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Research Strategies in Proton Therapy:Research Strategies in Proton Therapy:Proving the Promise and Avoiding the Perils

Nancy Price Mendenhall M DNancy Price Mendenhall, M.D.University of Florida Proton Therapy Institute

Medical Director

Research Strategies in Proton Therapy:ObjectivesObjectives

P i•Promise•Perils Perils

– Clinical (3)Ethical– Ethical

– Health Care Cost

•Suggested Research Strategies

The Promise of The Promise of The Promise of The Promise of P t ThP t ThProton TherapyProton Therapy

d hd hRadiation Therapy BasicsRadiation Therapy Basics

Radiation damage is nonRadiation damage is non‐‐specificspecificRadiation damage is nonRadiation damage is non‐‐specific. specific. Response probability Response probability dosedose‐‐relatedrelatedand and volumevolume‐‐relatedrelated..Dose distribution key to outcomeDose distribution key to outcomeDose distribution key to outcome. Dose distribution key to outcome.

Improvements in Photon Dose Distribution

4 3D 1. ~1980Opp 6X

4. 3D Con-formal

1995~1995

2. ~1985Opp 15X

5. IMRT~2005

3 ~1990~105% to ~20%

d 100%

Courtesy: D Louis, 3. ~1990

Vertex Field

red = 100%

aqua = 20%D Yeung, Z Li, C Li

Improving Dose Distribution Improving Dose Distribution with photonswith photonswith photonswith photons

••Changes in photon energy Changes in photon energy ••Intersection and modulation of multiple photon Intersection and modulation of multiple photon beams overlapping over target *beams overlapping over target *beams overlapping over target beams overlapping over target

••These solutions* have resulted in significant and These solutions* have resulted in significant and favorable favorable redistributionredistribution of of integral doseintegral dose**.**.gg

••We may have reached the limit in our ability to We may have reached the limit in our ability to improve dose distribution with X rays and to improve dose distribution with X rays and to improve outcomes through theimprove outcomes through the redistribution ofredistribution ofimprove outcomes through the improve outcomes through the redistribution of redistribution of integral dose. integral dose.

*Gamma Knife, SRS, SRT, IMRT, Arc IMRT, Tomotherapy, Cyberknife.**Integral dose is dose to non-targeted tissues.

Proton Dose Proton Dose 4Proton Dose Proton Dose Distribution:Distribution:

h kTh B P k 3The Bragg PeakThe Bragg Peak 3

e D

ose

2

Rel

ativ

e

200 KV

60Cobalt

122 MV X-rays

22 MEV Electrons

0 10 20 30

Proton Bragg Peak

Spread Out Proton Depth in Tissue (cm)

Spread Out Proton Peak

Protons vs. Ext Beam PhotonsProtons vs. Ext Beam PhotonsProtons vs. Ext Beam PhotonsProtons vs. Ext Beam PhotonsNo matter how many beams are used and how much 2No matter how many beams are used and how much 2‐‐yydimensional static or dynamic field shaping occurs. . .dimensional static or dynamic field shaping occurs. . .

••Photons: Photons: most of radiation dose is wasted as integral f gdose deposited in non‐targeted tissues, i.e., an external photon beam is an inefficient1 and inaccurate2 means of radiation therapy with few prospects for further i timprovements.

••Protons: Protons: most of radiation dose is target dose, deposited in targeted tissues i e an external proton beamdeposited in targeted tissues, i.e., an external proton beam is a much more efficient and accurate means of radiation therapy with great potential for future improvement.

