Category Archives: Oligometastatic prostate cancer

PSMA PET-CT scans for Prostate Cancer


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PSMA stands for Prostate Specific Membrane Antigen, which is a protein (enzyme) that is expressed on the surface of prostate cancer cells (and on a few other cell types). As with many cell surface proteins, you can find ligands that will bind to the protein, and then label these with radioactive isotopes that allow imaging. PET stands for Positron Emission Tomography, and of course, CT stands for Computerized Tomography. When you put these technologies together, you obtain a powerful way to look for prostate cancer that has spread outside the prostate gland. The physics of this (how a positron interacts with an electron, releasing gamma photons at 180 degrees) is very cool, but probably of interest only to the most nerdy. (I made a cloud chamber for my 7th grade science project and my hiking buddy is a nuclear medicine doc who wrote a definitive text on the math/science of his craft…so go figure).

Prior to developing PET agents for prostate cancer, we had standard CT scans and bone scans and we used these to determine whether someone with, for example, a very high PSA or high Gleason score had cancer deposits that had escaped (metastasized) from the prostate. If so, it was felt that putting them through surgery or radiation treatments in an attempt to cure was fruitless and exposed the patient to the unnecessary toxicity risks (impotence, incontinence, rectal damage, etc.) Especially if they had symptoms (e.g. bone pain), hormone treatment reducing testosterone was the best approach. If you had a rising PSA several years after local treatment, the question was always, “Where is the cancer?” but the sensitivity of routine bone and CT scans was quite limited not showing anything until the PSA reached 10 or so at which time ~1/2 of scans would be positive. Screen Shot 2020-04-26 at 7.26.14 AMThis figure illustrates the difference in sensitivity. A normal sized lymph node on CT scan (left) is revealed to  contain prostate cancer with the PET isotope technique (right). At present, the only approved PET scan in the U.S. is fluciclovine, the “Axumin” scan, which the FDA approved for detecting cancer in patients with rising PSA, but not in newly diagnosed patients. In several studies PSMA-PET CT scans are even more sensitive (about 3x) than Axumin. At the risk of calling up an overused phrase, “this changes everything”.

First, it is clear that many high risk patients we would previously have treated with surgery or radiation to the prostate hoping to cure them might now be found to have prostate cancer deposits outside of the treatment target (prostate or prostate + pelvic lymph nodes). A superb study in this month’s Lancet found that PSMA PET-CT scans provided higher sensitivity (85% vs 38%) and specificity (98% vs 91%) than routine bone and CT scans in high risk patients (PSA >20, Gleason 4+3 or worse). Does this mean we shouldn’t treat the prostate in high risk patients with positive scans? In the study, conventional imaging changed the management in 15% of men, while PSMA PET-CT imaging changed the plans in 28% (p=0.008). Should all high risk patients have a PSMA PET-CT before deciding on treatment? Should the FDA approve this scan quickly? (It is currently available only in research centers and not covered by insurance…read my blog on how to search for such studies or click here).

Second, what about treating a small number of prostate metastases (oligometastatic prostate cancer) in a patient who was treated years ago and now has a rising PSA? Ongoing investigations suggest this might delay the need for hormone therapy in such patients or potentially even cure some of them. But the PSMA PET-CT isn’t perfect. How high do you let the PSA go up before ordering such a scan? – the farther it rises, the more likely the scan will show something, but that gives the cancer more time to spread. A negative scan is no guarantee there aren’t many more foci of a few prostate cancer cells that will eventually show up elsewhere in the body. Is this some version of Whack-a-mole? And how do we define “cure” anyway?? (My personal definition is that you die from something else, regardless of your PSA or scan results).

Finally, since even at research centers the PSMA PET-CT scan may cost you $3,000 or so, is it worth it? It is “free” in the European health care systems, but we all know nothing is free – even if Medicare pays for something it costs society and ultimately must be accounted for in terms of value. Medicare covered PSMA PET-CT’s vs fixing pot holes and bridges? How about finding a treatment for SARS Co-V2 instead? No easy answers, but if you are like me, homebound as a “high risk” senior citizen, plenty to think about. Wash your hands, wear your mask, and enjoy your grandkids on Zoom!

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Targeted treatment

What we see and what YOU get.


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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)

Screen Shot 2019-04-08 at 5.01.55 PM

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. Screen Shot 2019-04-09 at 9.56.43 PMWhat 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…

 

 

 

 

 

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Targeted treatment

Delaying metastatic disease – ASCO GU18


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Previously, we have discussed the conundrum of the rising PSA and when to start therapy. I also opined that for some men with a very slowly rising PSA, it might be best to just forget about it and enjoy life, comparing it to watching a clock, an opinion that understandably garnered negative comments from some. Of course the nuances surrounding PSA kinetics and their meaning are myriad. However, one graphic that helps understand this better is shown here.

Screen Shot 2018-02-12 at 2.49.27 PM

Smith, JCO 2013

This figure illustrates the fact that individuals with relatively long doubling times (>8-10 months) have a much lower risk of developing metastases or dying from prostate cancer than those with shorter doubling times. In a classic study published almost 2 decades ago, Pound et. al. followed a large number of patients who had rising PSAs following prostatectomy at Johns Hopkins. On average, men with rising PSA’s  who received no additional treatment, did not develop metastases for ~8 years. “In survival analysis, time to biochemical progression (P<.001), [i.e. the time from prostatectomy until PSA rise was detected] Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease.”

