1. 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

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

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

4. 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

5. 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.

6. 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

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

8. 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

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

10. 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.

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

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

13. 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
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)

14. 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)

15. 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

16. 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)

17. 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

18. 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

19. 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

20. REIRRADIATION
Patient Selection
Institutional Nomograms

21. REIRRADIATION
UNIV OF MICH 2016

22. REIRRADIATION
UNIV OF MICH 2016

23. REIRRADIATION

24. REIRRADIATION

25. REIRRADIATION
Riaz, N 2014 Memorial

26. REIRRADIATION
Riaz N 2014 Memorial

27. REIRRADIATION
Riaz, N, 2014 Memorial

28. Patient examples
To be added

29. 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

30. 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

31. Thank you