This document summarizes the use of intensity-modulated radiation therapy (IMRT) for lung cancer. It discusses: 1) Types of IMRT including LINAC-based step-and-shoot, dynamic, and VMAT techniques as well as tomotherapy-based helical IMRT. 2) Retrospective studies show IMRT improves target coverage and reduces toxicity compared to 3DCRT, though results for organ at risks are mixed. 3) Prospective studies demonstrate the safety and efficacy of hypofractionated IMRT schedules. 4) Proton therapy may further improve sparing of organs at risk compared to photon-based IMRT techniques.

1. IMRT for Lung Cancer
Yong Chan Ahn, MD, PhD
Dept. of Radiation Oncology
Samsung Medical Center
Sungkyunkwan Univ. School of Medicine
HICARE, 2017

4. Types of IMRT
• LINAC-based:
• MLC motion:
• Step & shoot
• Dynamic
• Rotating gantry (VMAT)
• Tomotherapy-based:
• Helical rotation

5. JTO, 2014
Clin Oncol, 2016

6. • Improved PTV coverage with IMRT.
• Mixed results to OARs:
• IMRT reduces V20, heart and spinal cord doses
• Variable V5 was variable

7. • Treatment time advantage in favor of VMAT over standard
IMRT: VMAT (6.5 minutes) vs IMRT (11.1 minutes) vs
Tomotherapy (15.9 minutes).
• Shorter treatment time reduces risk of intra-fractional
movement and maximizes linear accelerator capacity.

8. Retrospective clinical studies (Tx and planning parameters)

9. Retrospective clinical studies (toxicity and outcomes)

10. Retrospective studies
• Yom et al. (MDACC, Red, 2007):
– 68 NSCLC patients (85% stage III) treated with IMRT
(2002~2005).
– 222 historical controls treated with 3DCRT (2000~2003).
– Reasons for IMRT: large treatment volume, failure to
meet normal tissue dose constraints for 3DCRT,
synchronous lung primary tumors, and poor baseline
pulmonary function.
– Majority received 63 Gy in 35 fractions and concurrent
platinum-based doublet chemotherapy.
– Despite larger GTV in IMRT (194 cc vs 142 cc), V20 was
significantly lower, but V5 was larger than 3DCRT.
– Incidence of grade ≥3 TRP was significantly lower in
IMRT (8% vs 22% at 6 months).

11. Retrospective studies
• Liao et al. (MDACC, Red, 2010):
– 91 patients treated with 4DCT/IMRT (2004~2006).
– 318 historical controls receiving 3DCRT (1999~2004).
– Median 63 Gy using conventional fractionation.
– IMRT group contained greater proportion of patients
who were older, current smokers, or staged with PET-
CT (82% 4DCT IMRT vs 49% 3DCTRT).
– GTV was not reported.
– Reduced rate of TRP in IMRT group, with significantly
lower V20 (34% vs 37%) and higher V5 (65% vs 57%).
– Similar LC and DM, but improvement in OS in IMRT
group (median OS 1.40 years for 4DCT/IMRT and 0.85
year for 3DCRT).

12. Retrospective studies
• Jiang et al. (MDACC, Red, 2012):
– Long-term outcome of 165 patients treated with 4DCT
IMRT (76% stage III) +/- concurrent chemotherapy.
– Median 66 Gy in 33 Fxs and median GTV was 124.6
(4.3~730) cc.
– 11% developed grade ≥3 TRP at 6 months; one grade
3 pulmonary fibrosis at 18 months.
– 29 (18%) experienced grade 3 esophagitis and majority
settled within 6 weeks; 4 developed esophageal
stricture.
– Incidence and severity of toxicities were lower in IMRT
patients than historical controls.
– With median 16.5 months FU, 2-year DFS and OS were
38% and 46%.

