Locally Recurrent Head and Neck Cancer (Salvage IMRT - Dose, fractionation, volumes) Eddy S. Yang, MD, PhD Professor and Vice Chair of Translational Sciences Department of Radiation Oncology University of Alabama-Birmingham

Disclosures Research support from Eli Lilly, Bayer, Janssen, Tesaro Advisory Board Strata Oncology Consultant Nanostring Technologies

REIRRADIATION Objectives Review of clinical data for re-irradiation Discuss technical considerations

REIRRADIATION Locally advanced head and neck cancer patients have loco-regional failure rates which approach 50%. Second primary tumor can develop in 15% of patients Vast majority of these occur in previously irradiated areas and thus poses a common challenge to H&N oncologists

REIRRADIATION Salvage surgery is the standard option but produces disease control in 15-20% of patients. Chemotherapy is commonly used in the recurrent/metastatic population when patients are inoperable. The median survival is 6-10 months.

REIRRADIATION Retreatment with radiotherapy for many years was not feasible because of the risk of increase toxicity Institutional experiences, RTOG, and French randomized postop studies documented the feasibility and efficacy. Toxicity however is still a concern Osteonecrosis Fistulas Carotid rupture Pharyngeal Stenosis Aspiration

REIRRADIATION – recurrence or 2nd primary Unresectable Disease Postoperative Salvage surgery alone: 2 Yr LC of 20% Only 20% of patients are eligible for surgery

H&N Re-Irradiation (Recurrence or Second Primary) IMRT: 60Gy in 1.5Gy/fx BID on alternate weeks SBRT: Various regimens Toxicity: late tissue toxicity, especially soft tissue necrosis, fistula formation, and potential nerve damage. No prophylactic /elective treatment PS: ECOG 0-1 BID regimen at least 4 hours apart Nancy Lee - No parotid sparing was enforced with either modality, Just followed brain stem doses and SC. Median salvage RT does ranged 30-70Gy NCCN HN 2017 RTOG 96-10, 99-11

REIRRADIATION – RTOG 99-11 and 96-10 Langer et al. JCO 2007

OS: 4% @ 5yrs Better survival if ≥1yr Previous RT Outcome: 2-year OS 15%, 5-year OS 4%; better survival if >1 year from prior RT. No dose-response Toxicity: Acute Grade 4 in 18%, Grade 5 in 8% (Mostly due to hematologic tox). Late (>1-year) Grade 3-4 9% Graph 1: OS ( 3 / 79 pts alive at 5 yrs) Acute Toxicity: Mostly due to hematologic toxicity.

REIRRADIATION Janot et. al. JCO 28:(34), 2008

REIRRADIATION Janot et. al. JCO 28:(34), 2008

H&N Re-Irradiation (Recurrence or Second Primary) MSKCC experience IMRT predicted better LR control than conventional modalities Single institutional retrospective review of re-irradiated HN cancers b/w 1996-2005 75 pts received chemo (platinum based in the majority) The cumulative radiation dose delivered to the spinal cord was limited to 50 Gy, and to the brainstem, 60 Gy Conventional, 3DCRT, and IMRT used Different chemo agents used. Graph: LRDFS improved with IMRT (Lee et al, IJROBP 2007)

REIRRADIATION – technical considerations RTOG multicenter phase I/II trials established the feasibility of re-irradiation in the pre-imrt era. Eligibility criteria included limitations for the spinal cord of 50Gy cumulative doses. Inclusion criteria included mucosal SCC histology, 6 months since initial RT, non nasopharyngeal sites. “PTV” treated on studies 1.5 – 2.0cm Margin recommendations are 3 – 5 mm Requires Adequate immobilization Daily imaging (IGRT)

REIRRADIATION N Margins Median Dose (Gy) Late Toxicity 2 Yr Surv %   N Margins Median Dose (Gy) Late Toxicity 2 Yr Surv % Spencer 79 GTV +2cm 60 23% 15 Salama 114 GTV +1+ LN 64 18 22 Lee 105 GTV+1-2 59 11 37 Biagoli 42 12 48 Crevoisier 169 GTV+1.5-2 65 50 21 Langer 99 GTV+2+Nodes 38 25 Schaefer 32 GTV+2 40-50 10 Hehr 27 GTV+1 40 Kramer 50-60 35 Goldstein 28 GTV+1+Nodes 61 57 Eisburch 66 GTV+0.5 68 29

H&N Re-Irradiation - SBRT Current investigated regimens rage from 30-44Gy in 5 fractions. (NCCN 2017) Not recommended if if tumor surrounds ≥1/2 carotid wall. Cengiz et al. IJROBP 2011: 17% rate of carotid blowout syndrome. Kodani et al, J Radiat Res 2011 : 2 pts died of carotid blowout. Maximum dose to carotid artery in these pts were 30.7Gy and 31.7Gy. Smaller target volumes assoc. with better OS (Kodani et al) and LC ( Vargo et al)

SURVEY OF CURRENT PRACTICE REIRRADIATION – SBRT SURVEY OF CURRENT PRACTICE 15 INTERNATIONAL INSTITUTIONS SBRT USE IN 10-15% OF CASES Centers use 3-5cm and 25-30cc constraint for disease Volume expansions vary from 1-10mm Fractionation varies from 15-22Gy in 1 fx to 30-50Gy in 5-6Fx Carotid blowout varies from 3-20% Lo, SS Future Oncol Nov 2016

Systemic statistical analysis on 5 trials of re-irradiation 233 pts included in analysis Dose response analysis could not be done due to wide range of fractionation regimens These include trials with/without Cetuximab Baliga S et al, Head Neck 2017

OS data from individual lesions treated in each study were aggregated to form a single dataset. Kaplan–Meier curves for OS were generated from each study. 1yr actuarial survival was 49%, 2yr= 24%. Baliga S et al, Head Neck 2017

REIRRADIATION Patient Selection Institutional Nomograms

REIRRADIATION UNIV OF MICH 2016

REIRRADIATION UNIV OF MICH 2016

REIRRADIATION

REIRRADIATION

REIRRADIATION Riaz, N 2014 Memorial

REIRRADIATION Riaz N 2014 Memorial

REIRRADIATION Riaz, N, 2014 Memorial

Patient examples To be added

RTOG 3507 PHASE II RANDOMIZED REIRRADIATION FUTURE RESEARCH RTOG 3507 PHASE II RANDOMIZED SBRT 40GY/5FX VS 40GY/5FX WITH PEMBROLIZUMAB N = 102 5cm maximum tumor size RT every other day Pembrolizumab q3 weeks

Summary HN re-irradiation is feasible for select patients with recurrent cancer or second primary in previously irradiated field Nomograms Care is required to reduce risk of toxicity

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