Technical Brief on Particle Beam Radiotherapies for the Treatment of Cancer (Text Version)

On September 27, 2010, Tom Trikalinos made this presentation at the 2010 Annual Conference. Select to access the PowerPoint® presentation (1.8 MB). 

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Slide 1

Technical Brief on Particle Beam Radiotherapies for the Treatment of Cancer

T Trikalinos, T Terasawa, S Ip, G Raman, J Lau
Tufts EPC

Presenter: Tom Trikalinos, MD, PhD, Co-Director, Tufts EPC.

Slide 2

Introduction (I)

• Radiation therapy is pivotal in cancer treatment
• Based on physics, there are 3 broad groups of external radiation therapy:
  • Photons
  • Electrons
  • Charged particles (e.g., protons)

Slide 3

Introduction (II)

• Charged particle radiotherapy has been clinically available since 1954.
• Appropriate clinical utilization is controversial.
  • No documented superiority over radiotherapy alternatives in comparative data
  • Expensive

Slide 4

Technical Brief

Rapid report that describes:

• The technology
• Its availability, diffusion and cost
• Type of facilities, provider training
• State-of-science:
  • Type of studies, participants, interventions, designs
  • No focus on findings

Slide 5

Technical Brief Methods

• Combination of general Internet searches
  • Information on the technology, the principles it operates on, its availability, uptake and cost one has to search beyond the published literature
• And systematic scan of the published literature
  • Describe published research

Slide 6

General Internet Searches

• Google "particle beam therapy" and "proton beam therapy"
• Visiting relevant links (first 10 pages)
• Websites of radiotherapy organizations, treatment centers, manufacturers
• FDA Center for Devices and Radiological Health; Manufacturer and User Facility Device Experience Database

Slide 7

Systematic literature scan (I)

• MEDLINE searches to identify studies:
• Charged particle radiotherapy performed
• Cancer in >80% of patients
• Any clinical outcome, any harm
• Any design, =10 patients treated*
• English, German, Italian, French, Japanese

Slide 8

Systematic literature scan (II)

• Descriptive statistics for designs, clinical and treatment characteristics, clinical outcomes and adverse events reported
• We stratified results by cancer type
  • (ocular, head and neck, spine, GI, prostate, bladder, uterus, bone and soft tissue, lung, breast, miscellaneous)

Slide 9

Results

Slide 10

Physics of Charged Particle Versus Photon Radiotherapy

Photon radiotherapy

• Uses ionizing photon (X- or gamma-ray) beams for the locoregional treatment of disease
• Radiation damage to DNA of healthy and tumor cells alike triggers complex reactions that ultimately result in cell death
• Cellular damage increases with the (absorbed) radiation dose (measured in Gy)

Slide 11

Depth-dose Distribution of Photons

Image: A line graph shows distribution of photons by depth (mm)/dose (%). The line begins at ~25% dose at 0 mm and rises sharply to 100% at 20-30 mm, then declines steadily to ~50% at 200 mm.

Slide 12

Particle Beam Radiotherapy

• Uses charged particles (e.g., protons, helium ions, carbon ions)
• Charged particles deposit most of their energy in the last millimeters of their trajectory (when their speed slows).
• Sharp localized peak of dose (Bragg peak).

Slide 13

Image: A line graph shows the pristine Bragg peak (I). The line begins at ~22% dose at 0 mm and rises slowly at first, to ~25% at 50 mm and ~30% at 100 mm, then rises sharply to peak at ~90% at 150 mm before immediately dropping to 0 just beyond 150 mm.

Slide 14

A Pristine Bragg Peak (II)

Image: A line graph shows the pristine Bragg peak (II). There are two lines on this graph. The first line (in grey) begins at ~22% dose at 0 mm and rises slowly at first, to ~25% at 50 mm and ~30% at 100 mm, then rises sharply to peak at ~90% at 150 mm before immediately dropping to 0 just beyond 150 mm. The second line (in blue) begins at ~19% dose at 0 mm and rises slowly at first, to ~20% at 50 mm and ~22% at 100 mm, then rises sharply to peak just above ~60% at 150 mm before immediately dropping to 0 just beyond 150 mm. Both lines end at the same point just beyond 150 mm.

