Protect, E

nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

Protones/Fotones

Dra. Berta Roth

Advances in Science, biology, physics, imaging allows:

More efficient and better tolerated treatments

Increasing proportion of patients free of tumour with less side effects

Radiotherapy in 2016

Precision

Individualization

Organ Preservation

Radiotherapy. What we can do better?

• IMRT, IGRT • Dose per fraction • Protons

Field

• Functional Images • Radiobiology Target

• New Drugs • Biology of the Tumour • Biological predictors

Biological Modifiers

cost / sophistication

precision

2D RT

IMRT (XR Intensity modulation)

IGRT Image guided

3D RT, conformal

stereotactic radiotherapy

cyberknife

tomotherapy

Carbon ions

protons

photons « hadrons »

>80% radiotherapy

Optimal Therapeutic Ratio: cure/toxicity

Precision !!!

To adapt the machine to the patient

and not the patient to the machine

Individualized versus “one fits all” !!!!

IGRT / IMRT / SBRT / SRS/ PROTON.........

Why heavier hadron beams? • Precision therapy conformed to tumor • Sparing of normal tissues • Increased DNA damage in tumor • Increased effect on hypoxic tumors • Less repair of sublethal anf potentially lethal damage in cell

cycle • Short overall treatment course • Use of radioactive beam component for treatment

verification

Charged particles are being increasingly used in cancer treatment

Highest Dose is near the point of beam entry.

Tumor Dose is less than the entry dose.

Dose is also delivered beyond the tumor target. Photons

(X-Rays)

Protons

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The Best in P

roton Therapy, Today and Tomorrow

Ballistic advantages No radiation beyond the Bragg Peak tumor;

Homogeneous dose along the defined modulation

Distal & Proximal Conformality to tumor shape

(PBS)

Example: Single Field Uniform Dose using in Pencil Beam Scanning

11

Why Proton Therapy? The dose deposition / Bragg peak

42 centres with protons (USA 14, Europe 12, Japan 8, …..) 6 centres with carbon ions (Japan 3, Europe 2, China 1) 3 dual centres (p+ C-12) 27 new centres planned 107,792 treated patients (93,452 with p+, 10753 with C-12) + 46,000 in the past 5 years ( ≈ 10,000 patients per year )

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1950 1960 1970 1980 1990 2000 20100

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4540,000 patients

22 PT centers

Research centres Hospitals

Protons: Expansion Centers Worldwide

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The Best in P

roton Therapy, Today and Tomorrow

15

Growing interest in PT clinical advantages: Publications

Number of publication up to end 2015

…

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1950 1960 1970 1980 1990 2000 2010 2020

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ly p

ublic

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Pubmed search with:

Proton Therapy or

Proton Radiotherapy or

Proton Beam Therapy

From Technical and Standard indications publications

(Ocular, Pediatrics, Base of Skull Chondrosarcoma and Chordoma) to

New indications (Lung, Breast, Head and Neck)

expending the use of PT

Protect, E

nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

PT Advantages: From Beam properties to Clinical benefits

16

Tumor control Toxicity PR

OBA

BILI

TY

DOSE OF RADIATION

Photons Protons Widening of the

Therapeutic Ratio

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The Best in P

roton Therapy, Today and Tomorrow

PT Advantages: From Beam properties to Clinical benefits

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Current standard (IMRTphotons)

Protons

Prob

abilit

y (%

)

Complications Local tumour control

Improvement of local

tumor control Prevention of complications

Photons

Protons

Courtesy of Prof Lagendijk

Pro

babi

lity

Improve Local Control Reduce Normal

Tissues Complications Decrease

integral dose (secondary cancer) PT is the

treatment of choice for retreatment

Tumor control Toxicity

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nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

23

52

60

Trial type

RCTNonRandomized, comparativeothers

26 Source: http://www.clinicaltrials.gov

End February 2016 135 prospective clinical trials on ClinicalTrials.gov with status of ‘ongoing and/or

recruiting’ Randomized Controlled Trials have increased to 23 Non Randomized Studies have increased to 52

3 9 5

11 8

5 17

1

6 17 9

19

16 1 8

Ongoing clinical trial Total 135

ocular head and neckspine liverpancreas esophagus, analprostate uterus, cervixbone soft tissues lung

Growth in prospective clinical trials

Meduloblastoma

Meduloblastoma

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The Best in P

roton Therapy, Today and Tomorrow

Proton therapy for Pediatric Tumor

33

Side Effects* Protons Photons

Restrictive Lung Disease 0% 60%

Reduced exercise capability 0% 75%

Abnormal EKGs 0% 31%

Growth abnormality 20% 100%

IQ drop of 10 points at 6 years 1.6% 28.5%

Risk of IQ score < 90 15% 25%

Courtesy of Newhauser et al PMB 2009

Secondary malignancy (Cancer generated by the RT treatment itself)

