Medical experience •erice2009.na.infn.it/TalkContributions/LinzSummary.pdf · 2009. 4. 30. · U.Linz Summary Talk of the Workshop Linz-MediConsult Forschungszentrum Jülich10 1

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Summary Summary Talk of Talk of the the WorkshopWorkshop

Linz-MediConsult Forschungszentrum Jülich

• Medical experience •

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• History of IBT •

1954 1975 1976 1977 1982 1987 1992

Pituitary 1st He pt 1st C, Ne ptTreatment

Eye treatment

Phase-1 He Phase I-II Ne Phase I-II Ne & He

1st Comp Tx Plan 3D planning

LBNL CT LBNL MRI

Image Correlation

1957 Uppsala1961 MGH/HCL

1967 Dubna

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• LBL: evolution of treatment planning •

1992

1977

1985

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• the first clinical proton therapy center: LLUMC •

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• IBT facilities in the USA •

Courtesy of Mark Courtesy of Mark Buntaine Buntaine (Still(Still--RiversRivers--Systems)Systems)

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• is prostate cancer a good indication? •

1. The dose distribution difference between IMRT &

protons is very small, so there is no reason to belie ve

there should be a difference.

2.2. Neutron contamination issues?Neutron contamination issues?

3.3. Not cost effective? Not cost effective?

4.4. Early stage pts require long fu & many pts & PSA Early stage pts require long fu & many pts & PSA

inadequate! High risk pts inadequate! High risk pts Tx Tx systemic systemic DzDz??

5. The NCI will not fund a study that does not use

Overall Survival as an endpoint (e.g. RTOG 0815)

6.6. There are very few Centers & it is not in their $$$ bes t There are very few Centers & it is not in their $$$ bes t

interest to turn away pts. interest to turn away pts.

MRIIIMRIII

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Conclusions:“… In the range higher than 60 Gy/CGE,

IMRT achieved significantly better sparing of the

bladder, whereas rectal sparing was similar … ”

• is prostate cancer a good indication? •

IJROBP 69, 444, 2007

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• prostate cancer: H-scattering vs. X-IMRT •

7F-IMRT 2F-proton

RatioV70(Bla) 1 1.5V30(Rec) 1 ≤0.84V50 1 0.5

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• example: prostate cancer •

LLUMC ca. 2000 patients

tumor stages T1c-T2c ≈ 23% eachT1a/b & T3 3% each

10Y survival (bNED) 73%(brachytherapy: 70%)

complications grade 2 9% grade 3 <1%grade 4 none

2-F proton

6-F photon

equivalent survival ratesno surgery, no hormone therapy necessary

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Linz-MediConsult Forschungszentrum Jülich10

1. Proton Beam Radiotherapy touted as “best choice” bu t not

supported by the evidence!

2. Same doses will yield same results!

3.3. Risk of second cancers higher with passive scanning?Risk of second cancers higher with passive scanning?

4.4. Cost of facilities is prohibitive and not Cost of facilities is prohibitive and not ““ GreenGreen ”” !: !: a.a. Single prototype vaults ~ 20 MSingle prototype vaults ~ 20 Mb.b. MultiMulti --vault units: 70 to 140 Mvault units: 70 to 140 M

5.5. Brachy Brachy yields equal or better results & is:yields equal or better results & is:a.a. Less expensiveLess expensiveb.b. More availableMore availablec.c. Has broader applicationsHas broader applicationsd.d. Potential for further improvements?Potential for further improvements?

• prostate cancer: pro and con protons •

MRIIIMRIII

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Linz-MediConsult Forschungszentrum Jülich11

• Doses are highly

facility dependent

• Full benefit of protons

achieved with

scanning technique

but none use it!

MRIII

(6-MV)

10 x 10 cm2 field

Hall, IJROBP 65:1-7;2006)

• neutrons: scanning vs scattering •

These data are considered incorrect!