13. Retrospective studies
• Sura et al. (MSKCC, Green, 2008):
– Assessed toxicity of IMRT in 55 stages Ib–IIIb (62%
stage III) NSCLC patients (2001~2005).
– 60 Gy in 30 fractions with either sequential (53%) or
concurrent (24%) chemotherapy.
– Mean GTV was 136 cc.
– With median follow-up of 12 months, 6 (11%) grade 3
pulmonary toxicity, and 2 (4%) grade 3 esophageal
toxicity.
– 2-Yr OS was 58% with median survival of 25 months.

14. Retrospective studies
• Govaert et al. (Green 2012):
– 71 stages IIb–IIIb NSCLC patients treated with IMRT
(2008~2011).
– up to 66 Gy in 33 fractions with chemotherapy.
– Mean GTV volume was not reported.
– No grade 3/4 pulmonary or esophageal toxicity was
observed, and no treatment-related deaths.
– With median follow-up of 12 months, median survival
was 29.7 months and 2-Yr OS was 56%.

15. Retrospective studies
• Uyterlinde et al (Clin Lung Ca, 2013) and Chen et al
(Green, 2013) (Netherlands Cancer Institute):
– Hypo-fractionated IMRT (66 Gy in 24 fractions) and
concurrent chemotherapy.
– 35% developed grade >3 acute toxicity and 7%
developed TRP.
– 6% (11/171) developed severe late esophageal toxicity
(stenosis in 8 and fistula in 3), which was comparable
to historical cohorts treated with 3DCRT.
– 2-Yr OS was 52%.

16. Prospective studies
• Cannon et al. (JCO, 2013):
– Phase 1 dose escalating hypo-fractionated IMRT in
NSCLC (79 patients based on TRP risk in 25 fractions).
– Patients with all stages of disease were recruited and
62% received neoadj or adj chemotherapy.
– All were PET staged, planned using 4D-CT and treated
with helical tomotherapy.
– No grade 3 acute or late esophageal or lung toxicity
up to 85.5 Gy/25 fractions.
2.28 Gy/Fx
2.53 Gy/Fx
2.77 Gy/Fx
3.0 Gy/Fx
3.22 Gy/Fx
3.42 Gy/Fx

17. Prospective studies
• Cannon et al. (JCO, 2013):
– 6 grade 4/5 toxicities (massive hemoptysis and
broncho-cavitary fistula) associated with central tumors,
doses above 75 Gy, and specific 1~3 cc doses to
proximal bronchial tree.

18. Prospective studies
• RTOG 0617 study (Lancet Oncol, 2015):
– Phase 3 trial (60 Gy/30 Fxs vs 74 Gy/37 Fxs + conc
paclitaxel/carboplatin, +/- cetuximab.
– Survival and LC disadvantage for high-dose arm.
– Under ½ of patients were treated with IMRT (46.5%:
46.1% in 60 Gy arm and 47.1% in 74 Gy arm).
P=0.0042

19. Population-based studies
• Shirvani et al. (2001~2007 SEER DB, Lung Cancer, 2013):
– Year of diagnosis and treatment in dedicated center
were the only independent predictors of IMRT use.
– Lung and esophageal toxicity was equal between IMRT
and 3DCRT groups.
• Harris et al. (2002~2009 SEER DB, Red, 2014):
– Comparative effectiveness study on outcomes in stage
III NSCLC for IMRT, 3DCRT, and 2DRT techniques.
– Nearly 7,000 patients
– IMRT was associated with similar toxicities and OS to
3DCRT.
– IMRT and 3DCRT showed advantage over 2DRT.

20. Conclusions
• IMRT can achieve better dose conformality, avoid
OARs and lower treatment toxicity.
• Compared to 3DCRT, planning process and treatment
delivery is time consuming and places strain on
valuable resources.
• IMRT is best indicated when tumor volume is near to
OAR or when treatment volumes are too large to
treat to radical dose with 3DCRT.
• Further prospective data are needed to strengthen
evidence base.