Slide 15

A Pristine Bragg Peak (III)

Image: A line graph shows the pristine Bragg peak (III). There are two lines on this graph. The first line (in grey) begins at ~22% dose at 0 mm and rises slowly at first, to ~25% at 50 mm and ~30% at 100 mm, then rises sharply to peak at ~90% at 150 mm before immediately dropping to 0 just beyond 150 mm. The second line (in blue) begins at ~30% dose at 0 mm and rises to ~40% at 50 mm and then peaks sharply at ~90% at ~80 mm before dropping to ~10% at 100 mm.

Slide 16

Multiple Bragg Peaks

Image: A line graph shows the Multiple Bragg peak. There are two lines on this graph, both in blue. The first line begins at ~22% dose at 0 mm and rises slowly at first, to ~25% at 50 mm and ~30% at 100 mm, then rises sharply to peak at ~90% at 150 mm before immediately dropping to 0 just beyond 150 mm. The second line begins at ~7% dose at 0 mm and rises to ~10% at 50 mm and 12% at 100 mm, then peaks sharply at ~22% at ~130 mm before dropping to ~0% at 150 mm.

Slide 17

Spread-out Bragg Peak (SOBP)

Image: A line graph shows the Spread-out Bragg peak (SOBP) peak. There are five lines on this graph. The first line, in red, begins at ~42% dose at 0 mm and rises to ~50% at 50 mm and ~60% at 100 mm, then rises sharply to peak at ~100% at 120 mm; this line remains near 100% with some minor fluctuations until 150 mm, then drops to 0 just beyond 150 mm. The second line (in blue) begins at ~22% dose at 0 mm and rises slowly at first, to ~25% at 50 mm and ~30% at 100 mm, then rises sharply to peak at ~90% at 150 mm before immediately dropping to 0 just beyond 150 mm. These two lines end at the same point just beyond 150 mm.

The third line, also in blue, begins at ~10% dose at 0 mm and rises slightly to ~12% at 50 mm and 15% at 100 mm, then peaks at ~25% at ~140 mm before dropping to ~0% at 150 mm. The fourth line, also in blue, begins at ~9% dose at 0 mm and rises slightly to ~10% at 50 mm and 12% at 100 mm, then peaks at ~22% at ~130 mm before dropping to ~0% at 140 mm. The fifth line, also in blue, begins at ~5% dose at 0 mm and rises slightly to ~7% at 50 mm and 9% at 100 mm, then peaks at ~18% at ~125 mm before dropping to ~0% at 130 mm.

Slide 18

Spread-out Bragg Peak (SOBP)

Image: A line graph shows the Spread-out Bragg peak (SOBP) peak. There are 13 lines on this graph. The first line, in red, begins at ~75% dose at 0 mm and rises to ~80% at 50 mm, then rises to peak at ~100% at 100 mm; this line remains near 100% with some minor fluctuations until 150 mm, then drops to 0 just beyond 150 mm. The second line (in blue) begins at ~22% dose at 0 mm and rises slowly at first, to ~25% at 50 mm and ~30% at 100 mm, then rises sharply to peak at ~90% at 150 mm before immediately dropping to 0 just beyond 150 mm. These two lines end at the same point just beyond 150 mm.

The third line, also in blue, begins at ~10% dose at 0 mm and rises slightly to ~12% at 50 mm and 15% at 100 mm, then peaks at ~25% at ~140 mm before dropping to ~0% at 150 mm. The fourth line, also in blue, begins at ~9% dose at 0 mm and rises slightly to ~10% at 50 mm and 12% at 100 mm, then peaks at ~22% at ~130 mm before dropping to ~0% at 140 mm. The fifth line, also in blue, begins at ~5% dose at 0 mm and rises slightly to ~7% at 50 mm and 9% at 100 mm, then peaks at ~18% at ~125 mm before dropping to ~0% at 130 mm.

Lines 6 through 13 are in blue; all begin at ~3-4% dose at 0 mm rise to ~5% at 50 mm, then begin to diverge. The sixth line peaks at ~15% at ~120 mm and drops to 0 at 125 mm. The seventh line peaks at ~12% at ~110 mm and drops to 0 at 120 mm. The eighth line peaks at ~10% ~100 mm and drops to 0 at 110 mm. The ninth line peaks at ~9% at ~90 mm and drops to 0 just beyond 100 mm. The tenth line peaks at ~8% at ~85 mm and drops to 0 just below 100 mm. The eleventh line peaks at ~8% at ~80 mm and drops to 0 at ~90 mm. The twelfth line peaks at ~8% at ~70 mm and drops to 0 at ~80 mm. The eleventh line peaks at ~8% at ~60 mm and drops to 0 at ~70 mm.

Slide 19

Photons vs SOBP

Image: A line graph compares photons versus SOBP. The photon line, in black, begins at ~25% dose at 0 mm and rises sharply to 100% at 20-30 mm, then declines steadily to ~50% at 200 mm. The SOBP line, in red, begins at ~75% dose at 0 mm and rises to ~80% at 50 mm, then rises to peak at ~100% at 100 mm; this line remains near 100% with some minor fluctuations until 150 mm, then drops to 0 just beyond 150 mm.

Slide 20

Large Facilities

Images: An architectural model and the University of Pennsylvania (Perelman center for Advanced Medicine) under construction are shown.

January 2007

Slide 21

Practical Information (I)

Operating particle beam facilities in the US (2008)

Institute	Particle	Maximum Clinical Energy (MeV)	Start	Patients treated
				Number	Date of count
LLU, CA	proton	250	1990	11414	Nov-06
MPRI, IN	proton	200	1993	379	Dec-07
UCSF, CA	proton	60	1994	920	Mar-07
NPTC-MGH, MA	proton	235	2001	2710	Oct-07
MD Anderson, TX	proton	250	2006	527	Dec-07
FPTI, FL	proton	230	2006	360	Dec-07

Slide 22

Practical Information (II)

Large particle beam facilities being planned/constructed in the U.S. (2008)

Institute	Now in construction	Particle	Maximum Clinical Energy (MeV) [Accelerator]	Treatment rooms	Gantries	Cost (million $)	Estimated start date
University of Pennsylvania, PA	Yes	proton	230 [Cyclotron]	5	4	140	2009
Hampton University, VA	Yes	proton	[?]	5	4	225	2010
Northern Illinois Proton Treatment and Research Center, IL	No	proton	250 [?]	4	2 or 3	159	2010

Slide 23

Evidence Maps

Image: A chart maps evidence studies into the following categories:

All Identified Studies

Topic Area	Randomized controlled trials (RCT)			Nonrandomized comparative studies (nonRCT)			Single-group studies
	OS	CSS	Other	OS	CSS	Other	OS	CSS	Other
Ocular	1	2	4	4	2	7	34	33	73
Head/neck	1	1	2	1	1	1	43	30	53
Spine							8	3	9
GI	1		1	1		2	15	11	18
Prostate	3	1	3	1		2	5	4	14
Bladder							3	3	3
Uterus						1	4	3	4
Bone/soft tissue							5	3	5
Lung							13	9	17
Breast							1	1	1
Other							7	5	13

Slide 24

Evidence Maps

Image: A chart maps evidence studies by University:

Topic Area	MGH-US	UCSF-US	LLU-US	MD Anderson-US	NIRS-Jap	Tsukuba-Jap	Hyoga-Jap	Shizuoka-Jap	NCC-Jap	Nice-Fr	Orsay-Fr	HMI-Ger	GSI-Ger	Clatterbridge-UK	PSI-Swi	Uppsala-Swe	CATANA-It	ITEP-Rus
Ocular	33	22			2					7	11	2		5	4	1	2	1
Head/neck	15	5	6	1	5	4			1		7	5	4		1
Spine	4	3			1										1
GI		5	1			13			2
Prostate	5		7		4		1		1
Bladder						3
Uterus					3	2
Bone/soft tissue	1	1			2										2
Lung			4		7	4			1
Breast	1		1
Other	3	3			1	6		1