Decreased risk of 2nd cancer with protons

• 503 proton patients, 1974-2001 • Matched with 1,591 photon pts, by site, year, pathology • Mean F-Up 7.7 vs 6.1 y. • Risk : 6.4% (protons) vs 12.8% (photons) adjusted: 2.73 (p < .0001)

Chung CS et al, ASTRO, 2008, abstr 17

Protect, E

nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

Proton Therapy for Head and Neck

44

Protect, E

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The Best in P

roton Therapy, Today and Tomorrow

Vol

ume

(%)

Vol

ume

(%)

Dose (Gy) Dose (Gy)

Proton Therapy for H&N: Brain Stem DVH

Courtesy of Dr Nancy Lee MSKCC.

All the lines correspond to the different patients

Photons Protons

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The Best in P

roton Therapy, Today and Tomorrow

Vol

ume

(%)

Vol

ume

(%)

Dose (Gy) Dose (Gy)

Proton Therapy for H&N: Spinal Cord DVH

Courtesy of Dr Nancy Lee MSKCC.

All the lines correspond to the different patients

Photons Protons

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nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

Photons Protons

Vol

ume

(%)

Vol

ume

(%)

Dose (Gy) Dose (Gy)

Proton Therapy for H&N: Oral Cavity DVH

Courtesy of Dr Nancy Lee MSKCC.

All the lines correspond to the different patients

Protect, E

nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

Photons Protons

Vol

ume

(%)

Vol

ume

(%)

Dose (Gy) Dose (Gy)

Proton Therapy for H&N: Larynx DVH

Courtesy of Dr Nancy Lee MSKCC.

All the lines correspond to the different patients

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nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

Cost effectiveness of Proton Therapy: MD Anderson

49

MD Anderson

Head and neck 50 to 60% reduction in Gastrostomy tube

IMPT for Oropharynx is cost effective

Breast Proton therapy less expensive than some conventional radiotherapy techniques

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The Best in P

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Cost effectiveness of proton therapy

50 50

CONCLUSIONS: The current results provide the first evidence-based guide for identifying children with brain tumors who may benefit the most

from Proton-Therapy with respect to endocrine dys-function. Proton-Therapy may be more cost effective for scenarios in which radiation dose

to the hypothalamus can be spared, but protons may not be cost effective when tumors are involving or directly adjacent to the hypothalamus if there is a high dose to this structure. Cancer

2015;121:1694-702. © 2015 American Cancer Society

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The Best in P

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Cost effectiveness of proton therapy

51 51

CONCLUSIONS: With greatly limited amount of data, PBT offers promising cost-effectiveness for pediatric brain tumors, well-selected

breast cancers, loco-regionally advanced NSCLC, and high-risk head/neck cancers. Heretofore, it has not been demonstrated that PBT

is cost-effective for prostate cancer or early stage NSCLC. Careful patient selection is absolutely critical to assess cost-effectiveness. Together with increasing PBT availability, clinical trial evidence, and

ongoing major technological improvements … Cancer 2016;122:1483-501. © 2016 American Cancer Society

RACIONAL DE LOS PROTONES EN CÁNCER DE MAMA

• EL CANCER DE MAMA ES UNA ENFERMEDAD ALTAMENTE CURABLE Y POR LO CUAL LAS PACIENTES SON LARGAS SOBREVIVIENTES POR LO QUE PUEDEN EXPERIMENTAR MAS TOXICIDADES TARDIAS.

Breast RX-associated cardiac toxicity

(Darby et al., NEJM, 2013) Estudio de 2160 mujeres desde 1958 a 2001

ANATOMIA: ARTERIAS CORONARIAS (Nilsson, JCO, 2011)

1+2+3 = Right CA 5+6 = Left main 7+8+9+10 = Left Anterior descending

Lt Tangential fields = Lt breast/chest Wall

( Rt Int Mam = Rt breast = Electrons++)

SPARING HIGH DOSE RT • For tangent

field to cover IMN left, LAD & portion RV & LV would receive full dose.

• For a tangent field to cover IMN right, RCA would receive

Protect, E

nhance and Save Lives

The Best in P

roton Therapy, Today and Tomorrow

Proton Therapy for Breast

58

58

IMRT PT

Reduction of Side Effects Reduced dose to the heart Reduced dose to the lung Reduced dose to the left anterior descending

artery

Images Courtesy of Dr. S. Both, Penn Med.

