This is an excerpt from our free eBook, “Prostate Cancer and Imaging in Clinical Trials.”
In clinical trials, it can be challenging to evaluate tumor response in the context of metastatic prostate cancer. Bone lesions, for example, can be difficult to assess. Recommendations have been published and are regularly revised by the Prostate Cancer Clinical Trials Working Groups, an international expert committee of prostate cancer clinical investigators. The latest consensus is from the Prostate Cancer Working Group 3 (PCWG3) published in 2015. It provides recommendations for best practices at each stage of clinical trial development and defines:
- Clinical states models
- Principles of trial conduct
- Eligibility criteria for enrollment
- Pharmacokinetics markers
- Baseline disease assessments
- Methods for outcomes measurements and reporting
- Methods to distinguish when treatment beyond progression would benefit the patient vs when it was more beneficial to stop therapy
The key recommendation is to report changes for each disease manifestation separately to prevent the premature discontinuation of treatment when, for example, PSA shows a slow increase but there are no clinical changes. PCWG3 therefore suggests that efficacy should be assessed by the interpretation of outcome measures: blood-based markers, patient reported outcomes, and imaging response.
For imaging, PCWG3 confirms that CT/MRI and bone scans should be the imaging modalities of choice in prostate cancer trials. However, updated guidelines considering the recent advances in PET imaging are expected in the near future.
Imaging outcomes include two components: soft tissue assessed with CT/MRI and bone disease assessed with bone scans.
For soft tissue, response to treatment is based on changes in tumor size according to Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Readers select at baseline lesions to represent tumor burden: target lesions and non-target lesions. The selected lesions are then evaluated at each time point to assess change in tumor burden over time.
- Five target lesions are measured, and the sum of their longest diameters (SOD) is calculated at every time point.
- Non-target lesions are evaluated qualitatively.
When it comes to bone metastases, readers must assess bone lesions on bone scans and not on the CT/MRI. Readers should follow PGWG3 rules in order to distinguish flare from true progression. The flare effect is a phenomenon where bone remodelling occurs at the site of a dying tumour which was not seen on the baseline scan. What first appears to be a new lesion is actually a favourable response to treatment. This phenomenon can occur in the first 12 weeks following initiation of therapy. New bone lesions are therefore assessed differently if they appear within the flare window or after:
- Within the flare window: When two new bone lesions appear at the first post-treatment scan compared to baseline, the time point is considered Progressive Disease unconfirmed (PDu). If the next bone scan shows that the original two bone lesions persist and there are at least two additional new bone lesions, then the initial time point that showed the first two lesions is considered to be the date of progression. If this 2+2 rule is not met, the lesions that initially appeared are regarded as flare effect and will not contribute to overall lesion count moving forward. The first post-treatment scan becomes the new baseline against which the number of new lesions is compared.
- Outside the flare window: When bone lesions appear outside the flare window, the appearance of only two new bone lesions compared to the first post-treatment scan is enough to call for progression. The two new lesions do not need to appear on the same visit but do need to be persistent (i.e., the lesions are still present at the time of the next scan). The time point is PDu until confirmation of Progressive Disease (PD) at the following scan. The date of progression is the date of the scan that first documents the second lesion.
At each time point, the readers must therefore count the number of bone lesions on the bone scan and compare the result with baseline and the first post-treatment scan as applicable.
The development of a superscan appearance exhibiting diffuse skeletal uptake with little or no uptake in the soft tissues calls for PD without confirmation being required.
Examples of bone scan assessments can be found in Keosys’ latest infographic: Prostate Cancer Working Group 3: Imaging Assessments Infographic.