This document summarizes salvage radiotherapy approaches for locally recurrent nasopharyngeal cancer. It reviews outcomes from 2D/3D radiotherapy era showing unsatisfactory results. IMRT era studies showed improved local control and survival, especially for early T stages. Proton therapy studies demonstrated favorable dosimetry with lower normal tissue doses and less toxicity compared to photon therapies. Overall, IMRT remains the standard approach but particle therapies like proton therapy may further improve therapeutic ratio for recurrent nasopharyngeal cancer.

1. Salvage re-RT for locally recurrent
nasopharynx cancer
Yong Chan Ahn, MD, PhD
Dept. of Radiation Oncology
Samsung Medical Center, Sungkyunkwan University School of Medicine

2. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

3. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

4. • 176 local recurrence among 903 non-metastatic patients (19.5%) @ PWH
from ’84 till ’89.
• 103 were treated with re-RT, 20 with surgery +/- postop RT, 43 with
palliative Tx.
• Outcomes following high dose re-RT were not satisfactory (OS and LCR
@ 5 years were 7.6% and 15.2%) with TLN in 20.4%.
• DFI ≤1.5 years and advanced rT and rN stages were significantly adverse
prognosticators for OS and/or further LC.
• Restricting to rT1-2, nasopharyngectomy was better than re-RT.
Red 1998

5. 15.2%
7.6%
• In 123 Pts following local
Tx, 5-Yr LCR, RFS, and
OS were 18.7%, 11.5%,
and 9.4%.

7. Unsatisfactory clinical outcomes with
high incidence of severe late toxicity!

8. • 847 local recurrence among 4,460 non-metastatic patients
(19.0%) @ QEH from ’76 till ’85.
• 678 were treated with re-RT.
• Long latency  different behavior.
• Better prognosis d/t lower risk of distant failure.
Red 1999

13. • 319 local recurrence as 1st failure (10.9%) among 2,915 Pts @ HK
Nasopharyngeal Ca Study Group (PWH, TMH, QMH, PYNEH,
and QEH) from ’96 till ’00.
• OS @ 3 years 74%.
• Early initial T and use of salvage Tx were favorable factors.
• Salvage Tx improved OS only in rT1-2, but not in rT3-4.
HN 2005

16. Promising outcomes in early T categories!

17. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

18. • Re-RT (IMRT) to 239 locally recurrent NPC Pts @ SYU from ’01 till ’08.
• OS, LCR, DMFS and DFS @ 5 years were 44.9%, 85.8%, 80.6% and
45.4%.
• Pts with rT3-4 and GTV >38 cm3 experienced grade 3-5 late toxicities more
frequently.
• GTV >38 cm3, fractional dose >2.3 Gy, age ≤46 years, rN0 and rI/II stage
were all independent favorable prognostic factors for OS.
Clin Oncol 2012

19. • Re-RT (IMRT) to 151 locally recurrent NPC Pts @ SYU from ’01 till ’06.
• OS, LCR, DMFS and DFS @ 5 years were 38.0%, 80.7%, 83.5% and
69.0%.
• 39% of rIII/IV Pts experienced Grade 3~4 late toxicities.
• Larger rGTV >42 cm3 and rT3-4 were adverse predictors for OS.
EJC 2012

20. • Re-RT (IMRT) to 70 locally recurrent NPC Pts @ Fujian Univ. from ’03 till
’09.
• OS, LCR and DFS @ 2 years were 67.4%, 65.8% and 65.8%.
• Moderate to severe late toxicities in 25 Pts (35.7%): mucosal ulcer (11, 15.7%);
CN palsy (17, 24.3%); trismus (12, 17.1%); and deafness (12, 17.1%).
• Longer DFI ≥36 months and advanced initial T stage were adverse prognostic
factors for OS, LCR and DFS.
Red 2012

21. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

22. Oral Oncol 2012
• Tx should be highly individualized, depending on site and extent
of recurrence, availability of equipment and expertise.
• For re-RT, most conformal and precise technique should be
used:
– IMRT and/or FSRT are current standard.
– Hope for proton and particle beam Tx.
– Optimization of dose schedule remains to be explored.

