Adaptive radiation therapy (ART) in lung cancer aims to improve treatment outcomes by adapting the radiation plan based on anatomical changes observed during treatment. This allows for dose escalation to the tumor while reducing doses to healthy tissues. Key aspects of ART include using deformable image registration to propagate contours, monitoring for changes like tumor shrinkage or atelectasis, and replanning typically every 2-3 weeks. ART has been shown to allow for dose escalation of up to 10 Gy on average and improve local control and survival for lung cancer patients.

1. Overview of ART in Lung cancer
Naveen Mummudi
Tata Memorial Hospital, Mumbai

2. Outline
• Adaptive radiation
• Why?
• Where?
• When?
• How?
• Deformable Image Registration (DIR)
• Challenges and the Future

3. Increase in practice of thoracic RT
• Radiation in Lung cancer is
challenging at best
• Treatment related toxicities
• Technical difficulties
Vest et al; Chest 2013

4. Geometric uncertainties
• Delineation and target definition
uncertainty
• Microscopic disease
• Organ motion
• Tissue heterogeneity
and dose calculation
uncertainty
• Tumour volume changes
Inter-fraction and intra-fraction
changes

5. Opportunity
• Anatomical changes had larger impact on the target dose distribution
than internal target motion.
Schmidt et al, Acta Oncologica 2013

6. Adaptive Radiation Therapy
• “a feedback loop that incorporates measurements of treatment variation in
modifying and re-optimizing the treatment plan, as opposed to a fixed plan
approach..”
De la Zerda, Phys Med Biol, 2007

7. Process of ART
Set criteria
Monitor
changes
Adapt plan

8. Adaptive Radiotherapy
• Rationale behind ART is, by creating a new treatment plan in which
treatment fields are adjusted according to geometric changes,
• Ensure coverage of tumour
• Reduce normal tissue doses and
• Escalate doses to target volumes

9. Rationale
• Escalation of the radiation doses increases local control
• 1-Gy escalation was associated with 5-year local control improved by 1.25%
and a 3% reduction in risk of death
• Michigan dose escalation trial - transform into improved survival
• Meta-analysis of concomitant radio-chemotherapy
• 1% of improved local control transferred into 1% improved overall survival
• Dose escalation studies in lung cancer
• Large single institutional studies
• RTOG 0617 study
• “Iso-toxic” dose escalation
Kong FM, IJROBP 2005
Auperin, JCO 2010

10. Adaptive Radiotherapy
• Plan adaptation can be simple
• acquire a new CT scan of the patient mid-way through treatment after a
dramatic change is observed and
• optimizing the treatment plan to accommodate the new anatomy.
• More complex adaptation strategies have also been investigated with
varying re-planning frequencies.

11. Adaptive RT strategy
• Reduction in PTV margins
• Adaptive management of treatment response
• Anatomical changes
• Tumour regression

12. Margin reduction
• Population based - global margin
• Hybrid margin - incorporates patient-specific measurement of
respiratory motion based on initial fluoroscopy, and population
estimates of all other error;
• Online margin
• daily target position is measured and compared to pre-
determined tolerances.
• Online correction of the mean daily target position is
allowed if the tolerance criterion is exceeded.
• Online adaptive margin
• sub-strategy of the online strategy.
• The daily online correction simulation is the same, but an
adaptive correction is applied after an initial number of
fractions to account for any inter-fraction variability in the
respiratory pattern.
• Offline adaptive strategy
• an initial set of images to estimate patient-specific inter-
and intra-fraction variation
• online strategies - useful for patients exhibiting large
variability
• offline strategy - appropriate for patients with less
variability in the daily mean tumor position.
Hugo, Phys. Med. Biol 2007

13. Margin reduction
Harsolia, IJROBP 2008

14. Volume changes
• Positional shift
• Resolution of atelectasis – re-aeration
• Progression
• Pleural effusion
• New consolidation
• Tumour volume changes
• Tumour progression
• Tumour regression
• Infiltrative change
INCREASE IN TARGET
VOLUME
DECREASE IN TARGET
VOLUME

15. Atelectasis
• Common with centrally located tumours.
• Central airways can become constricted or obstructed, inducing a
collapse of the portion of the lung.
• Can range from complete collapse, affecting an entire lung, to partial
collapse, affecting only a portion of a lobe.
• In CT images, appears as a smaller region of uniform, high intensity.
• Delineation difficulties – if located close to the collapsed lung
• positron emission tomography (PET)

16. Atelectasis

17. Atelectasis

18. Atelectasis

19. Pleural effusion

20. Tumour volume regression
• Tumour regression appears as a
gradual, continuous change in
tumour volume
• ranging from 0.6% to 2.4%
shrinkage per day
• Reported average tumour
volume reductions
• 24.7% halfway through treatment
and
• 44.3% by the end of treatment.

21. Tumour volume regression

22. How to adapt? - Shrinking CTV
• Extent of microscopic disease beyond the visible tumour - estimated
based on microscopic tumour spread using surgical resection
specimens.
• patients who are candidates for a thoracotomy and patients receiving thoracic
irradiation for lung cancer are quite different.
• specimens hampered by tissue deformations and under-sampling.
• Dose levels for the microscopic cells is unknown
• May be substantially lower than necessary for (GTV).
Guckenberger, IJROBP 2011

23. Shrinking CTV
• Areas of suspect microscopic disease might become underdosed if
the radiation fields are adapted to a shrinking GTV but the MD does
not shrink synchronously and remains stationary within the lung
tissue
• Two scenarios:
• Shrinkage of the MD synchronously with the GTV, which would be consistent
with an expansive growth pattern of the GTV (best-case scenario for ART) and
• Stationary MD despite tumor shrinkage consistent with an infiltrative growth
pattern of the GTV within the lung (worst-case scenario for ART).

