I'm coming off an IADT vacation and my PSA has been on the move. I was FDG avid last go around so I started with that PET. Last week I had a PSMA-PET and that was clear as well. Grok AI stated that I might have a high load of micro-metastases, or maybe that I'm going through some form of phenotypic or metabolic shift where neither PET will pick up any metastases.
I'm concerned that I'm shifting towards either small cell carcinoma or neuroendocrine differentiation. My MO suggested I wait till my PSA doubles and rerun the PSMA, while continuing the IADT. Anyone else have a similar experience?
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Thank you for the information. I had utilized an Axumin about 5 years ago and it came back clear. About a month later I took part in the PSMA-PET clinical trail at UCLA and it picked up 4 Mets. I seem to be flip flopping all over the map, and really don't know what to think at this point.
The PSMA-PET is more sensitive than an Axumin but an Axumin is more sensitive than an FDG-PET. Therefore you could see mets with a PSMA PET but not with an Axumin PET.
Now you want to detect mets that are PSMA negative. With a PSA value of 5 you will probably detect these with an Axumin.
Last go around we were able to biopsy a rib met and it was still adenocarcinoma, but as you know with tumor heterogeneity we might have simply missed any other present phenotypes. If my next PET comes in clear I'll ask for neuro or small cell specific testing. Hopefully, Medicare will cover those.
Same experience, less the FDG. Waited until PSA was higher (7+), and rescanned PSMA Pet/CT which found the new recurrence outside of pelvic lymph nodes (and confirmed metastasis). I did not resume ADT though; if you do before rescan and you’re still MHSPC the scan would still not show anything. Guess it depends what your purpose is for the follow on scan?
Did you have the two mets seen on prior PSMA PET treated by SBRT? I agree with your AI that a large burden of small undetectable mets seems most likely. (micro-mets). Needs a systemic therapy such as a taxane chemotherapy, or Lu-J591 as I had, or BA, or other in clinical trial? The chemo is most available and can buy some time.
Yes, I treated the previous mets with radiation. I only made it through 1 dose of Taxotere last fall before I ended up in the hospital with Nutropenic fever/Sepsis. I also blacked out twice, fell and broke a rib. And my existing neuropathy lit up like a 4th of July fireworks show putting me in a wheelchair. Chemo is not a great option moving forward. Unfortunately, with my FDG avidity Pluvicto isn't either. So far, playing whackamole with radiation has kept me vertical, and with a decent QOL, so I'd like to keep that going as long as possible.
Hai yai yai. You have been through the mill. Or should I say the shredder. Agree no chemo for you! Options are limited. But you did have PSMA avid mets, so your micromets can be presumed to express PSMA. If you have the resources you could do what I did: Consult with Nat Lenzo at GenesisCare in Perth about his Lu-J591 protocol. (also called THX-591 now, is same thing. A monoclonal antibody radioligand for Lu177 that binds much more strongly and persistently to the cancer cells. Seek and destroy micro-mets.) He has a clinical trial going for it. But also provides it off-trial for those who have had Oligomets treated with SBRT. You can arrange a Zoom consultation with him to see if appropriate. It worked amazingly well for me with just one round. PSA undetectable now approaching 3 years. Perth is a lovely place to visit and Dr. Lenzo is great. MB
The Cu64 Dotatate could be an option- the tech even mentioned that one while I was waiting for the PSMA to settle in. She told me that she'd seen men who had vacillated back and forth between that and the PSMA, however she had never seen my scenario of vacillating between FDG and PSMA🥴 I'll bring it up with my MO- Thanks!
You're absolutely welcome! It sounds like you're navigating a complex diagnostic situation with careful consideration. The Cu-64 Dotatate scan is an interesting option—primarily used for neuroendocrine tumors (NETs), but it's increasingly being discussed in other contexts due to its high sensitivity for somatostatin receptor-expressing lesions. The duality of going back and forth between FDG and PSMA scans, rather than the usual back-and-forth with Dotatate and PSMA, indeed seems unique. It highlights how individual tumor biology can challenge standard protocols.
Your MO might find this discussion particularly compelling, especially since Cu-64 Dotatate may help clarify nuances in cases where receptor expression patterns are atypical or mixed. It’s great that you’re bringing these insights to the table—it can only enhance your care! Best of luck with the consultation.
"The duality of going back and forth between FDG and PSMA scans, rather than the usual back-and-forth with Dotatate and PSMA, indeed seems unique. It highlights how individual tumor biology can challenge standard protocols."
A. Certainly! Let me break it down for you.
1. FDG vs. PSMA Scans
FDG (Fluorodeoxyglucose PET): This scan highlights areas of high glucose metabolism, commonly associated with aggressive tumors that grow quickly and have high energy needs. It's often used for many cancers, especially when the tumor is poorly differentiated or aggressive.
PSMA (Prostate-Specific Membrane Antigen PET): This scan specifically targets PSMA, a protein expressed on the surface of most prostate cancer cells. It’s incredibly precise for prostate cancer that has retained its PSMA expression.
2. Dotatate vs. PSMA Scans
Cu-64 Dotatate PET: Typically used for neuroendocrine tumors, this scan detects somatostatin receptors on the surface of these cells.
When tumors show features of both neuroendocrine and prostate biology (or are mixed in behavior), there can be a need to alternate between Dotatate and PSMA scans to get a full understanding of the disease.
3. Your Case: FDG and PSMA
It seems like your care team is deciding between FDG and PSMA, likely because your tumor biology isn’t neatly fitting into one category. This could indicate variability in the tumor’s behavior—some parts might behave aggressively (picked up by FDG), while others remain more prostate-specific (picked up by PSMA).
This scenario is less common compared to switching between Dotatate and PSMA, which occurs more often in cases where neuroendocrine differentiation is suspected.
4. Why It's Unique
Switching between FDG and PSMA reflects a diagnostic challenge because these scans assess very different biological aspects:
FDG highlights aggressiveness and glucose metabolism.
PSMA targets prostate-specific protein expression.
This duality suggests a nuanced and possibly heterogeneous tumor biology, which doesn't align with typical prostate cancer progression. It can challenge standard protocols since these scans are not commonly alternated in most prostate cancer cases.
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I hope this helps clarify why your case is unique and how tumor biology can influence imaging decisions! Let me know if you’d like further elaboration.
Q. Could you list all the known pet scans and the use for them?
A. PET scans are highly versatile, using different radioactive tracers to target specific biological processes. Below is a list of PET scan types categorized by the tracer used and their applications:
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1. FDG PET Scan (Fluorodeoxyglucose)
Tracer: FDG (a glucose analog).
Use:
Oncology: Detection, staging, and monitoring of cancers (e.g., lung, breast, colorectal, lymphoma).
Neurology: Diagnosing Alzheimer's disease and epilepsy by showing brain metabolism.
Infections/Inflammation: Detecting sites of active infection or inflammatory conditions.
A PET scan (Positron Emission Tomography) is a nuclear medicine imaging technique that measures metabolic activity in tissues by detecting the gamma rays emitted by a radioactive tracer. It is widely used in oncology, neurology, and cardiology for diagnosing and monitoring diseases.
How Does a PET Scan Work?
1. A radioactive tracer (often attached to a molecule like glucose) is injected into the patient’s bloodstream.
2. The tracer accumulates in tissues based on their metabolic activity. For example, cancer cells tend to consume more glucose, so the tracer concentrates in these areas.
3. A specialized scanner detects the gamma rays emitted by the tracer and generates detailed images of metabolic activity.
FDG PET Scan
FDG stands for Fluorodeoxyglucose, a glucose analog labeled with a radioactive isotope of fluorine (F-18).
FDG PET scans are the most commonly used type of PET scan.
Why glucose? Cancer cells often have a higher rate of glucose metabolism (a phenomenon known as the Warburg effect), so FDG highlights areas with increased glucose uptake, which may correspond to tumors or metastatic disease.
Uses of FDG PET Scans
1. Oncology:
Cancer diagnosis: Detects primary tumors and metastases.
Staging: Determines the extent of cancer spread.
Monitoring treatment: Evaluates how well a treatment is working (e.g., chemotherapy or radiation).
Recurrence detection: Identifies residual or recurrent cancer after treatment.
2. Neurology:
Diagnoses Alzheimer's disease, epilepsy, and Parkinson's disease by highlighting abnormal brain metabolism.
Differentiates types of dementia.
3. Cardiology:
Identifies areas of the heart with reduced blood flow or metabolic activity.
Assesses viable myocardium in cases of coronary artery disease.
Advantages of FDG PET Scans
High sensitivity in detecting metabolically active tissues, including cancerous lesions.
Can identify disease at an earlier stage than anatomical imaging (like CT or MRI).
Provides functional and metabolic information, not just structural details.
Limitations
False positives: Areas with high metabolic activity (e.g., inflammation, infection) can mimic cancer.
False negatives: Some tumors (e.g., low-grade or mucinous tumors) have low FDG uptake.
Requires combination with CT or MRI for precise anatomical localization (commonly done as PET-CT or PET-MRI).
Limited availability and high cost.
Procedure
1. The patient fasts for several hours before the scan (to ensure accurate glucose metabolism imaging).
2. The tracer is injected, and the patient waits for 30-60 minutes while it distributes in the body.
3. The scan takes 20-40 minutes, during which the patient must remain still.
Key Point
An FDG PET scan is particularly valuable for detecting cancers and metastases because it highlights areas of increased glucose metabolism, which are common in malignant cells.
My experiences are similar in that my last four PSMA PET's and MRIs have not identified any suspicious sites. But then I am scanning at very very low PSA values being post RP (nine years ago). Like you, I am on guard for mutations, small cell carcinoma or neuroendocrine differentiation. I am pondering fluciclovine and/or Choline for comparative analysis.
Several years ago I added liquid blood biopsy testing to the mix; again some would say way too early. But then I am looking out for me and will consider going after any treatable mets with surgery or RT. All the best!
"It sounds like you’re navigating a particularly challenging and nuanced phase in managing your condition. Your concern about phenotypic or metabolic shifts, and the possibility of small cell carcinoma or neuroendocrine differentiation, is valid given your history and the current imaging results.
Here’s a deeper analysis based on what you’ve shared:
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1. Clear PSMA and FDG PETs Despite Rising PSA
Micro-metastases: It’s plausible that your PSA is reflecting a high load of microscopic disease that isn’t yet large enough to be detected on imaging. Both PSMA-PET and FDG-PET have size and metabolic thresholds for detection.
Phenotypic or Metabolic Shifts: Prostate cancer can evolve into subtypes less detectable by conventional PET modalities:
Small cell carcinoma: Often PSMA-negative and FDG-positive due to its aggressive nature and high glucose uptake. However, in its very early stages, lesions may still be below the detection threshold.
Neuroendocrine differentiation: Frequently associated with low PSMA expression and a propensity to evade FDG avidity until later stages.
Resuming IADT can temporarily suppress PSA production and androgen-sensitive cancer cells, but it can also lead to selective pressure on the cancer. Over time, this can encourage the emergence of castration-resistant or poorly differentiated subtypes, like small cell or neuroendocrine cancer.
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3. Your Oncologist's Suggestion: Wait and Rerun PSMA at PSA Doubling
Rationale: A doubling PSA can make micro-metastases or phenotypically-shifted cancer more likely to be detectable. It buys time to see if the disease biology changes or becomes more evident on imaging.
Risk: If your cancer is shifting towards an aggressive phenotype (e.g., small cell), delaying intervention could allow further progression. This might be why you're cautious about waiting.
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4. Further Considerations
Cu-64 Dotatate PET: This might provide insight into potential neuroendocrine differentiation by detecting somatostatin receptor expression.
