The Perils and Pitfalls of "Treating PSA" in Advanced Prostate Cancer

Prostate Specific Antigen (PSA) is a protein on the surface of all benign prostate cells and most malignant prostate cancer cells. In prostate cancer, expression of PSA is correlated with the size of the tumor (see this link). When prostate cancer first metastasizes, the tumor is limited in size by its blood supply. As it grows, the cancer creates its own blood supply by secreting growth factors called VEGF. The PSA from the cancer activates VEGF to form blood vessels that bring oxygen and nutrients to the cancer and lymph vessels to drain fluids from the growing tumor (see this link). Tumor blood supplies are not as patent as those of benign tissues. Healthy prostate tissues with patent blood supply, and micrometastases that have little or no blood supply put out very little detectable PSA into the serum (although the cells express high levels of PSA). But the leaky blood supply of tumors allows PSA to enter the serum where it is detected by a PSA test. So, the larger, more established tumors of a given patient create almost all of his detectable PSA (see this link).

"Treating PSA"

I. Selecting for low PSA subtypes

For most men with advanced prostate cancer, PSA is their best biomarker of progression - more detected PSA means more progression. This may change as the cancer evolves. A highly mutated tumor may put out less PSA. Highly undifferentiated kinds of prostate cancer, and other relatively rare sub-types (e.g., ductal, neuroendocrine, basal cell, "double negative," etc.) may evince little or no serum PSA.  

So it is possible, when such phenotypes are present and they are mixed with "normal" prostate cancer, to provide treatments that kill off the "normal" prostate cancer cells, leaving the low-PSA subtypes behind. Such a situation has been identified in patients heavily treated with chemo and enzalutamide. It is called "treatment-emergent neuroendocrine prostate cancer" (see this link) and has been identified in 17% of heavily-treated patients. 

Another example of a treatment that may select for low-PSA subtypes is Lu-177-PSMA. If the patient has two types of prostate cancer, one that expresses PSMA and PSA, while his other cancer expresses neither, PSMA-targeted therapy may eliminate the source of most of the PSA, leaving more virulent subtypes behind (see this link). 

This type of situation is dangerous if one relies on PSA as the principal biomarker of progression. One may be lulled into complacency by deceptively low PSA.

It is worth noting that two FDA-approved therapies for prostate cancer, Provenge and Xofigo,  have been proven to increase survival, but have little or no effect on PSA.

II. Supplements that interfere with PSA tests

Patients often self-medicate in the hope of wresting some control over their cancer. The internet is full of "evidence" that this or that natural supplement may slow progression or even cure the cancer.  Serum PSA is detected by an antibody that can detect amounts as low as a nanogram of PSA per ml of serum. This kind of sensitivity has a cost - the antibodies are subject to interference by other substances that may be present in the serum. So far, the list of substances that may interfere with PSA tests, creating false negatives, includes biotin, curcumin, genistein, EGCG, resveratrol, capsaicin, saw palmetto, pygeum, beta-sitosterol, and statins (see this link). The false negative PSA readings may fool the patient and his physician (who may not be aware of the patient's supplement use) into believing that the cancer is under more control than it really is. Patients who use any complementary therapies are twice as likely to die of their cancer (see this link).

III. SBRT of oligometastases

1. Exponential growth

Because of Covid-19, many of us are now used to seeing exponential growth curves. Deaths from Covid-19 started very slowly in December through February. But then in March, the number of deaths climbed markedly. This illustrates the two striking features of exponential growth - the "flat" part with a very slow increase, followed by a "steep" part with a very rapid increase.

Among the biological systems that also follow an exponential growth curve are bacteria, viruses, and cancers. Here is a prototypical graph of the number of metastases in a patient.

In men who are PSA-recurrent after prostatectomy, it takes a median of 8 years for the first metastasis to become detectable (see this link). After that, I've seen that more than a year can go by between the detection of the first metastasis and the next one. Some researchers, who should know better, observed that in their patients who had early metastases treated with radiation, new metastases did not occur for a long time. They attributed the delay to the treatment rather than the natural history of metastatic progression  (see this link). It is impossible to know if there was a delay in progression without a randomized clinical trial.