1 Inefficient in that most dose is wasted.2 Inaccurate in that most dose is placed outside the target.

Opp 6X 3D Conpp~1980

3D Con-formal~1995

Opp 15X~1985

IMRT~2005~105% to

~20%

Proton

red = 100%

aqua = 20%

3 Field

~2009

Courtesy: D Louis Vertex

~1990D Louis, D Yeung, Z Li, C Li

Research Strategies in Proton Therapy:The Promise The Promise

The promise of proton therapy is that a The promise of proton therapy is that a reduction in integral dose can be leveraged to:leveraged to:

1. Reduce toxicity2 Permit dose escalation/intensification to 2. Permit dose escalation/intensification to

improve cancer control3 Ultimately reduce overall health care costs*3. Ultimately reduce overall health care costs

Some Perils of Some Perils of Some Perils of Some Perils of Clinical Research Clinical Research Clinical Research Clinical Research P t Th P t Th Proton Therapy: Proton Therapy:

li i lli i lClinical IssuesClinical Issues

#1: #1: Failure to recognize Failure to recognize th i t f th i t f the importance of the importance of

integral doseintegral doseintegral doseintegral doseAKAAKA::The Concept of aThe Concept of aAKAAKA::The Concept of a The Concept of a “Safe Threshold Dose”“Safe Threshold Dose”

Paranasal SinusIMPTIMXT IMPTIMXT

Dose Difference

PSIPSI

Modeling Radiation Dosimetry to Modeling Radiation Dosimetry to Modeling Radiation Dosimetry to Modeling Radiation Dosimetry to Predict Cognitive Outcomes in Predict Cognitive Outcomes in

Pediatric Patients with CNS Pediatric Patients with CNS Pediatric Patients with CNS Pediatric Patients with CNS Embryonal Tumors Including Embryonal Tumors Including

d ll bld ll blMedulloblastomaMedulloblastomaMerchant et al, IJROBP Merchant et al, IJROBP -- 20062006

R lt R lt •• Results Results –– Exposure to supratentorial brain had significant Exposure to supratentorial brain had significant

impact on longimpact on long--term IQ and cognitive functionterm IQ and cognitive function–– Each Gy of exposure had a similar effectEach Gy of exposure had a similar effect

••NO DOSE THRESHOLDNO DOSE THRESHOLD

Additional studies by same group indicating exquisite relationship between radiation dose and neuroendocrine function

Juvenile Angiofibroma:Juvenile Angiofibroma: IMRT vs. ProtonsIMRT vs. Protons

V20 =50% V20 =4% V10 = 71% V10 = 9%

Courtesy: Robert Malyapa, Daniel Yeung, Zuofeng Li

Are low integral Are low integral Are low integral Are low integral doses relevant in doses relevant in doses relevant in doses relevant in

adults?adults?adults?adults?

“S f Th h ld D ”“S f Th h ld D ”“Safe Threshold Dose”“Safe Threshold Dose”

Dose Escalation in Prostate Dose Escalation in Prostate Cancer with X rays at MDACCCancer with X rays at MDACC

T1bT1b‐‐T3 Prostate CaT3 Prostate Ca19931993‐‐9898

Med F/U 8 7 yMed F/U 8 7 yMed F/U 8.7 yMed F/U 8.7 y

70 Gy70 Gy 78 Gy78 Gy

8y FFF8y FFF59%59%

8y FFF8y FFF78%78%P = 0 004P = 0 004 59%59% 78%78%P = 0.004P = 0.004

*Kuban et al, IJROBP,70:67*Kuban et al, IJROBP,70:67‐‐74, 2008.74, 2008.

Dose Escalation in Prostate Cancer: Dose Escalation in Prostate Cancer: What about toxicity? MDACCWhat about toxicity? MDACC

T1bT1b‐‐T3 Prostate CaT3 Prostate Ca19931993‐‐9898

Med F/U 8 7 yMed F/U 8 7 yMed F/U 8.7 yMed F/U 8.7 y

70 Gy70 Gy 78 Gy78 Gy

≥ GR2 GI ≥ GR2 GI 13%13%

≥ GR2 GI≥ GR2 GIP = 0.013P = 0.013 13%13% 26%26%P 0.013P 0.013

*Kuban et al, IJROBP,70:67*Kuban et al, IJROBP,70:67‐‐74, 2008.74, 2008.

