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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…
8 responses to “What we see and what YOU get.”
This is a perspective that I hadn’t thought of before. Thanks for sharing.
Thought provoking, excellent advice, and often overlooked by micro-vision versus being able to evaluate the forest and what it really is about.
Michael, thanks for your easy to understand post on scans for our disease. I have had all the scans you mentioned except Ga68 PSMA with negative findings when my PSA was rising. I am still responsive to Zytiga (12 months now) after becoming CRPC to ADT. Current PSA is <0.1. Please keep doing this to help us understand current research efforts, especially targeted immunotherapy, and how the efficacies of PC “cure” from “ab” and “ib” drugs with respect to our genetic markers/variants.
Thank you Michael for this illuminating and insightful article. I recently participated in a DCFPyl clinical trial after experiencing BCR in an attempt to locate the site(s) of PSA generation. The scan presented one suspicious pelvic lymph node; the real question is what to do with that information. As I have already had salvage IMRT to the prostate bed and 9 months of ADT monotherapy, I am reluctant to consider more radiation to the pelvic lymph field and am also not convinced that oligometastatic approaches to treatment have shown any success. On a positive note, the scan did reveal that I do not have extensive mets and would perhaps indicate a return to SOC ADT or a clinical trial which adds the second level hormone therapies ( Zytiga, Xtandi, Erleada) to SOC.
Excellent information–as usual. I have recommended your Blog to several MD’s- hopefully they are paying attention. Know that the information you provide is valuable and appreciated. Thank you.
Rogers had it right – I could not find an American doctor with a good plan as to what to do with my 0.091 PSA post prostatectomy and RT to prostate bed. Via medical consultations in London found my way to Netherlands for a nano- particle MRI combined with PSMA PET CT with Professor Barentsz of the Radbound University Nijmegen Prostate MR Center of Excellence. Five suspicious nodes identified. After numerous consultations in USA and London, selected robotic pelvic lymph node removal surgery with Professor Mottrie, OLV Ziekenhuis Hospital in Aalst, Belgium. Fourteen months later, continuing undetectable, <0.01. Mr. Rogers might just be impressed with these Europeans.
Great story. Although still challenging, for men with access to the internet (or Internet if you prefer) and resources, you can find options out there. It takes a lot of hard work however, and is something you really can’t expect your doctor to do for you. You CAN, however, expect your doctor to offer advice about pros and cons of choosing one approach over another when you make him/her aware of what you have found.
Specific to imaging, when I read other patients comments about their doctors focus on PSA doubling time, when in fact their PSA is above the level available imaging methodologies in other countries would be used to localize the remaining cancer(s) tumors, I say it is time to not only question but challenge the overall capability of prostate care in the USA. For example, for uPSA above 0.03 post prostatectomy, PMSA PET/CT is used – not PSA doubling time while the mans cancer metastasis progresses.