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• pro and con of heavy ions •

nuclear fragmentation

proton

helium

carbon

late

ral s

catte

ring

(mm

)

depth in water (cm)

narrower Bragg peak

0

0,2

0,4

0,6

0,8

1

1,2

0 4 8 12 16

60-Co

14.5 MeV Neu

20 MeV e

160 MeV H

270 MeV/u C

70 MeV Pi

rela

tive

dose

proton

carbon

less lateral scattering

increased biol. effectiveness

more expensive

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• prostate treatment with carbon ions •

Comparison of CRT vs. XRT (with or without hormones)for prostate cancer shows 10-15% higher OS for CRT

Tsujii et al., 2008

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The Spot Scanning Gantry at PSI

Spot scanning and a compact gantry for proton therapy of deep seatedtumors – PSIs (and Eros Pedronis) pioneering contribution to cancer treatmentGG-Erce 09

• contributions of PSI to proton therapy •

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Linz-MediConsult Forschungszentrum JülichGG03/09

OPTISOPTIS

The eye is the „perfect model“ for proton therapy:NO bones, NO strong inhomogeneities, a mobile and controllable organ,

a well circumscribed functional compartment –but nevertheless not an easy case! GG-Erce 09

• PSI: the eye tumor program •

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Linz-MediConsult Forschungszentrum JülichGG 03/09

2993 Patients analyzed (2006), who received proton radiation therapy between III/1984 and VIII/ 2005

• Follow up 15 months – 21 years; median 5ys 3ms

• Confirmed diagnosis of melanoma (HOJG Lausanne)

• Unilateral disease

• No reduced (<2mm) safety margin

• Negative familial history

• Visible fundus

• No adjuvant chemotherapy

• Proton dose of 4x15= 60 Gy RBE ( former CGE, Cobalt Gray Equivalent )GG-Erce 09

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Linz-MediConsult Forschungszentrum JülichGG 03/09

Center for Proton Therapy

OPTISConclusion - OPTIS

Proton radiotherapy for ocular melanoma results in very satisfyinglocal control (overall 97%@5ys, 96%@10ys, 94%@15ys)

and tumor specific survival (overall 91%@5ys, 83%@10ys, 79 %@15 ys)

Differentiated outcome analysis shows thatage tumor size (diameter and thickness)localization and relation to other structures (optic disc, ciliary body, iris)

have the strongest influence on local failure, enucl eation rate and survival

GG-Erce 09

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•• exampleexample : : uveal melanoma uveal melanoma ••

MGH, PSI, LLUMC: ca. 8 000 patients

15Y local control 95%eye retained ≥ 80%20/200 vision saved: ≥ 40%5Y survival > 70%

HMI, BerlinHMI, Berlin

local control similar to enucleation number of metastases not increased

more flexible than plaque therapy

tumortumor

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ChoroidChoroid --Plexus Plexus CarcinomaCarcinoma

2 2 year year old old girlgirl

PT

XRT

Slide courtesy of B. Timmermann GG-Erce 09

• PSI: pediatric tumors •

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• dose distribution: an example •

protons photons

1-field spot scanning 9-field IMRT

dose (%)

100

80

40

60

20

Lomax, 2003

Relapsing desmoid tumor in a 12 y/o boy

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• dose distribution: an example •

protons photons

1-field spot scanning 9-field IMRT

dose (%)

100

80

40

60

20

Lomax, 2003

6x higher integral dose for photons

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• example: comparative dose distribution for child with medulloblastoma •

Miralbell Miralbell et al, 2002et al, 2002

conventional conventional XX--raysrays intensityintensity --modulated modulated XX--raysrays spotspot --scanned protonsscanned protons

target volumetarget volume(spinal (spinal cordcord ))

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Pediatric Proton Therapy Conclusion

Patients are treated within or in adaptation to exist ing protocols

Outcomes are very satisfying with good local control rates

Acute toxicities where extension and protocol-define d safety margins require irradiation of normal tissues up to dose level s with known risk of acute (and late) toxicities.