Post Mastectomy trial on-going : NCT01340495

Complication Left Breast Right Breast

Chest pain 26% 12%

Coronary art. dis. 25% 10%

Myocardial Infrac. 15% 5%

Cardiac Death 6.4% 3.6%

• Protons allow for an external beam plan with non- target breast tisuue sparing more comparable to brachytherapy

• Modest reduction lung and heart (most patients)

El-Ghamry IJROBP 2002

PROTONES Y PARRILLA COSTAL (Mac Donald S et al., Rad Oncol, 2013)

PROTONS PROTONS

PROTONS XR+El XR

Trial RADCOMP • Randomized control trial for protons vs photons for patientes reciving Radiation for non-

metastatic breast cancer in reducing major cardiovascular events (MCE) • PCORI sponsored

total 1716 patients Dose specification 45-50Gy in 1.8-2Gy fractions with o whithout tumor bed or chest wall boost

Hypothesis For patients with locally advanced breast cancer proton therapy will reduce the 10 years MCE after radiation from 6.3% to 3.8%

Pancreatic Cancer Facts...

• 43,140 Annual Cases – Perhaps 50% present with localized disease

• Perhaps 50% of these are “resectable” or “curable”

–And yet the “cure” rate is only about 20% for these “curable” patients.

Particle therapy for locally advanced unresectable Pancreatic Cancer

More Facts

• Local control is a necessary condition for cure. • Surgery is a necessary condition for local control. • Surgery is not a sufficient condition for local control.

The problem with the Pancreaticoduodenectomy...

…is that even with negative nodes and negative surgical margins, 50% to 80% of patients will suffer a local failure if they do not receive postoperative radiotherapy.

Are you ready for the bad news?

• Hopkins data: – Pawlik TM, Surgery, 2007

• 905 Whipples from 1995 to 2005 –Node positivity was…79.3% –Margin positivity was …41.1%

Postoperative X-Rays?

Problems with postoperative radiotherapy…

MGH data shows a 36% local/regional failure rate at 3 years after postoperative chemoradiation.

RTOG 97-04 shows a 23% to 28% local failure rate.

Protons versus IMRT

Small Bowel V20 (15.4% vs. 47.0% p=0.03)

Protons versus IMRT

Right Kidney V18 (27.3% vs. 50.5% p=0.02)

What about efficacy?

PC01 Protocol (continued)

Median Survival 18.4 months

2 Year Local Control 69% 2 Year Overall

Survival 31%

Summary #1 • Surgical outcome data demonstrates

a high rate of local failure which is only marginally improved with postoperative radiotherapy.

Summary #2 • Our experience suggests that these fears

are unjustified with proton therapy: – Dosimetry – Lack of acute or late radiotherapy toxicity – Surgical experience showing no increase in complications for unresectable

patients receiving high dose radiotherapy before surgery.

UFPTI protocols: – PC01 … Unresectable disease … 59.40CGE with concomitant

Capecitabine (closed) – PC02 ... Resectable and marginally resectable disease … 50.40CGE

with concomitant Capecitabine. – PC03 … Postoperative adjuvant with weekly Gemcitabine

• 50.40CGE for R0 resections • 54.00CGE for R1 resections • 59.40CGE for R2 resections

UFPTI protocols:

– PC04 ( in development) … “initally unresectable” disease…63CGE in 28 fractions (mimics NRG 1201) with concomitant capecitabine.

• +/- equivalent of 70CGE at 2CGE per fraction

Case #1: Which best ? (LEC. Joelle)

Max:68%

Max:105%

Max:76%

TomoT

CyberK

Pr

•Choice: protons (sharp penumbra) •Stroke at 3 m

•NED at

•56Y old, RIII palsy •Past history: RON glioma as young adult(±45 Gy)

•Work up: B meningioma Rt ant clinoid •Management: partial resection+RT(52Gy)

Protons in choroidal melanomas: DFS

0102030405060708090

100

0 5 10

BostonLarge BostonSmall Villigen Orsay Nice

K K

Protons IMRT

Paraespinal Tumour

Treatment Plan...3DCRT

Pulmonary V20 = 50% - Not Feasible

Treatment Plan...IMRT

Pulmonary V20 = 35%

Mean Heart Dose 19.00Gy

Treatment Plan...Protons

Pulmonary V20 = 24%.

Cardiac Dose Minimal

Protontherapy for oligometastatic patients

Potential Number of Patients in Argentina

( Population: 40 M)

• RT Conventional: 20.000 pt/year every 10 M Hab = 80.000 patients Protontherapy: 10-15 % pt RT = 8.000-12.000 pt/year

Proton Therapy and Advanced Radiotherapy Center

Instituto Roffo FCDN

Protonterapia

Which future for Hadrons ?

Today...

Tomorrow…

CARBON ? Others ?

PROTONS

PHOTONS PROTONS

Be positive like a proton!