What is really happening during this extended time period? The accepted theory is called "seed and soil." There are millions of cancer "seeds" in the serum, the lymph, around nerves, and hiding in various tissue reservoirs (mainly in bone tissue). While they appear to be quiescent, they are in fact changing the "microenvironment" of the tissue they are in. They are transforming the tissue to make it more conducive to prostate cancer growth, building networks of collagen, fat, blood vessels and nerves, influencing healthy cells to become cancerous, and preventing the immune system from destroying the new nests (see this link for a fuller explanation).

Because it takes such a long time to build up the metastases to the point that they are detectable by even our most sensitive PET/CT scan (the tumor detection limit is about 4 mm - millions of cells), it seems that there is little there and even less going on. This is called "oligometastatic" cancer. It seems like all the cancer can be picked off by playing whack-a-mole -- zapping the few detected metastases with intense radiation (called SBRT) as they are detected. In fact, it is well-established that SBRT provides excellent "local control." "Local control" means that the metastases are usually completely annihilated by just one or two "zaps" (see this link). Because the detected metastases are the source of almost all the PSA, PSA can fall to undetectable levels after such treatment of oligometastases. But the cancer is far from cured - the PSA has been treated, but the cancer is still micrometastatic and systemic.

Those who believe that such treatment can result in a durable remission believe that the immune system can clean up the rest of the cancer.  The ORIOLE trial (reviewed here) showed that SBRT created a T-cell response. If that T-cell response is sustained, they argue, the activated immune system can "clean up" the rest of the cancer. The skeptics argue that T-cell responses are usually not sustained. Trials of numerous immunotherapies (e.g., Prostvac, GVAX, GM-CSF, etc.) have failed to show a benefit because the early T-cell responses are countered by adaptive responses. Prostate cancer is notoriously "cold" to immunotherapies.

2. PSA-based Endpoints

What we really want to know is this: will the treatment enable patients to live longer? Overall survival is the gold standard of success of randomized clinical trials. The "problem" for clinical trials is that prostate cancer is such a slow killer, that it may take 15 years or more to discern a difference (see this link) if patients have localized or recurrent prostate cancer at the start. (For most other types of cancer, 5-year overall survival is more than adequate.) Clinical trials are often ended when half of the control group die (median survival). But, depending on patient characteristics at the start, median survival may never be reached within the duration of the clinical trial (see this link and this one and this one).

Prostate cancer-specific survival (how long before patients succumbed to their prostate cancer) is little better. It is also hampered by the fact that patients with prostate cancer may die of something else sooner, possibly because their cancer was debilitating. It is often unclear to the doctor who signs the death certificate whether the cancer was the end cause, a contributing cause, or a non-contributing factor. To get clinical trial results before new medical science and technology renders the results irrelevant, we want to use surrogate endpoints that are highly correlated with and predict overall survival.

The earliest endpoints that can be used to measure the success of a prostate cancer therapy are PSA based. All of the following surrogate/secondary endpoints are PSA based:

• PSA50 - the percent who had a reduction in PSA by 50% or more
• Nadir PSA - the lowest PSA reached after therapy (see this link)
• PSA doubling time (PSADT) - whether the therapy slowed PSA growth
• Biochemical recurrence (BCR) - depending on initial treatment, and there may be multiple salvage therapies, each with a PSA failure defined for it (see this link)
• Biochemical Recurrence-Free Survival (bRFS)
• Biochemical Disease-Free Survival (bDFS)
• Biochemical failure (BF)- rise in PSA by a pre-specified amount post-therapy
• Biochemical No Evidence of Disease (bNED)
• Time to BCR/ BF
• Time to start of lifelong ADT (based primarily on a pre-defined PSA failure benchmark)
• Failure-free survival (FFS) or Progression-free survival (PFS) or Event-free survival (EFS) - defined as BF or radiological progression or clinical progression or death. 