23. Curr Oncol 2013

24. • Surgery for only in very select cases (good patients’ condition;
small rT1-2; technically accessible and resectable)
• Re-RT by 2D/3D RT can lead to very high complication rate
(48%~73% @ 5 years)
• IMRT +/- chemotherapy remains principle modality (OS of
45%~65% @ 5 years)!
CCO 2016

25. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

26. • Meta-analysis of 779 patients from 17 studies
• 5-Yr OS, LCR and DMFS of entire cohort were 51.2%,
63.4 %, and 88.7%
Ann Surg Oncol 2014

29. • 894 rNPC patients from ’00 till ’09 @ SYU.
• rT/rN were stratified as resectable and unresectable
and sT/sN were proposed.
EJC 2015

32. sStage I

33. sStage I
sStage II

34. sStage I
sStage II
sStage III

35. • ‘Surgical’ staging system exhibits better prognostic value
for rNPC patient survival and can aid clinicians in
selecting most suitable Tx option.
sStage I
sStage II
sStage III

36. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

37. SMC Experience
• 72 Pts with local or regional recurrence
underwent salvage re-RT from ’95 to ’15
@ SMC
• Median DFI between initial RT and re-RT
= 22.8 (3.4~111.0) months
• 54 local +/- neck; 18 regional only
• Symptoms @ recurrence:
– cranial neuropathy (n=8), local pain
(n=5), obstructive Sx (n=2), and
bleeding (n=2)
Characteristics Number
Median age (range) 50 (28-73) years
Sex
M 52 (72.2%)
F 20 (27.8%)
ECOG PS
0-1 54 (75.0%)
2-3 18 (25.0%)
Histologic type
Squamous cell ca. 17 (23.6%)
Non-keratinizing ca. 12 (16.7%)
Undifferentiated ca. 40 (55.6%)
Carcinoma, NOS 3 (4.2%)
Sx at recurrence
Yes 55 (76.4%)
No 17 (23.6%)
rT (AJCC 7th)
0 18 (25.0%)
1-2 22 (30.6%)
3-4 32 (44.4%)
rN (AJCC 7th)
0 41 (56.9%)
1 26 (36.1%)
2 4 (5.6%)
3 1 (1.4%)
Number of recurrence
Single 55 (76.4%)
Multiple 17 (23.6%)

40. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

41. • 16 recurrent HNC treated with particle beams @
Heidelberg.
Green 2011

42. • Treatment was tolerated well without severe acute toxicity.
• Favorable overall response rate @ 8 weeks (53.3%) in non-chordoma/
chondrosarcoma Pts; stable disease in 4/5 chordoma/chondrosarcoma Pts.
• Scanned particle beams in recurrent HNC seems feasible and
encouraging.

43. • Comparative dose planning with robust IMPT vs HT in 7
recurrent HNC patients @ Univ. Duisburg-Essen.
Rad Oncol 2013

44. • HT yielded steeper dose gradients @ ≤7.5 mm outside target and more
conformal high dose regions than IMPT.
• Comparable robustness against set-up errors of up to 2 mm by both.
• Satisfactory normal tissue exposure by both.
• IMPT delivered smaller mean body dose.
• Comparative dose planning is recommended!

45. • Comparison of IMPT and IMRT by 1:2 matching @ MDACC
from ’11 till ’13.
Int J Particle Ther 2015

47. • Significantly lower mean doses to
OC, brainstem, whole brain, and
mandible by IMPT.

48. • Less GT insertion mainly by lower OC dose by IMPT (2 vs 13).

49. • There appears to be significant clinical benefit for protons
in full dose re-RT of skull-base tumors, although additional
F/U is required.
• Integration of IMPT is still considered investigational for
bulky OPSCC and requires strict attention to variables
causing dose deposition uncertainty.
• Results of ongoing randomized trial (IMPT vs IMRT for
OPSCC) will provide valuable insight into safety and
potential for reduced toxicity with IMPT.
Curr Opin 2015

50. • Pending additional clinical and health economic evidence,
allocation of patients to IMPT vs IMRT is done on case-by-
case basis, weighing expected costs and benefits.
• Biological optimization, taking advantage of biological
effectiveness, holds potential to further enhance therapeutic
ratio with proton therapy.
Curr Opin 2015

51. Soon or later, more and more will come!

52. • 2D/3D RT era
• IMRT era
• Review articles
• Surgical viewpoints
• SMC experience
• Proton therapy
• Summary

54. Therapeutic Ratio
% tumor control by therapy A vs therapy B
Therapeutic Gain Factor (TGF) =
% complications by therapy A vs therapy B

55. Proton Therapy Center
Samsung Medical Center