This trial will provide important level 1 evidence on the clinical benefits of protons for NSCLC. The primary outcomes of local control and toxicity will help determine if protons represent an improvement over IMRT. This type of comparative effectiveness trial is needed to fully evaluate new technologies like protons. 4  Future Directions  Continued improvements in proton delivery technology  Development of integrated PET/MRI for proton therapy  Advances in motion management and adaptive techniques  Combining protons with immunotherapy and targeted agents  Large, prospective comparative effectiveness trials  International data registries and collaborative research  Standardization of outcomes assessment and reporting

1. Proton Therapy
Stephen M. Hahn, MD
Department of Radiation Oncology
February 8, 2013

2. Outline
 The evolution of high technology in
Radiation Oncology
 The principles & rationale for proton
therapy
 Challenges with proton therapy
 Assessing the ‘value’ of proton
therapy
 Future directions

3. Effect of underdosage and overdosage
Tumor control Late normal tissue damage
Effect
Tumor Dose

4. The Evolution of Radiation Therapy
1980’s 1990’s
1960’s 1970’s Computerized 3D CT 2000’s
The First Clinac Treatment Planning
Functional
Imaging
Cerrobend Blocking Multileaf Collimator
Electron Blocking Dynamic MLC High resolution IMRT
Standard Collimator and IMRT
Blocks were used to IMRT Evolution
MLC leads to 3D evolves to smaller and
The linac reduced reduce the dose to conformal therapy Computerized IMRT smaller subfields and
complications normal tissues which allows the first high resolution IMRT
introduced which
compared to Co60 dose escalation trials. along with the
allowed escalation of
introduction of new
dose and reduced imaging technologies
compilations

5. Principles of Proton Therapy
The Physical characteristics of protons provide the rational for
its use
 Protons have a finite depth of penetration in material
depending on their energy and density of the material
 Protons have a relatively low energy loss per unit path
length (ionization density) at the surface that slowly
increases to near the end of beam range and create a high
ionization density region ( Bragg Peak) with negligible
dose beyond
 Proton beam deposited dose falls off sharply laterally and
distally

6. Characteristics of Proton and Heavy Particle Therapy
Ar
HIGH LET ADVANTAGE
Fast Neutron
Neutrons IMRT
2002 Si
Ne
Pions C
250 kVp 4 MV 22 MV MV
60
X-rays Co X-rays X-rays
X-ray p
IMRT
DOSE DISTRIBUTION ADVANTAGE
Kohler, A

7. Comparison of dose distributions
GSI/HIT

8. The Evolution of Conformal Radiotherapy
2-D IMRT
3-D Proton

9. Principles of Proton Therapy
 Accelerated protons are near monoenergetic and form a beam
of small lateral dimension and angular divergence
 There are two approaches to form a desired dose distribution :
 Passive Scattering and modulation ( referring to the method of
spreading the beam laterally and with method of spreading the
beam in depth)

10. Principles of Proton Therapy
b . Dynamic Scanning of a pencil beam laterally and in depth
involves scanning of a PB both laterally and in depth ( by changing its energy) => in
a near arbitrary dose distribution laterally and dose sharpening in depth ( Pedroni et
al.)
- lateral distribution determined by the lateral positions and weights of each pencil
beam of a chosen energy
- distribution in depth is determined by weighting the pencil beam at each position
within the field.
Note: Beam Scanning is the only practical technique which enables IMPT to be performed.
10
1

11. Spot scanning - The principle
The dynamic application of scanned and modulated proton pencil
beams
AA proton pencil beam
full set, with a
Some more… beams
A few pencil
together….
(spot)…...
homogenous dose
conformed distally
and proximally
Images courtesy of E Pedroni and T Lomax, PSI
1

12. Cyclotron and Beam Line
1

13. Penn Medicine’s Gantry at the Duro Felguera factory
1

14. Why Proton Therapy?
An advanced form of targeted radiation therapy
– reduction in integral dose to normal tissues
compared to conventional radiation
including IMRT which may translate into
reduced toxicities
– Dose escalation to tumors – increased local
control
– Treat tumors close to critical organs –eye,
spinal cord
– More safely & effectively combine with
chemotherapy & surgery
1