The following surrogate endpoints are not PSA-based:

• Clinical Progression-Free Survival (cPFS) - worsening of symptoms or performance status (see this link)
• Radiographic Progression-free Survival (rPFS) or Disease-free survival (DFS)- progression on scans or death
• Objective Response Rate (ORR) - tumor size or number reduction using RECIST criteria
• Change in Bone Scan Index
• Time to radiographic progression or failure
• Metastasis-free survival (MFS)
• Clinical progression - pain, bone fracture, spinal compression

As an example of circular reasoning, we can see in the ORIOLE trial that 6-month Progression Free Survival (PFS) was chosen as the primary endpoint. PFS was defined as  PSA progression (by >25% over nadir and by > 2 ng/ml) or radiographic progression or death. As we can readily see in the exponential growth curve, the odds of a new metastasis on a bone scan/CT are very low and there are not likely to be any deaths. Therefore, PFS was almost entirely PSA progression. But the protocol "treated PSA." It is therefore illogical to conclude, even for a Phase II trial, that oligometastatic treatment slowed progression.

(Update 8/25/2022) Deek et al. combined ORIOLE and STOMP (n=162) with extended follow-up. After 52.5 months of median follow-up, they report:

• Progression-free survival (PFS) was 11.9 mo. for metastasis-directed therapy (MDT) vs. 5.9 mos. for observation. (HR=0.44)
• Radiographic progression-free survival (rPFS) was not significantly different
• Time to castration resistance was not significantly different
• Overall survival was not significantly different
• PFS increased by about 5-6 months regardless of whether there were high-risk mutations (BRCA, ATM, RB1, TP53).
• rPFS did not significantly increase for either group.

What is confusing is the endpoint used in this analysis. 

Progression-free survival (PFS) = 

1. a PSA rise, or 
2. radiographic progression, or 
3. new symptoms, or 
4. initiation of ADT, or 
5. death.

In 52.5 months, there was very low mortality (5), and asymptomatic local control is good (3). Initiation of ADT (4) is always based on either rise in PSA (1) or radiographic progression (2). So with no difference in rPFS, the difference between PFS and rPFS is just PSA. This suggests that the extended follow-up found that MDT only treated PSA without any real impact on survival or progression of the cancer.

(Update 10/26/2022) Another example of circular reasoning can be seen in the EXTEND trial from MD Anderson. They randomized oligometastatic patients to receive metastasis-directed therapy (MDT) + ADT or ADT alone. They only evaluated "progression-free survival" which, at 22 months, was almost entirely lack of PSA progression. They claimed that the lack of PSA progression made it safe to give patients a break from ADT.

It is worth noting that radiation of the prostate ("debulking") has no survival or progression advantage when there are multiple metastases, only when the metastatic burden is low (see this link). The prostate is, of course, the source of all metastases, and an ideal environment for metastases to develop and grow. Metastasis-to-prostate spread has been observed. In a meta-analysis of the two debulking trials called STOPCAP M1, researchers found that there was a statistically significant reduction in PSA progression (by 26%), even when there was no benefit in terms of metastatic progression or survival. Treating PSA even by debulking the entire prostate is not in and of itself of any oncological benefit (there may be a palliative benefit, however).

3. Danger of Withholding Early ADT

While ORIOLE, STOMP, and SABR-COMET were Phase 2 clinical trials whose results were not meant to change practice, many patients and their doctors (often under pressure from patients) would like to believe they do. If the metastases are in places that are safe to irradiate (e.g., away from the mediastinum), there is little risk in doing so. However, if they do not understand the circular reasoning evident in the ORIOLE trial, they may put off therapies that are known to increase survival. There is also a risk of unreasonable expectations.

Some patients (and doctors) believe that by delaying ADT, they can increase their quality of life, and delay castration resistance. Neither is true. Contrary to popular belief, decreasing the intensity of hormone therapy and delaying its use brings earlier castration resistance and death. The strongest evidence for this comes from the STAMPEDE (on Zytiga and Xtandi), LATITUDE, and SPARTAN trials. Among men who were newly diagnosed with metastatic prostate cancer:

• Overall survival was longer if men used Zytiga + ADT.
• No difference based on the number of metastases
• Failure-free survival was longer if they used Zytiga  + ADT
• Overall survival was longer if men used Xtandi+ADT
• Survival was especially lengthened if there were fewer metastases 
• PSA progression-free survival was longer if they used Xtandi+ADT
• Overall survival was longer if men used Erleada+ADT
• PSA progression-free survival was longer if they used Erleada+ADT

A clear pattern emerges: early use of intensive hormone therapy prolongs survival and prolongs the time to castration resistance. Men who were oligometastatic benefited from early, intense hormone therapy.

The TROG 03.04 RADAR trial examined the duration of hormone therapy in high-risk men treated with radiation.  They found that, after 10 years of follow-up, men treated with 18 months of ADT survived longer, and reached castration resistance later compared to men treated with 6 months of ADT.

The TOAD trial looked at starting ADT at the first sign of recurrence vs. waiting for metastases to be detected. Men treated earlier reached castration resistance later. It also showed there was no major detriment to global health-related quality of life by starting ADT earlier (see this link).

Maha Hussain reported the results of a randomized clinical trial comparing intermittent vs continuous ADT in recurrent men with metastases. She found that:

• Time to castration resistance was not different for the two protocols (Figure S5)
• For men with minimal disease, overall survival was 6.9 years for those on continuous therapy vs 5.4 years for those on intermittent therapy. The trial was underpowered for this difference to reach statistical significance.
• It took 4-5 years for the survival curves to start separating - long follow-up is needed to detect survival differences.

Taken together, all these major randomized clinical trials show that the best way to use ADT in the oligometastatic setting is to use it early and heavily. Reducing the number of cancer cells as quickly and effectively as possible, even reducing those cells that haven't begun to measurably contribute to PSA, extends survival. The effect of evolutionary selection pressure allowing castration-resistant cells to survive is dwarfed by the reduction in sheer numbers. Circular reasoning may harm patients.

4. Future Clinical trials

We have learned some lessons about clinical trials for oligometastatic treatment:

• It has to have long enough follow-up, depending on the setting: at least 5 years for  newly diagnosed or recurrent men to allow time to get to the steep part of the exponential curve. It will take longer if more sensitive imaging is used.
• It must use radiographic progression-free survival, or similar, as its primary endpoint
• It must not use a PSA-related endpoint
• ADT must be used in at least the control group. It would be unethical to withhold the standard of care (see AUA Guidelines for Advanced Prostate Cancer (mHSPC 14-18)) .
• It should preferably use a PSMA PET/CT to locate metastases. The ORIOLE trial only found an advantage if patients were oligometastatic on both a PSMA PET/CT and a bone scan/CT. The use of more sensitive imaging will move the starting point to the left on the exponential curve, so it will take that much longer to detect a benefit.

These randomized clinical trials (RCTs) are currently active:

• The CORE RCT at Royal Marsden Hospital in London will have 5 years of follow-up (completion in Oct. 2024) and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
• The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in April 2025) and has radiographic progression-free survival as its primary outcome. 
• The PLATON RCT (among hormone-sensitive patients) in Canada will have 6 years of follow-up (primary outcome in July 2025) and has radiographic progression-free survival as its secondary outcome. Oligometastatic men who have never had their prostates treated with RT will have prostate radiation too in both arms. ADT is given in both arms, advanced hormonals and chemo at the physician's discretion.
• The STEREO-OS RCT (study completion in Jan 2026) in France will look at radiographic progression-free survival with follow-up of up to 3 years. 
• The FORCE RCT at the University of Michigan (only recruited 13, primary completion in 2023) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful among men with mCRPC as it is in men with newly recurrent disease.
• The VA STARPORT RCT (primary completion in 2025) in many VA hospitals in the US will randomize patients to systemic therapy + PET-directed radiation to 1-5 oligorecurrences or to systemic therapy alone. Unfortunately, they are using castration-resistance as their primary endpoint, which is problematic.
• The START-MET RCT (primary completion in 2025) in Spain will randomize recurrent and newly diagnosed oligometastatic (≤3 on bone scan/CT and ≤5 on PSMA PET) men to standard-of-care (ADT+2nd line HT+prostate RT) or standard-of-care + SBRT to all metastases. 2-year radiographic progression is the primary outcome.
• The SPARKLE RCT (primary completion in 2027) in Belgium randomizes oligo-recurrent patients to either (1) MDT alone, (2) MDT+1 mo.of ADT or (3)MDT+6 mo (ADT+enzalutamide). Primary endpoint is 5 new lesions on PSMA PET scan.
• The ADOPT RCT (primary completion in 2022) in The Netherlands randomizes oligo-recurrent patients to either MDT ± ADT. 2.5 yr MFS on PSMA PET scan.

