Overview of adaptive radiation therapy in lung cancer

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.