It has long been a tenet of prostate cancer therapy (whether correct or not) that the appearance of evident metastasis (M1 disease) in men with supposedly progressive, micrometastatic (M0) disease is a key event in the management of patients because of the association between evident metastasis and the potential for onset of symptomatic bone disease.
However, a paper by Yu et al. (just published in the Journal of Urology) has shown clearly that a high percentage of patients thought by their doctors to have clinical stage M0 disease are actually already stage M1, which raises the question of whether men with stage M0 disease are sufficiently frequently monitored for their risk of evident metastatic (stage M1) disease.
The paper by Yu et al. is based on an analysis of data from the ENTHUSE M0 trial, which was a large, randomized, Phase III clinical trial designed to compare treatment with the endothelin A receptor antagonist zibotentan to treatment with a placebo in patients with non-metastatic, castration-resistant prostate cancer (nmCRPC). Although this study showed that zibotentan was not effective in the treatment of nmCRPC, it has proven possible to use data from this trial to explore other issues.
In the current study, Yu et al. show how an unexpectedly high number of patients thought to have M0 disease actually did not when they were given bone scans to confirm their eligibility for enrollment into the trial, and also discuss whether this screening failure rate can be used to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials of men with nmCRPC.
In examining the relevant data, the authors assessed the number of patients enrolled in and subsequently excluded from study and then analyzed these data by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients. Here are their core findings:
- 2,577 patients thought to be M0 by the referring physicians were initially enrolled at 350 hospital-based centers in 39 countries.
- 1,155/2,577 patients (45 percent) were not eligible for the trial after screening.
- The most common reason for screening failure was the detection of metastatic disease (M1 disease) by bone scan in 32 percent of all screened patients and in 71 percent of those in whom screening failed.
- The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region.
The authors conclude that, “The high frequency of asymptomatic metastasis in men thought to have [nmCRPC] highlights the importance of periodic staging assessments for the condition.”
They go on to point out that the optimal forms of treatmenet for men with metastatic and non-metastatic prostate cancer may differ, and that unless physicians carry out regular testing to assess the metastatic status of men with progressive disease while on hormonal therapy, they may miss a window of opportunity to modify treatment appropriately.
It should be noted that we have no definitive information about whether the visible presence or absence of metastasis is actually important. Some physicians would argue that is probably is not. On the other hand, one can also argue that by using new techniques such as PET/CT scanning one may be able to demonstrate the presence of clinically evident metastasis much earlier than is possible with bone scans (thereby expanding the number of men known to mave nmCRPC at a point in time). Whether this could or should lead to modifications in treatment for men previously being treated with standard forms of hormone therapy is not yet clear.
It could also be argued that men with a rising PSA while on hormonal therapy for progressive disease after first and/or second-line hormone therapy are inevitably metastatic, whether one can see the metastases or not, and that maybe we need to modify the subdivisions of metastatic disease stage into the following categories:
- Mo: No evidence of metastasis by any currently available test
- M1: Categorical evidence of metastasis to any site by tests other than a bone or a CT scan
- M2a: Categorical evidence of metastasis to any site by CT scan
- M2b: Categorical evidence of metastasis to any site by bone scan
- M3: Categorical evidence of metastasis to multiple sites by bone scan and CT scan
There may, of course, be better ways to reconsider the staging of metastatic disease, but it does seem as though some type of modification may be necessary and appropriate.