15. The potential advantages of Proton Therapy
Pediatric Malignancies
Combined modality setting
– NSCLC
– GI cancers
– cervical cancer
Hypofractionation
Re-irradiation
Tumors of the Brain, Spine & CNS
Tumors of the Mediastinum
1

16. 1

17. Proton = square, RA= triangle
1

18. Challenges in Proton Therapy
1. Beam Uncertainties -Why are these uncertainties of
concern?
 Protons STOP
 Protons scatter differently ( charged particle) – very sensitive to tissue
inhomogeneity
 Range Uncertainty
• Affects beam directions & introduces uncertainty about delivered dose
• Accentuate the issues related to random & systematic set up errors
2.Motion
3.Imaging
onboard imaging
imaging for QA
2.Cost & Value
1

19. Range Uncertainty
 One must account for this uncertainty by
delivering dose beyond the target
1

20. Motion and Setup uncertainties
What happens if the beam is nearly
tangential to the target?
Per ICRU 78
2

21. Challenges in Proton Therapy
1. Beam Uncertainties -Why are these uncertainties of
concern?
 Protons STOP
 Protons scatter differently ( charged particle) – very sensitive to tissue
inhomogeneity
 Range Uncertainty
• Affects beam directions & introduces uncertainty about delivered dose
• Accentuate the issues related to random & systematic set up errors
2.Motion
3.Imaging
onboard imaging
imaging for QA
2.Cost & Value
2

22. Passive PET
Measuring proton dose immediately after treatment
Figure 1- Dose Distribution for treatment Figure 2-PET/CT image with 1cm x 1cm grid
of prostate tumor
A PET/CT image illustrating radioactivity 20 minutes
after treating the patient in figure 1 was divided into a
Figure 1 shows the planned dose distribution for the grid such that the divisions on the patient were
treatment of prostate cancer. The target is outlined in approximately 1cm x 1cm. In this image, there are too
red near the center of the patient. few decays at the target. An earlier scan showing
oxygen decays could more clearly show decays at the
region of interest.
2

23. Passive PET
2

24. Challenges in Proton Therapy
1. Beam Uncertainties -Why are these uncertainties of
concern?
 Protons STOP
 Protons scatter differently ( charged particle) – very sensitive to tissue
inhomogeneity
 Range Uncertainty
• Affects beam directions & introduces uncertainty about delivered dose
• Accentuate the issues related to random & systematic set up errors
2.Motion
3.Imaging
onboard imaging
imaging for QA
2.Cost & Value
2

25. IMRT Cumulative Adoption
Mell et al, Cancer 2005 2

26. IGRT Technologies - Cumulative Adoption
Simpson et al, Cancer 2010
2

27. Proton Therapy Worldwide…
• PT center under operation 45
Estimated 40 centers
by 2010 40
35
30
25
25 PT centers 20
15
10
5
0
2005 2025
1960 1970 1980 1990 2000 2010 2020 2030
Technology & Protocol Advances in Scanning Government/ Business Standardization/
Development Technology & Increases Private Payor Optimization & Mass Adoption
in Computing Power Reimbursement &
Efficient Technology
2

28. What are the Clinical Data in Support of Proton Therapy?
REVIEW ARTICLE
Proton Therapy in Clinical Practice:
Current Clinical Evidence
Michael Brada, Madelon Pijls-Johannesma, Dirk De Ruysscher
From The Institute of Cancer Research and The Royal Marsden National
Health Service Foundation Trust, Sutton, Surrey, United Kingdom; and
Department of Radiation Oncology, Maastricht Radiation Oncology, Research
Institute Growth and Development, University Hospital Maastricht, Maastricht,
the Netherlands
Journal of Clinical Oncology, Vol 25, No 8 (March 10), 2007: pp. 965-
970
© 2007 American Society of Clinical Oncology.
2

29. Clinical Studies of Proton Therapy With at Least 20 Patients
and With a Follow-Up Period of at Least 2 Years
Tumor Site No. of Studies No of Patients
Head and neck tumors15,75 2 62
Prostate cancer14,16,17 3 1,642
Ocular tumors18-26 9 9,522
Gastrointestinal cancer27-31 5 375
Lung cancer32-34 3 125
CNS tumors28-35,54,55 10 753
Sarcomas43 1 47
Other sites44-46 3 80
Total 36 12,606
2

