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Will Rogers is said to have stated, “When the Oakies left Oklahoma and moved to California, it raised the IQ of both states.” This story has given rise to the concept of the “Will Rogers phenomenon” in medicine that is very well explained in this essay. Basically, it provides a cautionary message when evaluating new therapies in cancer medicine, because if a new study has taken advantage of newer diagnostic techniques to eliminate some of the patients with higher risk (say those with metastases), then it could easily be that an improved result is not from the new therapy, but from the ability to throw out the higher risk patients from a study cohort.
We are certainly at risk of this now in prostate cancer. In the last 5-10 years, a number of more sensitive scans have been introduced that can reveal metastatic deposits previously missed by standard technetium-99m bone scans or CT scans. Most of these rely on the technology known as PET (positron emission tomography) scanning. The first clinical PET scans mostly utilized glucose to which a positron emitter, Fluorine-18, was attached. For bone metastases, it is easy to see how much more sensitive F-18 scans are as shown in this image: (Same patient – A. “Regular” Tc-99m bone scan B. NaF-18 PET scan)
Suppose you have a new treatment that is for patients “with 10 or fewer” bone metastases. If you are comparing the new treatment with one that was used in the past, and you now use the PET scan (on the right), this patient would not be eligible, whereas in the past (old scanning technique) he would have been. He clearly has a higher tumor burden than 10 metastases. Hence, he is now eliminated from the new study, and therefore the new study will automatically look better in terms of outcome than previous treatments. This is called “stage migration” or the “Will Rogers phenomenon”.
For “soft tissue” metastases (lymph nodes, liver, lung, etc.) the regular Fluorodeoxyglucose FDG-PET scans were approved decades ago for lung cancer, colon cancer, lymphomas and breast cancer but they never worked well for prostate cancer. A simplistic explanation may have to do with the different metabolism of prostate cancer which tends to utilize lipid rather than glucose for energy. (see our study here). Therefore researchers looked for other metabolites that would light up prostate cancer. Acetate and choline could be labelled with Carbon-11 and worked well. However, C-11 has a half life of only 20 minutes, so making the label in a cyclotron had to be done essentially in the room next door to the scanner and injected immediately into the patient. Another metabolite taken up by prostate cancer, an artificial amino acid (fluciclovine), could be labeled with F-18, worked well and has now been approved, called the Axumin scan. Potentially even better will be the PSMA scan, now in research mode.
The net result of these new scans is to allow physicians to answer the frequent question patients ask, “Where is the PSA coming from?” The problem then becomes the title of this essay – What we see and what You get. There are numerous scenarios. For example, a patient who comes in with a very aggressive Gleason 9 cancer and a PSA of 12.3. Should we go immediately to a routine bone and CT scan, or just order an Axumin scan? And if we find 2 positive spots, one in a rib and the other in a lymph node, does that mean the patient can’t be cured?? Five years ago, we would have never known about the metastases and we would have operated or used radiation therapy in a curative attempt. What about the patient with a rising PSA 5 years after he had surgery. We do a PSMA scan and find a solitary node near the left iliac artery. Should we irradiate the node? What about operating and removing it – remember, it may not look any different from all the other nodes to the surgeon. Which one should he/she take out? And what is accomplished by these efforts? Should the PSA go down (yes if that’s the only metastasis) and what to do if it doesn’t go down. Are we playing “whack a node”? How many times do we go after spots that keep showing up, versus starting some sort of hormone therapy?
There is an excellent article addressing some of these questions written by my good friend Chris Sweeney and colleagues that you can read here. A summary quote from their article states, “Given the current limited understanding of how reliable these scans are in predicting the need for appropriate management change, data-driven guidelines and standardized consensus approaches are more critical than ever.” A review of some of the early attempts to treat a small number of metastases (called oligometastatic disease) has just appeared here. One example of a paper reporting interesting results is summarized as follows: “Of the retrospective reports, the largest includes 119 treatment‐naive patients who had ≤3 sites of oligorecurrence and received SBRT to all involved sites, with 92 of 119 (77%) undergoing pretreatment choline PET. The 3‐year distant PFS [progression free survival] rate of 31% and the 3‐year OS rate of 95% are favorable and suggest a subset of patients likely benefitted from aggressive local therapy; however, conclusions from these data are limited in the absence of a comparative control arm.”
Maybe we simply have to refer back to another quote from Will Rogers, “America is a nation that conceives many odd inventions for getting somewhere but it can think of nothing to do once it gets there.” Stay tuned…