21. Advantages
• Ability to spare OARs.
• Better coverage of irregular
shaped targets.
• Ability to dose escalate.
• Able to treat synchronous
primary tumors and multiple
targets simultaneously.
• Enables treatment of larger
volumes to radical dose.
Disadvantages
• Increased contouring,
planning, and QA time.
• Increased need to accurately
delineate CTVs and involved
nodes requiring treatment.
• Need for image guidance.
• Sharp dose gradient may
lead to under-treatment of
micro-metastatic disease.
• Potential interplay effects
depending on fractionation
and complexity of IMRT
technique used.
• Low-dose radiotherapy bath.

23. Sem Rad Onc, 2016
IMRT or VMAT can spare more
critical structures than 3DCRT in
bulky stage III NSCLC tumor located
near esophagus and heart.

24. • Little supporting clinical data:
– No randomized trial has compared conformal and IMRT,
– Few studies have reported late outcomes of IMRT,
– No evidence for improved control with increased dose.
• Best available evidence is level 3~4, and no ongoing phase II or
III trials.
• Currently IMRT should be regarded as promising but unproven
experimental therapy.
Sem Rad Onc, 2016

25. SMC experience

27. Selection of RT Technique
• RT technique selection was
individualized based on disease
extent and estimated toxicity
risks.
• IMRT was primarily offered if
DVH parameters were
unfavorable (if treated by 3D-
CRT):
– V20＞40%
– MLD＞25 Gy
– Spinal cord Dmax>50 Gy
• 3D-CRT: 3-4 portal, 4-10 MV
• IMRT: median 6 portals, 6 MV
Treatment Detail
• RT:
– Median 66 Gy in 33 Fxs
– Normal tissue constraints:
• Spinal cord: DMax<46 Gy
• Lung: V20<35%, V5<65%,
Mean<20 Gy
• Chemotherapy:
– Wkly docetaxel/paclitaxel + cis-
/carboplatin in 67 (87.0%)
– 3-wkly pemetrexed/etoposide +
cisplatin in 10 (13.0%)

28. Clinical characteristics

29. DVH parameters

30. Median PFS = 11.1 months

32. • IMRT has enabled to encompass larger disease extent
at high and homogenous radiation dose volume, which
could not have been achieved by 3D-CRT.
• Toxicities (esophagitis, pneumonitis) were not
increased though with IMRT group had more
unfavorable DVH parameters than 3D-CRT group.
• Early appearance of DM was most important factor in
PFS, which could be explained by high proportion of
adenocarcinoma histology and corresponding large
disease extent.
• OS might have been improved probably by effective
systemic treatment following progression (including
targeting agents).
Summary

33. • Frequent and early appearance of DM, associated
with adenocarcinoma histology, would require
modification of systemic Tx in concurrent &/or
salvage phases.
• RT technique selection guideline would be required.
Future Directions

34. • Beam angle optimization policy:
• No beam (incident or existing)
passing though complete
block is allowed.
• Only existing beam after
passing through target is
allowed to hit directional
block.

35. Proton Therapy Center
Samsung Medical Center

36. Example Case: Sq, cT2N3

38. Dose (Gy)
Normalizedvolume(%)
Dose-volume Histogram (DVH)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80
Proton PTV
Proton Spinal Cord
Proton Both Lungs
IMRT PTV
IMRT Spinal Cord
IMRT Both Lungs
3DCRT PTV
3DCRT Spinal Cord
3DCRT Both Lungs
Tomo PTV
Tomo Spinal Cord
Tomo Both Lungs

39. Normal Tissue DVH
Lowest lung dose by IMPT
Excessive cord dose by 3D-CRT

40. Normalizedvolume(%)
CTV DVH

41. IMPT
Tomo IMRT
3D-CRT

42. • Dosimetric study clearly showed more focal dose
distribution at lower toxicity risk by IMPT than
IMRT and 3D-CRT.
• RT technique selection guideline would be required
considering cost-effectiveness.
Future Directions

43. Fundamental Goals of RT
• To deliver high dose to tumor
• To safely limit dose to normal tissues

44. Different tools for same purpose!

45. Same tool for different purposes!

47. Thank you for attention!