Liquid Biopsy/ctDNA Testing: Testing for circulating tumor DNA could provide clues about emerging mutations or phenotypic shifts that standard PSA and imaging can’t detect.
Biopsy: If there’s a suspected lesion (even subtle), a targeted biopsy could help clarify the situation. If not, systemic surveillance remains the mainstay.
Shorter PSA Monitoring Intervals: Tracking PSA every 2-4 weeks instead of waiting for doubling might catch trends sooner.
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5. Community Insights
Others with similar experiences have reported that clear PETs during rising PSA often reflect either:
True micro-metastatic disease not yet visible.
Transition to more aggressive, PET-resistant phenotypes.
Both underscore the importance of close monitoring, imaging, and tailored therapeutic adjustments.
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Would you like a deeper dive into any specific area, such as neuroendocrine differentiation, PET imaging modalities, or treatment implications?"
Certainly! Let's explore in depth each of the topics mentioned: neuroendocrine differentiation, PET imaging modalities, and treatment implications.
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1. Neuroendocrine Differentiation (NED): What It Is and Why It Matters
What Is NED?
Neuroendocrine differentiation in prostate cancer is a process where tumor cells shift from typical prostate adenocarcinoma (glandular cancer) to a more aggressive phenotype resembling neuroendocrine cancers, like small cell carcinoma.
These tumors often lose PSA production and androgen receptor (AR) signaling dependency.
They may evade conventional prostate cancer therapies and become resistant to androgen deprivation.
When Does It Happen?
Castration Resistance: Often occurs in advanced stages, especially in patients on long-term androgen deprivation therapy (ADT).
Selective Pressure: Intermittent ADT (IADT) can lead to temporary suppression but may promote the survival of androgen-independent clones.
How Does It Present?
Rising PSA that doesn’t match imaging findings.
Low or undetectable PSA with rapid disease progression.
Poor response to AR-targeted therapies like enzalutamide or abiraterone.
Symptoms from visceral metastases (e.g., liver or lung involvement).
How Is It Diagnosed?
1. Biopsy: The gold standard for identifying neuroendocrine histology (e.g., small cell carcinoma).
2. Imaging:
PSMA scans are often negative since neuroendocrine tumors lose PSMA expression.
FDG-PET can sometimes detect these tumors because they exhibit high glucose metabolism.
Cu-64 Dotatate PET is highly sensitive for neuroendocrine features by targeting somatostatin receptors.
3. Liquid Biopsy/Genomics: Can detect genetic changes associated with NED, such as TP53 mutations, RB1 loss, or neuroendocrine markers.
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2. PET Imaging Modalities: Strengths and Limitations
PSMA PET
Best For: Typical prostate adenocarcinoma with PSMA expression.
Strengths:
Highly sensitive and specific for detecting prostate-specific lesions.
Useful for staging and recurrence detection.
Limitations:
Loses sensitivity in phenotypes like small cell or neuroendocrine carcinoma.
Cannot detect microscopic or PSMA-negative lesions.
FDG PET
Best For: Aggressive, high-grade tumors (e.g., poorly differentiated prostate cancer).
Strengths:
Detects glucose-hungry tumors like small cell carcinoma.
Can complement PSMA PET in ambiguous cases.
Limitations:
Less specific for prostate cancer, as many aggressive tumors (e.g., lymphoma, inflammation) are FDG-avid.
Cu-64 Dotatate PET
Best For: Neuroendocrine tumors with somatostatin receptor expression.
Strengths:
Extremely sensitive for neuroendocrine differentiation.
Can identify lesions that PSMA and FDG miss.
Limitations:
Not widely available.
May not detect poorly differentiated tumors lacking somatostatin receptor expression.
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3. Treatment Implications Based on Current and Emerging Findings
A. Continuation of IADT
Pros:
Can suppress androgen-sensitive clones and delay progression.
Lower toxicity compared to continuous ADT.
