Using PCWG3 Classification in Prostate Cancer
This is an excerpt from our white paper, “Using PCWG3 Classification in Prostate Cancer.” To access the full white paper, click here.
HISTORICAL OVERVIEW OF PROSTATE CANCER CLINICAL TRIALS WORKING GROUP
The initial criterion for prostate cancer evaluation in clinical trials was published in 1999 by the Prostate Cancer Clinical Trials Working Group. In 2008, even as new therapeutic strategies began to emerge, chemotherapy with docetaxel was the only drug proven to prolong survival in metastatic CRPC (mCRPC). This was the landscape in which the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) outlined more extensive standards for clinical trials.
The Importance of 99mTc Bone Scans in PCWG2 Criteria for Radiographic Progression
Bone metastasis is one of the most common sites of metastatic disease in men with prostate cancer (the other being nodal disease). As such, 99mTc bone scans provide a very sensitive way to detect sites of bone disease. One of the novel observations made during prostate cancer treatment is the appearance of “new lesions”. Known as a flare phenomenon, this type of pseudoprogression can last for up to 8 weeks from the start of therapy and is almost exclusively detected on 99mTc bone scans in which there is a worsening of bone scan manifested by the apparent development of new lesions. The appearance of new lesions on 99mTc bone scans is due to localized tumor control and/or killing of tumor in the bone, which then allows for the local healing process or repair to occur at the site of disease. This type of bone repair will then show up as a new lesion on bone scans.
Since the development of new lesions always raises a concern of disease progression (and thus impacting the date of rPFS) there is a need to be able to differentiate the treatment flare phenomenon from true progression. Fortunately, by repeating a 99mTc bone scan no sooner than 6 weeks after acquiring the first post-baseline scan, it may be possible to distinguish flare from progression. For example, if there are additional new lesions that develop on subsequent follow-up 99mTc bone scans compared to the first post-baseline scan, then the original observation of new lesions at the first post-baseline bone scan time point was due to true progression. If there are no more new lesions that develop on subsequent 99mTc bone scans compared to the first post-baseline 99mTc bone scan, then the new lesion development at the first post-baseline bone scan time point was due to a treatment flare and rPFS has not yet been met.
When considering treatment flare from true progression, PCWG2 required that there must be at least two or more new lesions that developed on the first post-baseline 99mTc bone scan obtained during the 8-week flare window compared to baseline/screening 99mTc bone scan; and then, two or more additional lesions that developed on the subsequent follow up 99mTc bone scan outside the flare window. This became known as the 2+2 rule. The rationale for incorporating the 2+2 rule in PCWG2 rather than allowing only one new lesion to drive progression is based upon the non-specific nature of 99mTc bone radiotracer uptake, which may be due to tumor, trauma, and other benign lesions and the sometimes-difficult task of counting the number of sites with bone metastasis, especially when the disease is widespread. Outside the flare window, two or more new skeletal lesions that develop compared to either screening/baseline 99mTc bone scans or, during the flare window, followed by the persistence of those two or more new lesions constituted disease progression, with the date of rPFS being dated to the 99mTc bone scan in which the two or more new lesions were first noted.
