients for Lower Dose Radiation ELIGIBILITY INDUCTION (3 cycles) CR CONCURRENT IMRT 54Gy/27 fxs Stage III,IVA,B Resectable Weekly Paclitaxel Cetuximab 250mg/m2 qwk HPV + Oropharynx + Cetuximab CONCURRENT IMRT 69.3Gy/33fxs N=83 <CR Cetuximab 250mg/m2 qwk Cetuximab loading dose = 400mg/m2 on Day1 of Cycle1 with Induction

246 Advancement in Surgery Historical surgeries for OPC were open resections Advent of minimally invasive transoral techniques TLM transoral laser microsurgery TORS transoral robotic surgery

247 Minimally Invasive Surgery First author, year Moore, 2012 Genden, 2009 Weinstein, 2012 Weinstein, 2010 White, 2010 Haughey, 2011 Patient number 66 TORS +ND 20 TORS +ND 30 TORS +ND 47 TORS +ND 89 TORS +/- ND Surgery T1 2 (%) / N2c(%) XRT / Chemo- XRT LRC 90% /12% 21% / 42% 97% LC/94% RC 100% / 0% 35% / 15% ND 83% / 0% 0%/ 0% 97% LC 76% / 4% 28% / 57% 98% LC/96% RC 80% / 13% 63% / ND 89% 204 TLM +ND 66% / 8% 54% / 25% 93% Courtesy of Dr. Garden

248 ECOG 3311 P16+ Trial Low Risk OPSCC: Personalized Adjuvant Therapy Based on Pathologic Staging of Surgically Excised HPV+ Oropharynx Cancer Assess Eligibility: HPV (p16) + SCC oropharynx Stage III-IV: ct1-3, N1-2b (no T1N1) Baseline Functional/ QOL Assessment LOW RISK: T1-T2N0-N1 negative margins Transoral Resection (any approach) with neck dissection HIGH RISK: Positive Margins > 1 mm ECS or 4 metastatic LN R A N D O M I Z E Observation Radiation Therapy IMRT 50Gy/25 Fx INTERMEDIATE: Clear margins 1 mm ECS 2 3 metastatic LN PNI LVI Radiation Therapy IMRT 60 Gy/30 Fx Radiation Therapy IMRT 66 Gy/33 Fx + CDDP 40 mg/m 2 wkly Evaluate for 2-yr PFS Local-Regional Recurrence, Functional Outcomes/QOL

249 RTOG Randomized Phase II High Risk OPSCC: Risk Based Therapy for HPV negative Oropharynx Cancer Assess Eligibility: HPV (p16) negative SCC oropharynx Stage III-IV: ct1-3, N0-2b Baseline Functional/ QOL Assessment R A N D O M I Z E IMRT 70 Gy +/- chemotherapy Transoral Resection and Neck dissection Risk-based PORT +/- chemotherapy

250 Conclusions Increased incidence of oropharyngeal cancer due to HPV Concurrent chemoxrt is the standard for locally advanced oropharyngeal cancer. IMRT offers better QOL in oropharyngeal cancer. Dose de-escalation under investigation in HPVrelated oropharyngeal cancer. Role of minimal invasive surgery needs to be defined.

251 The Question: The best radiotherapy regimen for T2N0 glottic squamous cell carcinoma is: A. 1.8 Gy per fraction daily to 70.2 Gy B. 2.0 Gy per fraction daily to 70 Gy C Gy per fraction daily to Gy D. 1.2 Gy perfraction twice daily to 79.2 Gy