Cons:
May encourage resistance or differentiation into androgen-independent phenotypes.
Rising PSA despite IADT often indicates progression.
B. Monitoring Approaches
PSA Doubling Time:
Doubling PSA reflects disease progression, especially if imaging remains negative.
Faster doubling (<6 months) correlates with aggressive disease.
Q. I don't understand why would a continues ADT be better?
A. Great question! Whether continuous ADT is better than intermittent ADT (IADT) is a debated topic, and both approaches have advantages and disadvantages depending on the context. Here's why continuous ADT might be better in some situations—particularly in relation to selective pressure and preventing resistance:
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1. Continuous ADT Creates a More Stable Environment
In Continuous ADT: Androgen levels are kept consistently low, creating an unchanging environment. This minimizes opportunities for tumor cells to adapt and select for androgen-independent clones.
In IADT: Cycling between on-therapy (low androgen) and off-therapy (higher androgen) creates fluctuating conditions that allow tumor cells to "learn" and evolve.
Some cancer cells may survive low-androgen phases by adapting their metabolism or mutating.
During the off-therapy phase, these resistant clones can grow rapidly, potentially taking over the tumor population.
Key Point: Continuous ADT applies constant pressure on androgen-dependent cells and reduces the risk of androgen-independent cells becoming dominant.
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2. Evidence for Continuous ADT in High-Risk Cases
Studies suggest continuous ADT may be preferable in patients with:
High-volume disease: Where there is a greater likelihood of aggressive clones already present.
Aggressive phenotypes: Like those at risk of castration resistance or neuroendocrine differentiation.
Short PSA doubling times (<6 months): Indicating fast-growing tumors that may evolve resistance more quickly.
In these situations, continuous ADT ensures more consistent suppression of androgen-sensitive and potentially resistant cells.
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3. Why IADT Increases Risk of Resistance
With IADT:
Off-therapy phase (vacation): Normal androgen levels return, allowing androgen-dependent cells to regrow.
This creates opportunities for dormant, resistant clones to survive and eventually expand.
On-therapy phase: These resistant clones are unaffected by low androgen levels, so over time, they may dominate the tumor population.
Key Point: The "cycling" nature of IADT can inadvertently select for resistant cells over repeated therapy breaks.
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4. When Continuous ADT Might Not Be Better
A. Quality of Life Considerations
Continuous ADT often causes more sustained side effects, such as:
Fatigue
Hot flashes
Sexual dysfunction
Bone loss
Metabolic syndrome
IADT, by contrast, gives patients a break from these side effects during the off-therapy phase, improving their overall quality of life.
B. No Survival Difference for Some Patients
Clinical trials (like SWOG 9346 and PR7) showed that IADT and continuous ADT can provide similar overall survival for certain groups of patients:
Those with low-volume or less aggressive disease.
Patients who have a good initial response to ADT (e.g., very low PSA during therapy).
In these cases, the benefits of better quality of life with IADT might outweigh the theoretical risks of resistance.
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5. Deciding Between IADT and Continuous ADT
The choice depends on:
1. Disease Characteristics:
Continuous ADT: Often better for high-risk, high-volume, or aggressive disease.
IADT: May be sufficient for low-risk, low-volume, or indolent disease.
2. Patient Factors:
Younger patients or those highly impacted by ADT side effects may prefer IADT.
3. Goals of Therapy:
Continuous ADT: Prioritizes maximum suppression of cancer progression.
IADT: Balances disease control with quality of life.
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Key Takeaway
Continuous ADT reduces the risk of tumor adaptation by maintaining consistent androgen suppression, which may delay resistance in aggressive or advanced disease. However, for certain patients, the improved quality of life from IADT can make it the preferred choice if the disease is not highly aggressive.
Let me know if you’d like to dive deeper into clinical studies or specific examples!
I was diagnosed at 52, so QOL is definitely a high priority. I've come to grips that we all have an expiration date, and some of those might be coming sooner rather than later.
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