30. Challenges
How do we demonstrate the benefit of
proton therapy and other high technology
(HT) treatments?
The dose distributions are undeniably
better in many patients
Yet, cost containment pressures are real
Technological changes are rapid and
proton therapy tomorrow is likely to look
different from proton therapy today
The difficulties in assessing cost
effectiveness
3

31. Comparative Effectiveness
The essence of comparative effectiveness research
(CER) is to understand what health interventions
work, for which patients, and under what conditions
In the US, attention has focused on radiotherapy
technological advances, including IMRT, proton
therapy, and SBRT, that have been quickly adopted
with few studies investigating whether they
represent an incremental improvement in patient
outcomes, the defining evaluation threshold of CER.
Bekelman, Shah & Hahn. PRO 2011
3

32. When Should We Use Protons?
Serious AE with x-rays
Importance of surrounding normal tissue
Improvements in local control are needed
Late morbidity is an important issue
Complex geometry
Target volume large relative to normal
tissue compartment
– Zietman, Goiten, Tepper JCO 2010
3

33. Possible Clinical Situations for Particle Therapy
 Pediatric Malignancies
 Combined modality setting – dose avoidance
– NSCLC
– GI cancers
– cervical cancer
 Hypofractionation
 Re-irradiation
 Tumors of the Brain, Spine & CNS
 Tumors of the Mediastinum
 Low grade or benign tumors
 Hypoxic & radio-’unresponsive’ Tumors
3

34. What are the Data For the Clinical Use of Protons?
 Pediatric Malignancies – Protons based not on the
existence of Level 1 data but the unarguable
necessity for reducing integral dose
 Ocular Melanoma
 Skull Base and Spine Tumors
 Emerging proton data in the combined modality
setting
 Current randomized trials in protons – locally
advanced NSCLC & low/intermediate risk prostate
cancer
3

35. Pediatric Cancers
Serious AE are a problem
Sparing surrounding normal tissues related
to growth and future function is an important
goal
Late morbidity is a serious issue
There is a significant rationale for the use of
proton therapy in pediatric cancers-
prospective studies, registries are needed,
RCT probably not
3

36. Second Malignancies
 MGH-Harvard Cyclotron Laboratory
 Matched retrospective cohort study of 1,450 HCL proton
pts and photon cohort in SEER cancer registry.
 Matched 503 HCL proton patients with 1591 SEER
patients
 Median f/u: 7.7 years (protons) and 6.1 years (photon)
 Median age 56 (protons) and 59 (photons)
 Second malignancy rates
• 6.4% of proton patients (32 patients)
• 12.8% of photon patients (203 patients)
 Photons are associated with a higher second
malignancy risk
• Hazard Ratio 2.73, 95% CI 1.87 to 3.98, p< 0.0001
Courtesy of H. Shih, MD
Chung et al. ASTRO 2008
3

37. Ocular Melanoma
Uveal Melanoma
70 GyRBE, 5 fractions
LC 95% at 15 years
Harvard Cyclotron
Lab
Slide Courtesy of H. Shih JM Collier
3

38. Skull Base Sarcoma
 Skull base chondrosarcoma
(MGH)
• 69.6 Gy(RBE), 37 fx
• LC 95% at 10 years
 Skull base chordoma (MGH)
• 70-78 Gy(RBE)
• LC 42-65% at 10 years
J Adams
Slide Courtesy of H. Shih
3

39. Lung Cancer
Serious AE are a problem
Sparing surrounding normal tissues is an
important goal
Improvements in local control are needed
Complex geometry
There appears to be a reasonable
rationale for protons in lung cancer &
some preliminary data suggesting a
benefit
3

40. Lung Cancer
Non-small cell lung cancer (NSCLC)
– ~ 200K cases per year in the US
– ~35-40% treated with a combination chemotherapy & radiation
– 3-D radiation therapy or IMRT is used
Substantial morbidity and some mortality
result from the concurrent use of
chemotherapy and radiation in this patient
population
We achieve 80% complete response rates
with radiation and chemotherapy
4

