# Presentation: 866141

## Phase III Clinical Trials with Protons: Their importance for Patient Centered Carefor:  NCI Workshop on Advanced Technologies in Radiation Oncology: Examining the EvidenceNov. 30 – Dec.2, 2006

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

** **

## 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.**

## The first dose-escalation trial

**with Conformal Radiation**

**Notes:**
	Before I discuss this paper I want to acknowledge to work of the MGH group.  For residents and those that finished training in the last 10 years, you may not be aware of this paper published in JAMA now 25 years ago where the idea of conformal therapy for prostate cancer was first elaborated upon.  The second paper is the final results of the first dose-escalation trial in prostate cancer again accomplished by the MGH group.  I want to congratulate them, in particular, Dr. Shipley for continuing to integrate proton therapy into clinical trials.

## 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**

## 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**

## 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**

## 	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**

**Notes:**
IMRT – the machine is on longer, more normal tissue is irradiated, integral dose may be higher.

## 	Proton beam therapy

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

## Intensity-modulated proton therapy

**Intensity-modulated proton therapy**

**Good news:****	**** ****	****Highly conformal**
**Bad news:****	****	****Not here yet**

## 	There has been a big change in the therapeutic landscape in the last decade for Proton Radiation:

**Other forms of conformal radiation now exist**

## Summary of Clinical Trial Design Issues with Protons in 2006

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

**Median follow-up 5.3 yrs**

- Brachy

- HD Protons

**Case Matched comparison: ****MGH  Brachytherapy vs high dose proton beam**

## Summary of Clinical Trial Design Issues with Protons in 2006

**2.****	****More Proton facilities now exist **

**Proton beam therapy – US treatment centers**

## 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) .    **

## Patient Centered CareThe 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**

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

## 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%.**

**Notes:**
RTOG, one of the major cooperative groups sponsored by public funds from the NCI
Data was extracted from all RCTs conducted by the RTOG

## 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.**

**Notes:**
Results above based on quantitative pooling of treatment effects
When look at trialists’ judgements...RTOG investigators did not  favor new treatments they were hoping would be better...in fact the contrary
This rules out interpretation bias in favor of experimental treatments

No QOL data

Did not have access to the researchers’ subtle thinking re cost or logistics of new treatments

Treatment successes in oncology should be evaluated according to the trials’ null hypothesis on a specified primary outcome.

Improvements can only come from empirical testing of new treatments in RCTs.

## 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**

## 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”**

## 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.**

## 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**

## 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).**

## 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.**

## 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.**

## 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.**

**Closing thoughts**