With these findings as a background, two studies were presented at the ASCO GU18 meeting, both involving use of improved analogues of bicalutamide (Casodex): enzalutamide (Xtandi) or apalutamide (Erleada). These drugs block the androgen receptor, thus preventing stimulation of prostate cancer growth, but are more potent than bicalutamide. Patients with rising PSA’s in spite of having low levels of testosterone from surgical (orchiectomy) or medical (GnRH agonists/antatgonists) castration, short doubling times (<10 months), but no metastases were treated either with apalutamide/placebo (SPARTAN trial) or enzalutamide/placebo (PROSPER trial). The trials were both remarkably positive in delaying the time to development of metastatic disease.

Screen Shot 2018-02-19 at 8.44.28 AM

SPARTAN TRIAL (Apalutamide)

Screen Shot 2018-02-12 at 2.42.37 PM

PROSPER TRIAL (Enzalutamide)

These are remarkable findings and great news for patients with the most aggressive forms of prostate cancer. However, there are (as usual) numerous questions raised by the trials, as was nicely discussed by Dr. Kantoff after the data were presented. These included a more careful analysis of the side effects and clinical benefits. Obviously patients are psychologically better off when they don’t have a rising PSA or metastases, but neither study reached statistical significance when it came to improved survival (both are trending in this direction). What are the side effects of being on such drugs for longer periods of time? In the enzalutamide study, there were more deaths from “other causes” – not pca within 3 months of progression. Why? In the apalutamide study there were more falls and fractures compared to placebo. Why? To these, I would add the issue of “pay me now or pay me later” – how much time/quality of life do you really lose by waiting until the first metastasis shows up, never mind the extraordinary costs (to patients, insurers, medicare, etc.) of remaining on these drugs for years. Further, neither study compared the outcome to using bicalutamide, the generic and much cheaper alternative anti-androgen, instead of placebo. And what about using the newer scans? All of the patients have metastatic disease, we just can’t see it until there are enough cells in one spot to turn a scan (e.g. fluciclovine or PSMA PET) positive. We can possibly gain advantages in staying off ADT of any sort in some patients by radiating oligometastatic disease. Nevertheless, these studies are great progress and landmarks in the fight against prostate cancer. Apalutamide became the first drug to be approved by the FDA for use in this setting with a “snap approval“. And I need to disclose that I am a paid advisor to J&J, although I have no personal stock in their company, and did not treat patients on either trial.

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Uncategorized

Rising PSA – When to start therapy


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One of the most frequent situations I encounter in my small “prostate cancer only” practice is a man who has had treatment (usually surgery or radiation) several years ago and now has a rising PSA. He feels absolutely fine, may be exercising daily, and his PSA is often so low that a routine scan won’t show anything. What to do?

The options in this situation are changing. Treating oligometastatic disease (few metastases) is somewhat of a new frontier in this situation. In the “old days” when I wrote about this subject, we reviewed the non-randomized data that suggested no advantage to starting ADT earlier. More recently, the idea of treating some men with radiation or surgery directed at the mets if they have only a few has become more popular. Added to this is the increased sensitivity of the newer PET scans (choline, acetate, PSMA targeted) that may reveal metastases even with PSA values less than 1.0. While it is hoped that some men could be cured by this approach, it is also possible that one could delay the implementation of ADT and its side effects. There are multiple ongoing clinical trials looking at this issue. With such rapidly changing technology, it will be difficult to come up with a “right choice” in every situation. What may have been considered “non-metastatic rising PSA” last year could become “oligometastatic” simply by the implementation of the new scans.

Beyond this is the issue of treatment-related side effects. In an article this week in Lancet Oncology, the side effects of treating men with asymptomatic, non-curable prostate cancer (TOAD and TROG studies) was reported. This study is one of the few randomized studies in this setting. The men were about 70 years old with rising PSA’s, most having been previously treated. They were randomized 1:1 to starting ADT immediately or waiting until at least 2 years later unless “symptoms or metastases developed or PSA doubling times decreased to 6 months or less”. Earlier, the investigators published the survival data in this study, indicating some advantage to starting earlier, as shown in this graph. Screen Shot 2017-09-12 at 9.14.48 PM

However, keep in mind that the men who were in the immediate ADT arm also experienced the ADT side effects sooner according to the new report. The most important areas of symptoms were the hot flashes and decreases in sexual activity (reported only in the men who were sexually active) which were significantly worse with the immediate treatment, as might be expected. In a “global quality of life” measurement there was also worse quality of life, although it was not significant (the score number was 72.39 for delayed therapy vs. 70.83 for the immediate group). Further, the type of ADT used varied, and included both intermittent and continuous therapy (usually intermittent therapy has at least some improvement in quality of life). Finally, none of the men in these studies received the newer (and vastly more expensive -but probably more effective) ADT agents, abiraterone or enzalutamide which have been shown to improve survival when used “up front” in the metastatic setting.

Thus, a rising PSA is obviously a reason for concern, but choosing a management strategy is quite complicated at the present time. The best news to come out of this study is that prostate cancer is a slow disease. “Overall, 18 (6%) men died from prostate cancer, 12 (8%) in the delayed treatment arm and six (4%) in the immediate arm…” This is not to say that as time goes on there will not be more prostate cancer deaths, and there was earlier metastatic progression in the delayed group, but it is equally important to realize that at age 70 there will be significant competing causes of mortality. Something will get us eventually, so the key is to not let prostate cancer (or the PSA) dominate our thinking. What other things can you work on? Stop smoking. Exercise. Improve your diet. And most of all, enjoy each day as a gift and live it to the fullest regardless of how you decide to deal with a rising PSA.

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy