The Current & Future State of Particle Therapy · 2019-12-16 · 1954 Proton Therapy 1960’s Radiosurgery 1970’s CT planning 1980’s BEV planning 1990’s 3D planning 1990’s

The Current & Future State of Particle TherapyThe MD Anderson Proton Therapy Center- Houston

Making Cancer History w/ Proton Therapy for 10 years!

• Maximize disease control• Minimize both early and late side effects• Preserve organ function• Preserve quality of life• Minimize extraneous radiation dose to the

patient

Goals of Radiation Therapy

“One cannot have a radiation-induced side effect in tissue that does not receive radiation.”

-H. Suit

The 4 Eras of RadiotherapyThe Era of Discovery (Rontgen - Late 1920s)

The Orthovoltage Era (Late 1920s - World War II)

The Megavoltage Era (1950’s – Current)

The Particle Therapy Era (1950’s – Current)

An early radiation therapy machine at Columbia

(1950s)

All Eras are a Continuum…Overarching goal – better

patient treatmentFundamental impetus for improvements- need for effective disease and improving quality of life.

Curiosity of physicians, physicists, and biologists led to development to meet these for patients’ benefit.

1900’s Brachytherapy

1952 Cobalt Teletherapy

1954 Proton Therapy

1960’s Radiosurgery

1970’s CT planning

1980’s BEV planning

1990’s 3D planning

1990’s IMRT

2000’s IGRTVMATIMPT

2010+

• Particle accelerators (1920s) constructed.

• Linear Accelerator (1927)- Developed by Widerøe

• Supervoltage X-ray tubes (1929)- for Linac developed by Coolidge

• Cyclotron (1930)- Lawrence’s laboratories (UC Berkeley)

• Synchrotron (1944–1945)- Veksler(Soviet Union) & McMillan [US]

• Electron Beam Therapy (1940)- Kerst developed the Betatron

• Concept of Proton Therapy (1946)-Robert R. Wilson proposed protons for medical purposes

• Proton Therapy (1954)- first clinical use at Berkeley in 1954.

Technology Advances



1954 Proton Therapy





1990’s IMRT


2010+

• Proton Radiosurgery at MGH (1961)• UCLA Medical Center obtained a

Commercially Produced Linac (1962) • Chemotherapy (1960s – 1970s)• Worldwide proton therapy growth

(1960s – 1980s)• Rotational Arc Therapy introduced

(1970s- 1980s)• CT-Based Treatment Planning (1978)• 1,000 Medical Photon Linacs in US

(1986)• Virtual Simulation (1987) at UNC

Technology Advances



1954 Proton Therapy





1990’s IMRT


2010+

Technology Advances• CyberKnife developed by J. Adler at

Stanford University (1990). • World’s first Hospital-based Proton

Facility opened at LLUMC (1990) • First commercial TPS developed in

(1990)• MLC developed (3D-planning) which

allows first dose escalation trials. (1990s)

• CT Simulations first used (1990s)• IMRT developed (1994)• KV Imaging & CBCT (1990-2000)• Tomotherapy clinically developed

(2003). • Intensity Modulated Proton Therapy

delivered at MDACC (2008)

Technology Advances

HEART DOSE (cGy):2833 1933 2200 1301

943 LUNG DOSE (cGy):

1747 1324 1103 966 775

LIVER DOSE (cGy):1184 1141 986 218 235

IMRTX-RAYS

3D-CRTX-RAYS

VMATX-RAYS

IMPT PROTONS

1980’s 1990’s 2000’s 2010+

PASSIVEPROTONS

2005+

The 4 Eras are a Continuum…Overarching goal – better patient treatment

Fundamental impetus for improvements is the need for DISEASE CONTROL and IMPROVING QUALITY OF LIFE.

The intent is to deliver a more EFFECTIVE DOSE to the target volume while REDUCING DOSE TO TISSUE that do not need to be irradiated.

Therefore, ONGOING RESEARCH to DEVELOP NEW TECHNIQUES to overcome these imposed limitations.

Rubin and Casarett demonstrated that there is NO “SAFE” RADIATION DOSE, in terms of avoiding sequelae in irradiated normal tissues[1,2].

The DEVELOPMENT OF PARTICLE THERAPY was a response to the need to PRESERVE NORMAL TISSUE as much as possible to REDUCE SIDE EFFECTS AND COMPLICATIONS.

[1] Ute Linz, Ion Beam Therapy: Fundamentals, Technology, Clinical Applications, [2] P. Rubin, G.W. Casarett, Clinical Radiation Pathology, vols. 1 and 2 (W.B. Saunders, Philadelphia, 1968)

Proton Therapy (IMPT) X-Ray Therapy (IMRT)

ELIMINATION OF UNNECESSARY RADIATION

Added Radiation w/ IMRT (X-Rays)

*25 Gy (25 Sv) of Unnecessary Radiation

Added Radiation w/ IMRT (X-Rays)

ELIMINATION OF UNNECESSARY RADIATION

*25 Gy (25 Sv) of Unnecessary Radiation =

H&N CTs (2 mSv)

12,500Intraoral X-Rays

(0.002 mSv)

5,000,000General Public

Annual Limit (1.0 mSv)

25,000x

Proton Therapy (IMPT)

Proton Therapy for Nasopharynx Ca60% reduction in feeding tubes

Frank SJ et al. ASTRO 2013Frank SJ et al. IJROBP 2014

Barriers for Rapid Proton Therapy Adoption

1)Large gantry designs2)Infrastructure requirements3)Shielding requirements4)Large equipment technology5)Power and cooling

requirements6)Old accelerator technology7)Time to First Treatment (3+

years)

Image Courtesy of HIL Applied Medical

1st Linac(1960)

2-D Planning &MV Port Films

(1970)

CT-Based Planning(1987)

3-D Planning(1990)

IMRT Implementation

(1992)

75% of RO using IMRT

(2002)

kV ImagingVMAT Implementation

(2006)

CBCT & VMAT Growth(2010)

VMAT Maturation(2014 )

MDACC(#5)

(2006)LLUMC (#1)(1990)

1st USA Spot Scanning

(2008)

1st USA IMPT(MDACC)*

(2009)

UCSF (#2)(1994)

MGH (#3)(2001)

Proton Therapy Development Lag = ~17 Yrs.

39 New PTCenters (45%)(2014 - 2018)

7 w/Spot Scanning &

0 w/ CBCT(2014)

Single Room PT Growth

(2018)

Future Potential of Proton Therapy

Technology Development Lifecycle

Technology Advancements

Size

Smartphone Image Courtesy MIM Vista Website

Technology & Functionality

PT Industry Developments

-28%Gantry Design

Courtesy of ProNova


-33%

Vault Design (Maze)

-46%

Floor Plan Design

97’ 7”

84’ 11”

Courtesy of VOA Associates


-27%

Modular Shielding

Shielding Design

-36%

Courtesy of VOA Associates & Veritas Shielding


Accelerator Design

-20%

-59%

Power Supply

Images Courtesy of Hitachi Medical & ProTom


Reduced Footprint

Superconducting Accelerators & Magnets

Images Courtesy of ProNova & Mevion


Proton Source (Nanotechnology)

Reduced Footprint

Images Courtesy of HIL Applied Medical

Rapid Adoption of Proton Therapy is Close

-46%Floor Plan Design

-33%Vault Design

-36%Shielding Design

-20%Accelerator Design

System Design

Proton Source

-59%Power Supply

-28%Gantry DesignCollective Industry Developments will Break the Financial-Viability Threshold

with Support!

Image Courtesy of HIL Applied Medical

-10-12months

Construction Time

Particle Therapy Facility Worldwide

MD AndersonRadiation Oncology Department

Accredited Radiation Oncology Program One of world’s largest Radiation Oncology programsLeader in Radiation Oncology research

Leaders in Proton Therapy: Academic and Technology Leaders

Leaders in the Field:ASTRO presidents – 7

ASTRO gold medalists – 6

[4]

Pioneering Proton Therapy Since 2006

Support

Research 315

Firsts 6,700+

[5]

• White House • Medicare (LCDs)• NCI/NIH• NCCN (prostate, lung)• ASTRO• California state government• Washington state government• Oklahoma state government• Louisiana state government – mandate for clinical trials• Institute for Clinical and Economic Review (ICER)

Proton Therapy Support

1. Required resources and cost of treatment2. A limited number (14) of proton therapy centers to

publish data and average time to publication3. Varying Definitions of Medical Necessity4. Lack of Validity and Accuracy in Insurance

Companies Medical Policies5. Only a few randomized studies

Roadblocks for Proton Therapy

Proton Therapy Operational CostProtons/Photon Cost = 3.2

Peeters et al, Radiotherapy and Oncology, 2010, “How Costly is Particle Therapy? Cost Analysis of EBRT with C-ions, t & h t ”

NCI Supported PT RCT Studies1. Trial #11-497 (Active, Accrual Goal- 400): “PARTIQoL: PIII RCT for Low or Intermediate

Risk Prostate Cancer”

1. NCI-2013-01850 (Active, Accrual Goal- 560): “PIII RCT for Inoperable Stage II-IIIB Non-Small-Cell Lung Cancer”

1. Trial #12-100 (Active, Accrual Goal- 80): “PI/II RCT with SIB to the High Risk Margin for Retroperitoneal Sarcomas”

1. NCI-2012-00071 (Active, Accrual Goal- 120): “PII RCT for centrally located Stage I, selected stage II & recurrent NSCLC”

1. Trial #10-308 (2P01CA021239-29) (Active, Accrual Goal- 90): “A PII RCT for Locally Advanced Sinonasal Malignancy”

1. NCI-2013-01879 (Active, Accrual Goal- 360): “PII/III RCT for the treatment of Oropharyngeal Cancer of the Head and Neck Cancer”

1. NCI-2012-00078 (Active, Accrual Goal- 180): “PIII RCT for the Treatment of Esophageal Cancer”

1. NCI-2014-01072 (Active, Accrual Goal- 576): “PII RCT for Patients With Newly Diagnosed Glioblastoma”

1. NCI-2011-01094 (Completed, Accrued- 275): “Phase II Bayesian RCT for locally Advanced NSCLC”

Nine (9) NCI-Funded ($19M) projected to accrue 2,500 patients, half protons and half photons

Making Cancer History with Proton Therapy

Making Cancer History with Proton Therapy

Current13 Treatment protocols

1 Prospective Normal Tissue Toxicity protocol

7 prospective lab and data collection studies

Nasopharynx Cancer 60% in Feeding Tubes

Prostate Cancer 39-62% Grade ≥ 2

Rectal Toxicity

14-29% 5-Year Cancer-Free Survival (Intermediate

Risk)

50% Bowel Problems(Moderate- Big)

26-39% SecondaryMalignancy Risk

Other Benefits

Chordomas49-56% 5-Year Local Control

Oropharynx Cancer 50% in Feeding Tubes

Esophagus Cancer 41% Lung Complications

20% Hospitalization Rate

Lung Cancer 57% Grade 3 Pneumonitis

Hepatocellular Cancer58% 2-YOverall Survival

32% 3-Year Overall Survival

Breast CACosmesis

The Clinical Benefits of

Proton Therapycompared to

X-Rays Therapies

Intrahepatic Cholangio CA54% 4-YR Overall Survival

Toxicities

Advanced technologies improve perioperative pulmonary

complications• 444 patients who had surgery after

Chemo Radiation Therapy (CRT)

• 3D (n=208, 1998-2008); IMRT (N=164, 2004-2011), and PBT (n=72, 2006-2011)

• Evaluated Pulmonary, GI, cardiac, wound healing within 30 days of surgery

• Pulmonary complications (ARDS, pleural effusion, RI, PNA) most predictive based on radiation type

• IMRT vs 3D (OR 0.50, 95% CI 0.27-0.91)• PBT vs 3D (OR 0.32, 95%CI 0.14-0.73)• IMRT vs PBT (OR 1.56, 95%CI 0.68-

3.60)

Pulmonary Complications

Wang J and Lin SH et al, IJROBP 2013

Protons Reduces 2nd CancersMGH report spanning 26 years (1974-2001)

Matched 558 patients treated with protons (20% also received some x-rays) vs. x-ray patients from SEER registry

CNS 32%, HN 24%, Prostate 33%, Sarcoma 7.8% (no ocular)

Secondary cancer rates were 6.9 vs. 10.3 (per 1000 person-years) for protons vs. XRT, respectively

Protons HR for 2nd cancers was 0.52(p=0.009)Adjusted for sex, age @ treatment, primary site, year of dx

[Chung et al. Int J Radiat Oncol Biol Phys 87, 2013]

Results:

Proton therapy reduced the risk of secondary malignant neoplasms by 26 to 39% compared to IMRT, respectively.

Protons Reduces 2nd Cancers

Value = (Outcomes) (Costs)

Thaker N et al. Oncology Payers2014

Equivalent at 21 Days

Value Proposition- H&N

• Varying Definitions of Medical Necessity• Lack of Validity and Accuracy in Medical Policies• Third-party involvement in proton therapy denials

(CareCore, Health Help)• No coverage options for prospective and

randomized studies by payors• Policies of State Governments• A limited number of proton therapy centers to

publish data• Centers with limited research infrastructures

Roadblocks for Proton Therapy

0

50

100

150

200

250

300

350

1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

PTCOGAetnaBCBSUnitedHealthcare

Year

# of

refe

renc

esCumulative Number of

PubMed Cited References

Number of PubMed Cited References per Disease Site

0

10

20

30

40

50PTCOGAetnaBCBSUnited Healthcare

Disease Site

# of

refe

renc

es

Levels of Evidence per Medical Policy

1 5

38

17

178

18

39 41

0

20

40

60

80

100

120

140

160

180

200

1 2 3 4 5 6 7 8

# of

refe

renc

es

Level of Evidence

PTCOGAetnaBCBSUnitedHealthcare

Level of evidence/Type of StudyLevel 1 Large multi-institutional prospective

randomized clinical trialsLevel 2 Single institution randomized controlled

studiesLevel 3 Well-conducted single arms studiesLevel 4 Prospective registriesLevel 5 Well-structured retrospective studies

and systematic review of lower level evidence

Level 6 Population or claims-based studies, and smaller case-series

Level 7 Anecdotal patient case reports, dosimetric studies, mechanism-

basedLevel 8 Clinical reviews

7 references removed from 2011 to 2015 medical policy

Overall Increase in References,Decrease in Prostate References

2011 BCBS-TX Medical Policy2015 HCSC Medical Policy

*Third Party (CareCore) Policy

…and Removal of ALLLevel 1-2 Prostate References

Level of evidence/Type of StudyLevel 1 Large multi-institutional prospective

randomized clinical trialsLevel 2 Single institution randomized

controlled studiesLevel 3 Well-conducted single arms studiesLevel 4 Prospective registries

2011 BCBS-TX Medical Policy2015 HCSC Medical Policy

*Third Party (CareCore) Policy

Definitions of Medical Necessity

Medical Evidence

Medical Necessity Coverage

Medicare and AMA Definition

Cost

2014+ Insurance Companies Definition

OmittedMedical

Evidence

AddedCost or Value

NoMedical

NecessityNo

Coverage

Randomized IMRT Studies?Randomized Controlled Trials (RCTs): IMRT compared with non-IMRT in only 3 RCTs.(1)

• Breast Cancer [2] (n = 100+). • Nasopharyngeal Cancer [1] (n=25)• Oropharynx Cancer [1]

Prostate: No RCTs comparing the 3D to IMRT.(2)

• RTOG 0126 Protocol: A Phase III RCT of High Dose 3DCRT/IMRT versus Standard Dose 3DCRT/IMRT...

• RTOG 0415 Protocol: A Phase III RCT of Hypofractionated 3DCRT/IMRT versus Conventionally Fractionated 3DCRT/IMRT…

Lung: No RCTs comparing the 3D to IMRT.(2)

(1) http://ac.els-cdn.com/S1470204508700986/1-s2.0-S1470204508700986-main.pdf?_tid=b04c6290-149c-11e5-9ba8-00000aab0f26&acdnat=1434510071_c1959e7c1a69880dc9621bbf181154f7

(2) https://www.premera.com/medicalpolicies/cmi_131265.htm

Action: 2015-04-20 - Approved by Governor 04/17/2015

“A health benefit plan, as defined in subsection C of Section 6060.4 of Title 36 of the Oklahoma Statutes, that provides coverage for cancer therapy shall be prohibited from holding proton radiation therapy to a higher standard of clinical evidence for medical policy benefit coverage decisions than the health plan requires for coverage of any other radiation therapy treatment.”

Oklahoma House Bill 1515

Reference: https://legiscan.com/OK/bill/HB1515/2015

The Upside!* Newer technology is more compact, efficient, & IMPT development

* Gating, painting, redirection to minimize effects of motion

*Real-time tumor tracking

*Dual Energy (DE) to reduce uncertainties

*Advanced IGRT w/ DE CBCT

*Robust Optimization to reduce uncertainties & margins

*TPS Developments

*RBE plan optimization

*Image Response Analysis

Protons Stop

where they

should!

Image Courtesy of Anita Mahajan, MD

Image Courtesy of Clifton Fuller, MD, PhD & Abdallah S.R. Mohamed, MD Msc

• Rapid Technology Changes in Radiotherapy

• Radiotherapy goal is to reduce unnecessary radiation

• Proton Therapy was developed due to its superior dosimetry.

• The upside of Proton Therapy is promising but still have roadblocks for widespread adoption.

Conclusions

We must Define the Value and Role of Proton

Therapy in Radiotherapy and use it as a tool when

indicated.

Image Courtesy of ProNova

Questions & Answers

Documents

The Current & Future State of Particle Therapy · 2019-12-16 · 1954 Proton Therapy 1960’s Radiosurgery 1970’s CT planning 1980’s BEV planning 1990’s 3D planning 1990’s