Protons can reduce CTX-related toxicities through sparin g of normal tissues (e.g. oral mucosa).

Local recurrences occured in-field; no geographic mis ses, but local relapses due to aggressiveness of the disease (? high er local doses beneficial?)

Late toxicities Grade 3 & 4 were related to the tumor g eometry – site, size, shape and necessary dose levels; 1 grade 5 fatalty occured in a high risk patient who was treated for recurrent disease. 1/51 GG-Erce 09

overall 86%

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25 25 Years Years of Proton of Proton Radiation Therapy Radiation Therapy at PSI at PSI -- ConclusionConclusion

Philosophy and performance in all medical and related projects at SIN/PSI were positiveIndications for proton therapy at a physics research ins titute were wisely chosen according to medical needs and technical/logi stic possibilitiesA new technology was introduced into the spectrum of Radiation Oncology with caution and great care , ongoing improvement and learning All developments were focussed on patient safety & c omfort and were optimized according to medical needsClinical outcomes for various tumors and sites were goo d to excellentOutcome analyses and comparison with other centers show ed appropriate and in part outstanding treatment results Adverse effects or events were understood and actions w ere taken

Technology and medical results have made PSI a refere nce place for PTGG-Erce 09

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Slide courtesy of E. Hug GG-Erce 09

• PSI: outlook •

From bony tumorsFrom bony tumors, , tumors attached tumors attached to to bones or bones or in in immobile immobile anatomic positions anatomic positions

totoSoft Soft Tissue tumors Tissue tumors in a soft in a soft tissue environmenttissue environment

totoMobileMobile soft soft tissue tumors moving with respirationtissue tumors moving with respiration

Step I. upper GI (Liver / Bile / Pancreas)

Step II. Lung Ca, Mesothelioma, Mediastinal tumors

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Who shall we treat

at CNAO?

• CNAO: treatment indications •

RO, CNAO

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Linz-MediConsult Forschungszentrum JülichRO, CNAO

• CNAO: identifying new indications •

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Category A

• All the tumors in which the use of hadrontherapy IBT is clearly demonstrated to be advantageous, being the only way to give a curative dose to the target volume minimizing the incidence of severe side effects

Category B• A great variety of tumors characterized mainly

by a local evolution, with a limited probability of distant spread, and therefore potentially cured if the locoregional control can be obtained

RO, CNAO

• ranking of indications •

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15%144960Paediatric solid tumours

9741.885TOTAL

10%75750Pituitary adenomas

15%45300Schwannomas of the cranial nerves

100%140140Paraspinal tumours

50%125250Meningiomas of the skull base

100%9090Chondrosarcomas of the cephalic extremity and of the trunk

100%4545Chordomas of the skull base and of the spinal column

100%310310Uveal Melanoma

Patients treatable with protons

New patientsper yearCategory A. Protons

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14367672

TOTAL

30%225750Recurrent tumours

10%4504500Liver/Biliary tract/Pancreatic tumours

20%2721360Soft tissue sarcomas

20%104520Bone sarcomas

100%3030Mucosal melanoma of the head and neck areaand other districts

10%45450Maxillary sinus adenocarcinomas

50%310620Salivary gland tumours

Patients treatable with Carbons

New patientsper yearCategory A. Carbon ions

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•• possible indications possible indications ••

tumor type applicability (%) pat./yearin Germany

chordoma and chondrosarcoma 100 70

eye melanoma 50 275

basal meningioma 70 175

pediatric tumors 20 150

soft tissue sarcomas 60 575

nasopharyngeal tumors 70 630

gliomas grade I & II 80 540

glioblastoma 25 300

hepatocellular carcinoma 25 1000

prostate carcinoma 25 5000

NSC lung carcinoma 20 8000

solitary metastases 50 2000

local recurrencies 50 2000

Sum ≈21000

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• estimate of patient numbers •

