Phase III Clinical Trials with Protons: Their importance for Patient Centered Care for: NCI Workshop

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Phase III Clinical Trials with Protons Their
importance for Patient Centered Carefor NCI
Workshop on Advanced Technologies in Radiation
Oncology Examining the EvidenceNov. 30 Dec.2,
2006

• William U. Shipley, MD, FASTRO
• Massachusetts General Hospital
• Harvard Medical School
• Boston, MA.

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The Goals of Prospective Clinical Trials

• To evaluate innovative treatments for possible
  benefits or harms in cancer management of
  patients with specific types and presentations of
  tumors.
• Phase I (or I/II) Evaluation of the safety and
  feasibility of an innovative treatment.
• Phase II A single arm trial to evaluate,
  roughly, cancer control efficacy. This can
  yield a hypothesis generating result, but not a
  definitive result.
• Phase III or a RCT (Randomized Clinical Trial)
  To evaluate if the innovative treatment is better
  (or worse) than standard treatment in cancer
  control or in morbidity reduction.

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The first dose-escalation trial with Conformal
Radiation
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Summary of RCTs Comparing Dose Using Protons

• Trial Site Accrual Endpoint Results
• MGH 820 T3-4 Prostate 202 DSS No benefit with HD
• PROG 85-26 Skull base 432 Local Pending
• control
• MEEI Uveal 188 Visual acuity No benefit with LD
• melanoma retention
• PROG 92-13 Meningioma 49 Tumor control No
  benefit with HD
• PROG 95-09 T1-2 Prostate 393 PSA and LC Signif.
  benefit of dose, not protons

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Randomized Dose Trial PROG 95-09
1996 1999 ACR HQ

• 2 center study
• MGH
• LLUMC
• 393 patients

T 1c-2b PSA lt 15ng/ml
randomize
70.2 Gy
79.2 Gy
5 year bNED results 70.2 Gy--- 66 79.2 Gy---
86 p lt 0.001
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Late GI Complications
Trial 1 2 3 4 5 PROG 79.2 Gy 22 9 1 0 0 MDAH
78 Gy 28 19 7 0 0 RTOG 79.2 Gy 20 6 1 0 0 MSK
81 Gy ND 4 1 0 0
78-81 Gy is safely delivered with 3D photons,
IMRT or Protons
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Intensity Modulated Radiation Therapy Good
news high dose volume is highly conformal Bad
news Hot spots within the target volume
The low dose bath is large
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Proton beam therapy Good news high dose
volume is highly conformal Bad news Beam not
sharp at prostate depth Very sensitive to
bone density
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Intensity-modulated proton therapy
Good news Highly conformal Bad news Not here
yet
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• There has been a big change in the therapeutic
  landscape in the last decade for Proton Radiation

Other forms of conformal radiation now exist
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Summary of Clinical Trial Design Issues with
Protons in 2006

• Good comparator RT exists -- highly-conformal
  photon treatments IMRT and BT

Brachy
HD Protons
Median follow-up 5.3 yrs
Case Matched comparison MGH Brachytherapy vs
high dose proton beam
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Summary of Clinical Trial Design Issues with
Protons in 2006

• 2. More Proton facilities now exist

Proton beam therapy US treatment centers
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Summary of Clinical Trial Design Issues with
Protons in 2006

• 3.New QOL instruments are now available to
  measure, with greater sensitivity, morbidity
  reduction using Patient Reported Outcomes (PROs)
  .

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Patient Centered CareThe Need for RCT with
Protons

• Is Equipoise possible for trials in Radiation
  Oncology using Protons?
• Equipoise holds that a patient should be
  enrolled in a RCT only if there is substantial
  uncertainty about which of the treatments would
  benefit the patient most
• 1. The RTOG experience with RCTs
• 2. The Pediatric COG experience with RCTs
• 3. The Proton experience with RCTs

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The evaluation of new treatments with Radiation
by Phase III trials Are they better than
standard treatments?Past RTOG experience
reviewedSoares et al. JAMA 331, 2005
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Objective

• Evaluate treatment successes in oncology
• Focus on RTOG 57 RCTs, 12,734 patients.
• Determine the success rate of innovative
  treatments by assessing
• Investigators conclusions and preferences
• Proportion of RCTs that achieved statistical
  significance of the primary outcome --- 10.

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Results

• Researchers favored standard treatment in 71 of
  comparisons
• Many inconclusive trials 88.
• New treatments--higher morbidity.
• New treatments are more costly.
• The standards for the adoption of new practices
  are high.

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RCTs in Pediatric Oncology-- COG

• Results In 53 of the RCTs the investigators
  conclusions favored the standard treatment arm.
• In 47 of the RCTs the investigators
  conclusions favored the innovative treatment arm.
• A. Kumar et al. BMJ 331 1295-1301, 2005

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Summary of RCT Outcomes

• 1. In RTOG In 71 of the RCTs the standard
  treatment was favored
• 2. In COG In 53 of the RCTs the standard
  treatment was favored
• 3. With Protons in only 1 of 4 trials was the
  innovative arm favored
• The value of new experimental treatments can
• not be confidently predicted in advance

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Clinical Trial Design Issues

• How often has the perception by academic
  clinicians that an experimental cancer treatment
  is superior to standard treatment been proven
  correct?
• So infrequently as to make us all humble.

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Summary of Clinical Trial Design Issues with
Protons in 2006

• 1. Where Proton radiation no longer has the
  unique ability to give higher doses to the CTV,
  its potential clinical advantages of morbidity
  reduction require testing by RCT using PROs
  instruments.
• a. Conventional fractionation
• b. Hypofractionation

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Summary of Clinical Trial Design Issues with
Protons in 2006

• 2. Only in children is the condition of equipoise
  for testing Protons Vs. IMRT justifiably
  questioned.
• In children the physiologic rationale for
  Protons is uniquely great because of the known
  unique morbidity in children from the transient
  photon radiation bath. (A decrease in body growth
  and in brain development plus the especially high
  rate in children of radiation-induced tumors).

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Summary of Clinical Trial Design Issues with
Protons in 2006

• 3. Evaluation of the benefits of Protons compared
  to elegant forms of conformal photon radiation by
  RCT is now an opportunity and a responsibility.

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Summary of Clinical Trial Design Issues with
Protons in 2006

• RTOG has opened a Proton Investigator Group with
  Tom DeLaney as chair that will begin by opening
  some Prostate studies RTOG 0626 and RTOG 0415.
• Through the ATC headed by Jim Purdy there is now
  electronic data transfer for both photons and
  protons allowing dose distribution comparisons
  and DVH analyses.

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Closing thoughts

• High technology is great but it is seductive and
  it is expensive.
• If all forms of high dose radiation are equally
  efficacious, then they need QoL testing
  (morbidity reduction by PRO) and economic
  analyses to determine their true justification
  and appropriate use.