# Presentation: 816513

## Re-evaluation of Radiographic Outcomes: The Casodex Early Prostate Cancer Trial Program Experience.

- Kevin Carroll, MSc, FRSS,
- Global Statistical Leader, Oncology, AstraZeneca Pharmaceuticals

## Contents

- The Casodex Early Prostate Cancer (EPC) Program.
- Radiographic re-evaluation protocol.
- Results.
- Recommendations.

## Contents

- The Casodex Early Prostate Cancer (EPC) Program.
- Radiographic re-evaluation protocol.
- Results.
- Summary and Recommendations.

## Casodex EPC Program: A clear objective

- Determine benefit of Casodex 150 mg therapy as an addition to standard care for patients with early-stage disease.
- Surgery or radiation of curative intent.
- Watchful waiting when curative intent is not considered possible or appropriate.

## Casodex EPC Program: Design

- Three randomized, double-blind, placebo-controlled trials conducted across 23 countries in 8113 patients.
- Powered to detect at least a 15% improvement in progression-free survival (PFS).
- Progression confirmed by bone scan, biopsy or other imaging technique.
- Mechanisms and procedures for radiographic imaging were as per local practice
- Stratified combined analysis at 3 yrs median follow-up prospectively captured in protocols.
- Program is ongoing.

## Significant improvement in PFS time at 3-yr median follow-up

- HR=0.63 (0.55, 0.72), p<0.0001
- Casodex events = 363 (9.0%)
- placebo events = 559 (13.8%)

- Progression-free survival  (yrs)

- Proportion progression free

- Significant improvement in PFS time at 3-yr median follow-up

## Pharmacological effects of hormonal therapies: Possibility of unblinding and investigator bias?

- Recognition at the outset that that pharmacological effects of drug may compromise blinding.
- _Acquisition bias_: Addressed in trial design by 2 yrly bone scans in all non-progressing patients irrespective of clinical indication.
- _Assignment bias_: FDA requested an independent re-evaluation of locally determined progression outcomes to rule out possibility of assignment bias in the comparison of Casodex and placebo.

## Variability

- Variability

- Falsely concluding an ineffective treatment  effective = wrongly approving a drug

- 

- 

- 

- Sensitivity:

- Providing trials are randomised and adequately powered, inter-site differences in imagining methods and technology do not introduce bias.

- Inter-site differences in imaging technology: Another potential source of bias?

## Contents

- The Casodex Early Prostate Cancer (EPC) Program.
- Radiographic re-evaluation protocol.
- Results.
- Summary and Recommendations.

## Re-evaluation of progression outcomes in over 1450 patients

- All 339 patients with a PFS event determined by positive bone scan or x-ray
- Sample of 1120 patients without a PFS event
- 2 year bone scan or x-ray retrieved for re-evaluation.
- N=1120 to estimate the negative-positive reclassification rate to within 2.5% with 90% confidence.
- Baseline scans to be retrieved for all above patients.

## Comprehensive re-evaluation protocol agreed in advance

- Three, independent expert radiologists.
- Training exercise to confirm inter and intra reviewer consistency.
- Reviewers blind to randomised treatment, patient origin and all clinical data.
- Bone scan positive patients separately re-evaluated by all 3 reviewers.
- Bone scan negative patients re-evaluated by 2 reviewers, chosen at random.
- Third reviewer provided a blind tie-break read as necessary.
- Majority re-read taken as outcome..

**Notes:**
In terms of the re-evaluation protocol there were three, independent expert radiologists.

Bone scan positive patients separately re-evaluated by all 3 reviewers and  bone scan negative patients were re-evaluated by 2 reviewers, chosen at random with the third reviewer acting as tie breaker as necessary.

The reviewers were blind to randomised treatment, patient origin and all clinical data and, finally, there was an initial training exercise to confirm inter and intra reviewer consistency.   

K, bullets seem out of order in that last two bullets should come before others (minor comment)
Also, 3rd bullet could delete first occurrence of “Patients” I.e., “Bone scan negative patients. . . “

## Contents

- The Casodex Early Prostate Cancer (EPC) Program.
- Radiographic re-evaluation protocol.
- Results.
- Summary and Recommendations.

## No evidence of investigator assignment bias in the Casodex EPC program

- *conditional on a determination being made

## No evidence of bias in the comparison of randomised treatments

- No difference in bone scan reclassification rates between treatment groups
- Approx 6 % negative to positive reclassification
- Approx 20% positive to negative reclassification
- Analyses based on re-evaluation outcomes continued to show a significant treatment effect.
- Investigator assessment:	RR = 0.63, p<0.0001
- Re-evaluation:			RR = 0.75, p<0.0001

## Contents

- The Casodex Early Prostate Cancer (EPC) Program.
- Radiographic re-evaluation protocol.
- Results.
- Summary and Recommendations.

## Summary of the Casodex EPC program experience 

- Large scale re-evaluation of radiographic outcomes in the Casodex EPC program did not change the result.
- The Casodex experience indicates that in randomised, blinded trials the investigator evaluation of the patient is a reliable basis on which to compare treatments.
- The re-evaluation exercise took 1.5 yrs to complete at a cost of $5m.

## Recommendations for future trials 

- In randomised, blinded trials, independent evaluation of clinical outcomes is unnecessary.

-   In practice radiologists are at least as blind to randomised treatments as investigators.
-   Independent evaluation places an unnecessary burden on sponsors, investigators and reviewers alike.

- If a review is undertaken, the key issue is a review blind to randomised treatment, not merely a review of images alone.

- Reviewers should receive images and all relevant clinical data to reflect in so far as possible clinical reality.