Dose Escalation in Prostate Dose Escalation in Prostate Cancer MDACCCancer MDACC

• Kuban et al have reported that the volume • Kuban et al have reported that the volume of rectum receiving lower doses (35 Gy to 60 Gy) is even more significantly 60 Gy) is even more significantly predictive of future rectal injury than volumes receiving doses of 70 Gy+volumes receiving doses of 70 Gy+.

Kuban et al, IJROBP,70: 67Kuban et al, IJROBP,70: 67‐‐74, 2008.74, 2008.

Vargas et al in a Vargas et al, in a comparison of IMRT and proton plans for prostate cancer patients treated at UFPTI, have demonstrated significant reductions in the volumes of non-targeted tissues of non targeted tissues receiving a full range of doses (10-80 Gy/CGE) with protons.

Vargas et al, IJROBP Vargas et al, IJROBP 70: 74470: 744--751, 2008751, 2008,,

Concept of “Safe Threshold Concept of “Safe Threshold Concept of “Safe Threshold Concept of “Safe Threshold Dose”Dose”

• Necessary compromises with X ray dosimetry:N y p y y– Decreased cure rates to avoid early and/or overt toxicity.– Assumptions that low integral doses below the threshold for early and/or

overt toxicity were safe. • I d i hi d hi ti t d t l f t th • Increased survivorship and sophisticated tools refute the

concept of “safe dose.”• Historical Examples:

C di di i b t i ff t i l b fit f XRT – Cardiac disease in breast cancer survivors offset survival benefit of XRT. – Infertility, cardiac and thyroid disease in CSI survivors

• No published literature does not excuse us, as clinicians, from our responsibility to our patientsfrom our responsibility to our patients

Clinical Research Strategies in Clinical Research Strategies in Proton TherapyProton Therapy

•Studies must be d i d h d designed that do not knowingly subject patients to j punnecessary integral dose radiation radiation.

#2: #2: #2: #2: Failure to control for

confounding variableslaffecting trial execution

and subject selection

Trial Execution: The Trial Execution: The importance of target definition importance of target definition

and treatment deliveryand treatment deliveryand treatment deliveryand treatment delivery• Because the vast majority of dose deposited goes

into the targeted area proton therapy may be into the targeted area, proton therapy may be more sensitive to errors in target definition and treatment delivery. y

• Imaging must be high quality and patterns of subclinical disease spread must be understood, to create an accurate CTV expansion to create an accurate CTV expansion.

• Otherwise a trial may yield the answer to a targeting or delivery question rather than a targeting or delivery question rather than a comparative effectiveness question.

Historical studies in prostate cancer are difficult to compare:

•Diff i •Different patients receiving surgery, brachytherapy, external y py,beam irradiation

•Different pretreatment conditions

•Clinical staging

•Different thresholds Different thresholds for toxicity intervention

T1C Low Risk Prostate CancerT1C Low Risk Prostate Cancer

A BA B

30 cc asymptomatic 110 cc symptomatic

•Both candidates for protons and IMRT, only A for brachy or surgery

30 cc, asymptomatic 110 cc, symptomatic

•Dissimilar pretherapy conditions impacting toxicities•Dependency on clinical exam for prognostic stratification

Future Comparative Effectiveness Research Should

•Compare apples with apples•Use more objective Use more objective stratification criteria than clinical exam•D l ith •Deal with confounding variables of pretreatment condition, medications, varying thresholds for interventionintervention

#3 #3 #3: #3: Failure to ask questions for which sufficiently for which sufficiently

sensitive tools and time are available to measure h dthe important end points

Failure to ask questions for which time and sufficiently sensitive tools are available to sufficiently sensitive tools are available to measure the important end points

• Example: Postmastectomy Radiation Therapy (PMRT) Trials(PMRT) Trials

• Despite the correctness of the now-survival benefit of PMRT, multiple trials involving many p g ythousands of breast cancer patients failed to detect a survival improvement, in part because imaging technology was inadequate for 1) evaluation of the technology was inadequate for 1) evaluation of the adequacy of treatment delivery and 2) for the detection of the endpoint of concern: local and regional breast cancer recurrence.