41. 4

42. Proton Total lung - PTV
Photon Total lung - PTV
4

43. Lung Cancer and Proton Therapy
Consecutive patients enrolled in two IRB
approved protocols at MDA Cancer Center
5/06-6/08
44 pts with Stage III NSCLC treated with 74
cGy, weekly carbo/paclitaxel
Median F/U 19.7 mos; Median OS 29.4 mos
Grade 3 esophagitis 5 pts (11%)
Grade 3 pneumonitis 1 pt (2%)
Local disease recurrence 4 pts (9%)
Chang JY et al Cancer Mar 22 2011
4

44. Cost Effectiveness Analysis
 We have begun to evaluate the “cost” of morbidities
in our NSCLC population when conventional
chemoradiotherapy is used
 If the major toxicities of chemoradiotherapy are
reduced or eliminated there appear to be significant
cost savings
 Question: Does reduction in morbidity or
improvement in local control (if shown by well
designed trials) associated with proton therapy
reduce costs in our health care system?
4

45. RCT in NSCLC
Randomized trial of protons versus photons
• Stage II/III NSCLC
• Adaptive randomization of pts to 74 Gy of IMRT or
74 CGE of protons (2 Gy/CGE fractions)
• If the dose constraints cannot be met, patient will
not be treated on study
• The primary outcome will be local control and
grade 3 or greater pneumonitis and esophagitis
• The study is nearing completion and is jointly by
MD Anderson and MGH
Cox J, ASTRO Advances in Technology Meeting 2008
4

46. The Near future -Technology Development
Multi-leaf Collimators
Cone Beam CT scan
On-Board PET Imaging
Intensity Modulated Proton therapy
(IMPT)
Single room proton therapy delivery
systems
4

47. Planning of Proton Therapy Future… ICRU 78
47
4

48. Protons – the Context
 There has been a substantial increase in the
technological complexity of radiotherapy over the
last 20 years
 Driven by advances in computing power, imaging
and more efficient methods for delivering radiation
 Proton therapy provides theoretical benefit over
conventional radiotherapy – does this translate into
clinical benefit?
 Rapid adoption of proton therapy will force us to
evaluate the value of this potentially beneficial
therapy
4

49. Conclusions
Current role for protons in pediatric tumors,
ocular melanoma, base of skull tumors
Heavy emphasis on questions related to the
role of protons in the combined modality
setting, dose escalation, & hypofractionation
Rethink the approach to clinical trials – RCT,
PCT, adaptive strategies and registries
Technological advances will further improve
the delivery, increase the indications for PBT,
& decrease the costs
4

50. Penn Radiation Oncology
Thank You
5

51. An Example: Prostate Cancer
 Despite the theoretical advantages of PBT, investigators have
yet to demonstrate prospectively a clinical benefit to PBT
compared to IMRT
 A 2008 AHRQ-sponsored systematic review of found little
high-quality evidence of either IMRT or PBT
 Interpreting the sparse evidence available is problematic
because of the absence of rigorous, prospective, randomized
trials of sufficient size and statistical power to assess key
clinical outcomes, failure to control for known confounders,
and substantial selection effects
Wilt TJ et al Ann Int Med 2008
5

52. Efficacy & Toxicity of IMRT and PBT
Outcome IMRT PBT FU (yrs) Evidence
OS >80-90% >80-90% 5 Limited
DSS8 >95% >95% 5 Limited
FFBF 74-95% 69-95% 1.5-6
Toxicity Acute vs. Late IMRT PBT
(Pooled Rate 95 CI) (Pooled Rate 95 CI)
GI Acute 18.4 (8.3, 28.5) 0*
Late 6.6 (3.9, 9.4) 16.7 (1.6, 31.8)
GU Acute 30.0 (13.2, 46.7) 40.1*
Late 13.4 (7.5, 19.2) 5.5 (4.6, 6.5)
ED 48-49** Not reported
** 2 studies * 1 study
5

53. Rationale for PBT in Prostate Cancer
5

54. Study Schema
A parallel registry will be conducted to assess the representativeness and potential
generalizability of the RCT.
Bekelman and Efstathiou
5