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

1. 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.

2. 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.

3. The first dose-escalation trial with Conformal Radiation

4. Summary of RCTs Comparing Dose Using Protons TrialSiteAccrualEndpointResults 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

5. Randomized Dose Trial: PROG 95-09 1996 – 1999 ACR HQ • 2 center study • MGH • LLUMC • 393 patients T 1c-2b PSA < 15ng/ml randomize 70.2 Gy 79.2 Gy 5 year bNED results: 70.2 Gy--- 66% 79.2 Gy--- 86% p < 0.001

6. 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

7. 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

8. Proton beam therapy Good news: high dose volume is highly conformal Bad news: Beam not sharp at prostate depth & Very sensitive to bone density

9. Intensity-modulated proton therapy Good news: Highly conformal Bad news: Not here yet

10. There has been a big change in the therapeutic landscape in the last decade for Proton Radiation: Other forms of conformal radiation now exist

11. 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

12. Summary of Clinical Trial Design Issues with Protons in 2006 2. More Proton facilities now exist Proton beam therapy – US treatment centers

13. 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) .

14. 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

15. 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

16. 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%.

17. 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.

18. 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

19. 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”

20. 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.

21. 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 reductionrequire testing by RCT using PROs instruments. a. Conventional fractionation b. Hypofractionation

22. 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).

23. 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.

24. 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.

25. 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.