Dose Escalation in Prostate Cancer Dose Escalation in Prostate Cancer using protons: PROG 95using protons: PROG 95--09*09*

T1b/T2b Prostate Ca, PSA < 15T1b/T2b Prostate Ca, PSA < 1550.4 Gy with X rays 50.4 Gy with X rays

Accrual: Accrual: 19961996‐‐1999 1999 Median F/U Median F/U

Proton boostProton boost Proton boostProton boost

6.7Y6.7Y

70.2 GyE70.2 GyE 79.2 GyE79.2 GyE

5y FFF5y FFF79%**79%**

5y FFF5y FFF91%**91%**

P = 0.001P = 0.001

*Zeitman et al, JAMA, September, 2005 and February, 2008*Zeitman et al, JAMA, September, 2005 and February, 2008**Originally reported as 63% vs. 81%.**Originally reported as 63% vs. 81%.

PROG 95PROG 95--09 Dose escalation using 09 Dose escalation using proton therapy in Prostate Cancerproton therapy in Prostate Cancer

T1b/T2b Prostate CaT1b/T2b Prostate CaPSA < 15PSA < 15

PROG 95PROG 95 0909PROG 95PROG 95‐‐0909

70.2 GyE70.2 GyE 79.2 GyE79.2 GyE

5y FFF5y FFFLR: 83%LR: 83%

5 y FFF5 y FFFLR: 97% LR: 97%

P = .001P = .001P = 02P = 02IR: 75%IR: 75% IR: 87% IR: 87%

*Zeitman Correction, JAMA, February, 2008.*Zeitman Correction, JAMA, February, 2008.

P = .02P = .02

Dose Escalation in Prostate Dose Escalation in Prostate Cancer PROG 95Cancer PROG 95--09*09*

T1b/T2b Prostate CaT1b/T2b Prostate CaPSA < 15, 1996PSA < 15, 1996‐‐1999 1999 Median F/U 6 7YMedian F/U 6 7YMedian F/U 6.7YMedian F/U 6.7Y

70.2 GyE70.2 GyE 79.2 GyE79.2 GyE

GR2(3) GI ToxicityGR2(3) GI Toxicity8(1)%**8(1)%**

GR2(3) GI ToxicityGR2(3) GI Toxicity17(1)%**17(1)%**

P = 0.005P = 0.005(ND)(ND)

*Zeitman et al, JAMA, September, 2005 and February, 2008*Zeitman et al, JAMA, September, 2005 and February, 2008

Dose Escalation and Quality of Life Dose Escalation and Quality of Life in Prostate Cancer PROG 95in Prostate Cancer PROG 95--09*09*

T1b/T2b Prostate CaT1b/T2b Prostate CaPSA < 15, 1996PSA < 15, 1996‐‐1999 1999 Median F/U 6 7YMedian F/U 6 7YMedian F/U 6.7YMedian F/U 6.7Y

70.2 GyE70.2 GyE 79.2 GyE79.2 GyE

Q of L GI Late Tox. Q of L GI Late Tox. 7.5%**7.5%**

Q of L GI Late ToxicityQ of L GI Late Toxicity7.7%**7.7%**NDND

Talcott, ASCO, 2008. “These results suggest that use of proton radiation boosts Talcott, ASCO, 2008. “These results suggest that use of proton radiation boosts may partially mitigate treatmentmay partially mitigate treatment‐‐related toxicity from increased dose.” related toxicity from increased dose.”

Trials Based on Quality of LifeTrials Based on Quality of LifeQ yQ y

• At this point in time, it is unclear that quality of At this point in time, it is unclear that quality of life tools are sufficiently sensitive to detect important differences among treatments despite very different documented toxicity outcomes.

• Trials designed primarily as quality of life studies may not be a wise use of resources at this stage in development of quality of life assessment tools particularly if the actual assessment tools, particularly if the actual treatment itself is a limited resource.