Slide 25

Evidence Maps: Comparative Studies

Image: A chart maps comparative studies by University:

Topic Area	MGH-US	UCSF-US	LLU-US	MD Anderson-US	NIRS-Jap	Tsukuba-Jap	Hyoga-Jap	Shizuoka-Jap	NCC-Jap	Nice-Fr	Orsay-Fr	HMI-Ger	GSI-Ger	Clatterbridge-UK	PSI-Swi	Uppsala-Swe	CATANA-It	ITEP-Rus
Ocular	1 RCT 2 nonRCT	2 RCT 3 nonRCT									1 RCT 1 nonRCT			1 nonRCT
Head/neck	1 RCT	1 RCT										1 nonRCT
Spine
GI		1 RCT 2 nonRCT
Prostate	2 RCT 1 nonRCT		1 RCT 1 nonRCT
Bladder
Uterus					1 nonRCT
Bone/soft tissue
Lung
Breast
Other

Slide 26

Evidence Maps: Comparators

Comparison	RCTs (n=10)	Nonrandomized comparative (n=13)	Example
Particles vs particles	4	1	Higher vs lower proton dose for uveal melanoma
Particles only vs other Tx	3	8	Carbon-ion vs photon + brachytherapy for uterine cancer
Tx with particles vs other Tx without particles	3	4	Photon RT + proton boost  vs photon RT + photon boost for prostate cancer

Slide 27

Discussion (I)

• The theoretical advantages of charged particle irradiation have not been demonstrated in comparative studies
  • Claims of "higher effectiveness" [vs what?]
  • Claims of "less toxicity" [vs what?]

Slide 28

Discussion (II)

Some authorities see no need for RCTs.

1. Superior dose distributions with charged particles vs photons
2. The biological effects of e.g. protons are similar to those of photons, and thus known
3. It is self evident that precise localization of dose is beneficial
4. This is a scarce (limited) resource. Use it in an optimal way (may not include RCTs)

Slide 29

Discussion (III)

• Even strong pathophysiological rationale can mislead
• Many instances of clinical equipoise between charged particle radiation and other modalities, in rare and common cancers
• Are any differences large enough to justify routine use?

Slide 30

Discussion (IV)

• For rare tumors near anatomically critical structures where extreme precision is sine qua non, relevant comparators are
  • Intensity modulated radiation therapy
  • Conformal radiation surgery

Slide 31

Discussion (V)

• For common cancers where "extreme" precision is currently not a mandate, relevant comparators are practically all currently used radiation modalities

Slide 32

Recommendations for Future Research

• Capitalize on existing data
  • Reanalysis of existing individual patient data with optimal statistical methods
• Generate comparative data, first for common cancers
  • Evaluate patient-relevant outcomes
  • RCTs
• Conditional coverage with evidence development?

Slide 33

Parting Points

• Tradeoff: high cost and limited availability against unclear effectiveness compared with contemporary alternatives
  • Cost-effectiveness (-utility) RCTs?
• Is pathophysiology and physics sufficient to justify diffusion to common cancers?
  • Antiarrhythmics for premature ventricular contractions
  • Erythropoetin for anemia in chronic kidney disease

Slide 34

Hidden Slides

Slide 35

What Does The Result Look Like?

Slide 36

Background on Photon and Particle Beam Radiotherapy

Slide 37

Comparators in RCTs

Cancer type and center	Comparison	N	Survival [Overall/ specific]
Ocular (uveal melanoma)
MGH (USA)	Higher vs lower dose proton RT	188	No/No
UCSF (USA)	Helium RT vs I-125 brachytherapy	136; 184	Yes/Yes
Orsay (France)	Proton RT vs proton RT + laser TTT	151	Yes/Yes
Head/neck (skull base chordoma/chondrosarcoma)
MGH (USA)	Higher vs lower dose proton RT	96	Yes/No
Head/neck (brain glioblastoma)
UCSF (USA)	Higher vs lower dose proton RT	15	Yes/Yes
GI (pancreatic cancer)
UCSF (USA)	Helium RT vs photon RT	49	Yes/Yes
Prostate
MGH & LLU (USA)	Photon RT + standard dose proton vs Photon RT + high dose proton	393	Yes/Yes
MGH (USA)	Photon RT + local photon boost vs Photon RT + local proton boost	202; 191	Yes/Yes