13.5%Estimation based # RT ptsMayer (Austria) 2004

14.5%Estimation based # RT ptsBaron (France) 2004

16%Estimation based # RT ptsOrrecchia (Italy) 1998

2200 - 2500 per yr or ~ 14-15% of all RT pts

Rad Onc, Physicist, tumor registry stats for Sweden, literature, #pts getting RT

Bengt (Sweden) 2005

ConclusionsType of studyFirst Author (Country) Year

approx. 15% of RT patients are presently considered candidates for IBT

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•• criteria for usage criteria for usage ••

deep-lyingirregularly shaped

extensive tumors

profit from precision

steep dose gradientfavorable dose distribution

improved local tumor controllower risk for healthy tissue

simplified treatment plan

tumors neighboring critical structures

well demarcatednon-invasive

tumors

pediatric tumors

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•• FDAFDA--approved indications approved indications ••

Pelvisprostate CAcervix CA

Wilms tumor

Abdomenparaspinal tumors

soft tissue sarcomas

CNSchordoma/chondrosarcoma

gliomas, meningeomapediatric brain tumors, metastases

Head & Neckoropharynx CA

nasopharynx CArecurrent tumors

Eye & Orbituveal melanomaretinoblastoma

choroidal hemangioma

ChestNSC lung cancer

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• Cervical cancer is the second most common cancer among women worldwide

• Estimated 468 000 new cases and 233 000 deaths in t he year 2000

Survival rates vary between regions • 69% in the North American Surveillance

Epidemiology and End Results registry (SEER)• 49% in developing countries

•• exampleexample : : cervical cancer cervical cancer ••

RM, MedAustron

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Radiotherapy of locally extended disease:Conventional RT Proton Therapy• Mean 5-year survival Mean 10-year survival

65-70% (Stage IIB) 89% (Stage IIB)34-52% (Stage III B) 40% (Stage IIIB/IV)0-19% (Stage IV)

Gerbaulet A et al. GEC ESTRO handbook of brachytherapy 2002

•• cervical cancercervical cancer : : treatment results treatment results ••

1 Arimoto T, et al. Cancer 1991; 68:79.2 Kagei K, et al. Int J Radiat Oncol Biol Phys 2003; 55:1265.

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• major schools of thought •

1. “Unethical to do Trial” - Protons are

obviously better so no trial needed2. “Ethical to do Trial” - Protons not obviously

better so a trial is needed3. “Not ready to do Trial quite yet” -Protons are

better but need to “Tweak” before trial started

4. “Waste of time & money to do Trial” - …obviously not better, conceptual framework does not justify trial.a. They (don’t) have them and (don’t) believe itb. They are financially motivatedc. They are a. & b.

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• 5th school of thought •

5. “Ethical to do Trial” - Protons are in principle better but treatment methodology might not always be optimum. So a trial is neededa. They don’t have them but believe in them

b. They are financially motivated

c. They are a. & b.

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Correct methodologyClear guidelines

Controlled clinical trials

Reproducibility of results

Small series Technical heterogeneityClinical heterogeneity

• necessary initiatives •

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STUDIES

YEARSCLINICAL PHYSIC BIOLOGICAL TOTAL

2004-2007 100 41 21 162

2000-2003 46 29 18 93

1995-1999 27 33 8 68

IJ ROBP, Lancet, Radiother Oncol, JCO,Semin Oncol, Rad Prot Dosimetry, Phys Med Biol,

Head and Neck, Int J Clin Oncol, J Radiat Res,J Thorac Oncol, Lung Cancer

2008

• IBT publications •

RO, CNAO

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• hadron therapy vs. ion beam therapy •

Hadrons : subatomic particles built from quarks

mesons

baryons

Ions :charged atoms or molecules with a lack or excess of electrons

Nucleus : ion with maximum positive charge

therapy with protons or other ions = IBT

Documents

Medical experience •erice2009.na.infn.it/TalkContributions/LinzSummary.pdf · 2009. 4. 30. · U.Linz Summary Talk of the Workshop Linz-MediConsult Forschungszentrum Jülich10 1