Comparative Effectiveness Comparative Effectiveness Trials: BNK 06-01

Courtesy of Dr. Chip Nichols

Bad Newz Kennels Cooperative Group Trial BNK 2006-01Group Trial BNK 2006 01

Purpose:Purpose:• Determine if pit bulls are better fighting

dogs than standard poodlesdogs than standard poodles.

Methods and Materials

• “Raoul ” a 2 year old standard poodle Raoul, a 2 year old standard poodle faced “Jaws,” a 2 month old pit bull, in a BNK sanctioned match BNK sanctioned match.

Results

• The dogs wagged their tails and sniffed The dogs wagged their tails and sniffed each other for 15 minutes.

• The match was declared a draw• The match was declared a draw.

Conclusion

• Standard Poodles and Pit Bulls are Standard Poodles and Pit Bulls are equivalent fighting dogs.

BNK 08-01 Trial

• In 2008 the BNK Cooperative Group in In 2008, the BNK Cooperative Group, in an effort to validate the results of the BNK 06-01 trial conducted the BNK 08-01 Trial06 01 trial, conducted the BNK 08 01 Trial.

• Methods and Materials: “Raoul” and “Jaws” again faced each other in a BNK Jaws again faced each other in a BNK sanctioned match.

RESULTS

R l JawsRaoul JawsCourtesy of Dr. Chip Nichols

Conclusion

• The study design for BNK 06-01 was The study design for BNK 06 01 was flawed.

• Early assessments underestimated the • Early assessments underestimated the mature performance of one arm of the comparative effectiveness trialcomparative effectiveness trial.

Disclaimer-Conflict of Interest

H Have a family investment in canines.

The Perils of The Perils of The Perils of The Perils of Clinical Research in Clinical Research in Clinical Research in Clinical Research in

P t Th P t Th Proton Therapy: Proton Therapy: hi lhi lEthical IssuesEthical Issues

#4: #4: #4: #4: Failure to ensure Failure to ensure

respect and beneficence pto the patient and research subject.

Hippocratic Oath*pp

*Three of the 6 basic tenets of the Hippocratic Oath define the

1 To practice and prescribe to the best of my ability for the 1 To practice and prescribe to the best of my ability for the

relationship between the physician and patient and inform the nature of “ethical” clinical research.

1. To practice and prescribe to the best of my ability for the 1. To practice and prescribe to the best of my ability for the good of my patients, and to try to avoid harming them. good of my patients, and to try to avoid harming them.

2. Never to do deliberate harm to anyone for anyone else's 2. Never to do deliberate harm to anyone for anyone else's 2. Never to do deliberate harm to anyone for anyone else s 2. Never to do deliberate harm to anyone for anyone else s interest. interest.

3. To keep the good of the patient as the 3. To keep the good of the patient as the highest priorityhighest priority. . p g pp g p g p yg p yThere may be other conflicting 'good purposes,' such as There may be other conflicting 'good purposes,' such as community welfare, conserving economic resources, supporting community welfare, conserving economic resources, supporting the criminal justice system, or simply making money for the the criminal justice system, or simply making money for the physician or his employer that provide recurring challenges to physician or his employer that provide recurring challenges to physicians.physicians.

The Belmont ReportThe Belmont Report

B l R A l 18 1979• Belmont Report, April 18, 1979• Principles and guidelines for the protection of

h bj t f hhuman subjects of research.• Three underlying principles

R– Respect– Beneficence

Justice– Justice

The Belmont ReportThe Belmont Report

• An autonomous person is an individual capable of deliberation about personal goals and of acting deliberation about personal goals and of acting under the direction of such deliberation. Non-autonomous persons require protection.

• To show lack of respect for an autonomous agent is – to repudiate that person’s considered judgments – to deny that person the freedom to act on those considered

j dy

judgments– or to withhold information necessary to make a considered

judgment, when there are no compelling reasons to do so.

Pertinence of Hippocratic Oath and ppBelmont Report in Consideration of Proton Therapy Trialspy

•• Assuming that confounding variables mentioned Assuming that confounding variables mentioned above are accounted for, the only difference between above are accounted for, the only difference between proton therapy and another form of external beam proton therapy and another form of external beam proton therapy and another form of external beam proton therapy and another form of external beam radiation therapy would be the difference in integral radiation therapy would be the difference in integral dose. dose.

•• Th t f th t i l th ld b t k th Th t f th t i l th ld b t k th •• The nature of the trial, then, would be to ask the The nature of the trial, then, would be to ask the question of whether integral dose to nonquestion of whether integral dose to non--targeted targeted tissue has a harmful effect. tissue has a harmful effect.

•• The patient has no potential benefit from such a trial. The patient has no potential benefit from such a trial. •• Therefore the guiding principles of both the Belmont Therefore the guiding principles of both the Belmont

Report and the Hippocratic Oath are violated. Report and the Hippocratic Oath are violated. p ppp pp

The Hippocratic Oath and Belmont Reportpp p

•• If the informed consent does not explain the If the informed consent does not explain the nature of the trial questionnature of the trial questionnature of the trial question,nature of the trial question,–– then critical information necessary for autonomous then critical information necessary for autonomous

decision has been withheld from the patient, further decision has been withheld from the patient, further violating the Belmont principle of respect. violating the Belmont principle of respect.

•• It is highly unlikely It is highly unlikely that an informed patient would choose to participate that an informed patient would choose to participate –– that an informed patient would choose to participate that an informed patient would choose to participate in a trial asking the question of whether integral dose in a trial asking the question of whether integral dose might be harmful. might be harmful.

l k ll k l•• It is unlikely It is unlikely –– that a treating radiation oncologist, who has taken the that a treating radiation oncologist, who has taken the

Hippocratic Oath and read the Belmont Report, would Hippocratic Oath and read the Belmont Report, would Hippocratic Oath and read the Belmont Report, would Hippocratic Oath and read the Belmont Report, would consider recommending such a trial.consider recommending such a trial.

Rights of Patients and the IRBRights of Patients and the IRB

•• The Belmont Report requires respect of the The Belmont Report requires respect of the patient’s considered judgment. patient’s considered judgment. p j gp j g

•• Proton therapy is not experimentalProton therapy is not experimental——efficacy efficacy clearly documented.clearly documented.

ff•• IRB unlikely to permit protocols that function IRB unlikely to permit protocols that function as gatekeepers to deny patients access to a as gatekeepers to deny patients access to a particular efficacious treatment by requiringparticular efficacious treatment by requiringparticular efficacious treatment by requiring particular efficacious treatment by requiring participation in a protocol.participation in a protocol.

Summary Ethical Concerns

RCT simply comparing proton therapy with other RCT simply comparing proton therapy with other RCT simply comparing proton therapy with other RCT simply comparing proton therapy with other forms of external beam radiation therapy will forms of external beam radiation therapy will present significant ethical problems for most present significant ethical problems for most physicians familiar with proton therapy and likely physicians familiar with proton therapy and likely physicians familiar with proton therapy and likely physicians familiar with proton therapy and likely be rejected by the informed patient. be rejected by the informed patient.

The argument might not be that we already have The argument might not be that we already have evidence of better outcomes with proton therapy, evidence of better outcomes with proton therapy, but that we do not believe that unnecessary but that we do not believe that unnecessary but t at e do ot be e e t at u ecessa y but t at e do ot be e e t at u ecessa y exposure of a patient to excess integral dose is in exposure of a patient to excess integral dose is in that patient’s best interest. that patient’s best interest.