GI: Gastrointestinal; RT: radiotherapy; TTT: transpupillary thermotherapy

Slide 38

Cancer type and center	Comparison	N	Survival [Overall/ specific]
Ocular (uveal melanoma)
Orsay (France) 34	Proton RT vs I-125 brachytherapy	1272	Yes/No
UCSF (USA)35	Helium RT vs I-125 brachytherapy	766	No/No
MGH (USA)36	Proton RT vs enucleation	556	Yes/Yes
UCSF (USA)33	Helium RT vs I-125 brachytherapy	426	No/No
[Wilson 1999—Unclear center]45	Proton RT vs I-125 brachytherapy vs Ru-106 brachytherapy	267	Yes/No
MGH (USA)44	Proton RT vs enucleation	120	Yes/Yes
UCSF (USA)37	Proton RT vs proton RT + laser TTT	56	No/No
Head/neck (skull base adenocystic carcinoma)
HMI (Germany)43	SFRT/IMRT vs SFRT/IMRT + proton boost	63	Yes/Yes

Slide 39

Uterus
NIRS (Japan)	Carbon RT vs photon RT + brachytherapy	49	No/No
GI (Bile duct)
UCSF (USA)55	Proton RT vs photon RT	62	Yes/Yes
UCSF (USA)42	Surgery + photon RT vs Surgery + proton RT	22	No/No
Prostate
LLU (USA)39	Watchful waiting vs surgery vs standalone photon RT vs photon RT + proton boost RT vs standalone proton RT	185	No/No
MGH (USA)38	photon RT + photon boost vs photon RT + proton boost	180	Yes/Yes

Slide 40

Technical Brief

• AHRQ has asked Tufts EPC to perform a Technical Brief on the role of particle beam radiotherapies in the treatment of cancer conditions.
• A Technical Brief is a rapid report on an emerging clinical intervention that provides an overview of key issues. Technical Briefs generally focus on interventions for which there are limited published data and too few completed protocol-driven studies to support definitive conclusions.

Slide 41

Key Question 1

1. a. What are the different particle beam radiation therapies that have been proposed to be used on cancer?
2. b. What are the theoretical advantages and disadvantages of these therapies compared to other radiation therapies that are currently used for cancer treatment?
3. c. What are the potential safety issues and harms of the use of particle beam radiation therapy?

Slide 42

Key Question 2

• 2.a. What instrumentation is needed for particle beam radiation and what is the Food and Drug Administration (FDA) status of this instrumentation?
• 2.b. What is an estimate of the number of hospitals that currently have the instrumentation or are planning to build instrumentation for these therapies in the USA?
• 2.c. What instrumentation technologies are in development?

Slide 43

Key Question 3

Perform a systematic literature scan on studies on the use and safety of these therapies in cancer, with a synthesis of the following variables:

3.a. Type of cancer and patient eligibility criteria
3.b. Type of radiation, instrumentation and algorithms used
3.c. Study design and size
3.d. Comparator used in comparative studies.
3.e. Length of followup
3.f. Concurrent or prior treatments
3.g. Outcomes measured
3.h. Adverse events, harms and safety issues reported

Slide 44

Schematic of a Proton Beam Radiotherapy Center

Image: An image of a Schematic of a proton beam radiotherapy center is shown. Labeled on the image are the following:

• Ion source
• Accelerator (cyclotron)
• Rotational gantries
• Beam transportation components
• Fixed beam
• Audrey Mahoney, Tufts MC EPC

Slide 45

Evidence Maps

Cancer type	Single arm	RCTs	Nonrandomized comparative	Total
Ocular	80	4	7	91
Head/neck	53	2	1	56
Spine	9	0	0	9
GI	18	1	2	21
Prostate	14	3	2	19
Bladder	3	0	0	3
Uterus	4	0	1	5
Bone/soft tissue	6	0	0	6
Lung	17	0	0	17
Breast	2	0	0	2
Miscellaneous	14	0	0	14