24. PET CT in ART
Feng, JCO 2007
• Significant reduction in FDG uptake and tumour volume during RT
• reduction associated with post-treatment response.
• Reduction in MTV was greater than reduction of CT-GTV during-RT.
• Adapting the planned target volume with a fixed composite NTCP of
15% allowed dose escalation by 30-102 Gy (mean: 58 Gy)
• Using MTV during RT, doses can be escalated above 74 Gy.
Feng, IJROBP 2009

25. How to adapt?
Feng, JCO 2007

26. When to adapt?
• Action level red:
• The GTV is outside the PTV due to ITACs.
• The radiation oncologist is called immediately and treatment is only given when approved by
the radiation oncologist.
• Action level orange:
• The GTV is just inside the PTV due to ITACs.
• The radiation oncologist is notified by email and has to respond before the next fraction.
• Action level yellow:
• There is an ITAC visible but the GTV is well inside the PTV.
• The radiation oncologist is notified by email about the ITAC but no response is necessary and
treatment may continue.
• Action level green:
• No change visible. No action needed.
Kwint, Radiother. Oncol. 2014

27. Kwint, Radiother. Oncol. 2014
TRAFFIC LIGHT PROTOCOL

28. When to adapt?
• the altered dose distribution was considered insufficient if:
• V95PTV (the volume of the PTV covered by 95% of the prescribed dose)
decreases more than 3%.
• PTVmean (the mean dose to the PTV) decreases more than 1%.
• V107(the volume receiving more than 107% of the prescribed dose) increases
more than 5 cm3.
• The extension of pleural effusion is measurable as a single figure and
for patients with no more than 2 cm effusion the dosimetric change is
always less than 1%.
• 30% reduction in tumour volume
Guckenberger, IJROBP 2011

29. Re-planning frequency
Dial, Med Phy 2016
ART yields clinically relevant reductions in normal tissue doses
for frequencies ranging from a single replan up to daily
replanning.
Increased frequencies of adaptation result in additional benefit
while magnitude of benefit decreases.

30. When to adapt?
• Single-plan adaptation in Week 3 or 5 and twice-plan adaptation in Weeks 3 and 5 reduced the
mean lung dose by 5.0% ± 4.4%, 5.6% ± 2.9% and 7.9% ± 4.8%, respectively.
• Twice ART allowed an iso–mean lung dose escalation of the GTV dose from 66.8 Gy ± 0.8 Gy to
73.6 Gy ± 3.8 Gy.
Guckenberger, IJROBP 2011

31. Clinical benefit
Weiss, IJROBP 2013
Study No. of
patients
Dose escalation
Dial 2016 12 Increase of 441cGy
Weiss 2013 10 Increase of 13.4 Gy with a maximum of 23.4 Gy was achieved.
Guckenberger 2011 13 Average escalation of 7 Gy based on a reduction in MLD of approximately
8%.

32. Clinical benefit
• Median overall progression-free
survival time
• ART-group - 10 months (95% CI 8 –
12), and
• No-ART-group - 8 months (95% CI
6 – 9).
• Severe pneumonitis (grade 3 – 5)
• 22% in the No-ART-group
• 18% in the ART-group
Tvilum 2015

33. Local Control and Toxicity of Adaptive
Radiotherapy using Weekly CT Imaging:
Results from the LARTIA Trial in Stage III NSCLC
• Local failures were in-field, marginal and out-of-field in 20%, 6% and
4% of cases, respectively.
Ramella, JTO 2017

34. ART in SBRT
• Target volume is small and a
large dose/fraction is delivered
• Missing a small volume in even
just one fraction can cause
significant underdosing or
overdosing.
• 17.9% median volume reduction
at RT completion.
• Increase in tumour volume at
some point during RT in 81.8%
Pathak, JAMIRO 2016

35. Adaptive SBRT
Qin, IJROBP 2012

36. Primary Objective :
Dose escalation
LRPF

37. DIR in lung cancer
• Performance of different DR algorithms has been validated on 4DCT
images by a number of studies.
• Fundamental assumption of current registration algorithms is that
corresponding anatomy exists between the two images being
registered such as the planning and weekly images.

38. DIR
Guckenberger, 2013

39. DIR
• Tumor regression may cause significant changes in the mass density
of the tumor.
• Intensity-based DIR algorithms register tumor volumes without
considering the dosimetric consequence of the mass changes.
• dose mapping errors possible
• Algorithms such as affine registrations or surface-based registration
methods may be better.
• For CT-based chest images, the B-spline registration algorithm is
generally quite accurate.

40. DIR alogrithms
Zhong, Phys. Med. Biol. 2017

41. DIR
Applications:
• Contour propagation / auto-contouring
• Adaptive plan – time efficiency
• Dose accumulation – delivered dose
• Synthetic CT
• Analyse patterns of failure

42. Functional lung volume estimation

43. Automatic selection
Bosch, 2017

44. Predicting shrinkage
Zheng, Phys. Med. Biol. 2017

45. Summary
• Volume changes during thoracic radiation provide an opportunity for
adaptation of plan.
• Iso-toxic dose escalation and reducing NTCP are potential benefits of
ART.
• Good clinical sense should prevail regarding timing and frequency of
ART.
• DIR in the presence of large volume changes introduces dosimetric
uncertainty.
• Clinical benefit of ART is still evolving.