#5#5#5#5Th C ti * Th C ti * The Competing* The Competing*

G d f C ti G d f C ti Good of Comparative Good of Comparative C t f T t tC t f T t tCosts of TreatmentCosts of Treatment

*But lower priority

The Slide Rule

February 1, 1972: $12.50February 1, 1972: $12.50

The Slide Rule


May 5 2009: $33 00May 5 2009: $33 00May 5, 2009: $33.00May 5, 2009: $33.00

The Hewlett-Packard HP-35


The Slide Rule andThe HP-35

AccuracyAccuracy

EfficiencyEfficiencyEfficiencyEfficiency

Increased potential for goodIncreased potential for good

The Hewlett-Packard HP-35

February 1, February 1, 19721972

Walmart Price Walmart Price May 4, May 4, 1972: 1972: $399.00$399.00

May 4, 2009: May 4, 2009: $7.99$7.99

2009: 2009: $79.99$79.99

Comparative Cost Assessment

I lid ifI lid ifInvalid if:Invalid if:it does not account for costs of recurrence, costs of acute and late it does not account for costs of recurrence, costs of acute and late morbidity, costs of lost social effectiveness… and equipment morbidity, costs of lost social effectiveness… and equipment morbidity, costs of lost social effectiveness… and equipment morbidity, costs of lost social effectiveness… and equipment replacement replacement

Will change with:Will change with:ggincreasing operational efficiency, volume, technical increasing operational efficiency, volume, technical development, competition development, competition

Highly likely that:Highly likely that:Highly likely that:Highly likely that:the treatment producing the highest therapeutic ratio will be the the treatment producing the highest therapeutic ratio will be the most cost effective, and, because of this, competition to provide it most cost effective, and, because of this, competition to provide it will drive down costs making it increasingly more effective with will drive down costs making it increasingly more effective with will drive down costs, making it increasingly more effective with will drive down costs, making it increasingly more effective with time. time.

Suggested Clinical Suggested Clinical ggggResearch Strategies Research Strategies ggin Proton Therapy*in Proton Therapy*in Proton Therapyin Proton Therapy

*I ti l th l t t li i l h*In particular as they relate to clinical research.

Suggested research strategies for proton therapy

• Randomized Controlled Trials f

for proton therapy

• Randomized Controlled Trials of proton therapy versus another external beam radiation therapy modality present basic radiation therapy modality present basic ethical issues (as well as practical issues related to the maturity of the technology available, at y gy ,this point in time, for control of potential confounding variables).g )


• Dosimetry studies to establish probable

for proton therapy

• Dosimetry studies to establish probable improved outcomes.

D i t t di h b d i ll – Dosimetry studies have been done in all areas of UFPTI investigation thus far.

Suggested research strategies for proton therapyfor proton therapy

• Prospective Outcome Tracking Trials: for all patients treated with proton therapy, which is p p pycurrently a limited resource.– 99% of all patients treated at UFPTI thus far have

gone on our IRB-approved outcome tracking gone on our IRB-approved outcome tracking protocol.

– This kind of trial can identify unanticipated t th t i f th t d f th outcomes that require further study, further

technical development, new opportunities.


• Specific Proton Therapy Trials as techniques

for proton therapySpecific Proton Therapy Trials as techniques are developed, to ask specific questions and establish specific benchmarks for proton h h ld b f dtherapy outcomes should be performed.– At UFPTI, 3 trials have been completed in low,

intermediate, and high risk prostate cancer and 14 , g ptrials are currently ongoing in head and neck cancer, brain tumors, pancreas, lung, Hodgkin’s, sarcoma, and prostate cancer, additional studies in and prostate cancer, additional studies in development in specific pediatric tumors.


• Virtual Controlled Trials: based on actual IRB

for proton therapyVirtual Controlled Trials: based on actual IRB proton therapy trials with a virtual internal control arm created by application of

i di i h h l competing radiation therapy technology treatment planning to actual proton target with estimation of virtual outcomes based on peer-estimation of virtual outcomes based on peerreviewed disease control and toxicity models.

• UFPTI proposal made in response to ARRA CER RFP.

Thank YouThank YouTo AAPM and ASTROTo AAPM and ASTRO

To The Particle Therapy CommunityTo The Particle Therapy Community

To m UF and UFPTI colleagues and To m UF and UFPTI colleagues and To my UF and UFPTI colleagues and To my UF and UFPTI colleagues and staff staff

And to all those who have made it And to all those who have made it possible for us to investigate the possible for us to investigate the possible for us to investigate the possible for us to investigate the promise of proton therapy. promise of proton therapy.

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