SABR to oligometastases slows progression via immune response

Stereotactic Ablative Body Radiation (SABR, or sometimes, SBRT) significantly slowed metastatic progression in men with 3 or fewer metastases (oligometastatic). SABR is a form of concentrated radiation accomplished in 1-5 treatments.

The ORIOLE trial has been previously described in detail here. To recap, it was a small (Phase 2) randomized trial with 36 men treated with SABR to bone scan/CT-detected oligometastases. There were 18 men in the untreated control group. The men were followed for 6 months to see if there was any progression of their cancer. Progression was defined as either PSA progression or new metastases detected on bone scan/CT or physical symptoms of decline (e.g., pain). Of course, with only 6 months of follow-up, most of the detected progression was PSA progression. Phuoc Tran, the lead investigator of the ORIOLE trial, reported the 6-month results here:

• Progression-free survival (PFS) was 81% in the SABR group vs 39% in the control group.
• Median PFS was not yet reached in the SABR group vs 5.8 months in the control group.
• The time to progression was increased by 70% by the treatment.
• Progression has not been reached among those treated patients followed for over a year.

Although patients were only treated for metastases discovered on a bone scan/CT, they were also given a PSMA-based PET scan (DCFPyL). Those in whom no additional metastases were discovered by the PET scan fared better:

• PFS was 84% in the fully treated group vs 36% in those with undiscovered metastases.
• Median PFS was not reached in the fully-treated group vs 11.8 months in those with undiscovered metastases.
• Distant metastasis-free survival (i.e., metastases distant from the ones that were treated) was 29 months in the fully-treated group vs 6 months in those with undiscovered metastases.

PFS in men in whom there were any untreated metastases was not improved compared to untreated men. This seems to be an all-or-nothing sort of thing.

SBRT has been found in lab studies to elicit a strong immune response. It releases cancer antigens into the bloodstream that are detected by T-cells, which become activated to find more cancer. That T cell response to radiation is thought to contribute to its effectiveness (called "the abscopal effect"). The investigators tracked the T cell response and found a significant response in the SABR-treated men.

Progression-free survival when most of the progression is PSA progression is not the endpoint we need to evaluate this therapy. SABR "treats" PSA. "Treating PSA" would occur if the radiation only provides excellent local control, while not necessarily delaying progression elsewhere. PSA is secreted in proportion to the size of the tumors, so treating only the tumors will do nothing to stop the micrometastases that are elsewhere. However, the strong T-cell response found by this study suggests that there may be a true delay in progression and not only a delay in PSA. Also, the fact that distant metastases were delayed by almost 2 years among those who had all of their PSMA-detected metastases irradiated, suggests a true response.

This is an important first step toward discovering whether oligometastasis-directed therapy provides a benefit, and how it works. It does not yet provide the answer to whether there is a survival benefit to such therapy. It also does not answer the question of whether ADT can be delayed when radiation has been given. There are several, larger clinical trials that will answer those questions more definitively. Meanwhile, the patient with rising PSA after prostate therapy should consider:

1. A PSMA-based PET scan (available in some clinical trials, and probably widely available within a year).
2. Talking to a radiation oncologist about SABR treatment of metastases if all discovered metastases are in places where it is entirely safe to treat them
3. Not forgoing ADT adjuvant to SABR treatment until there is more proof.

First US randomized clinical trial of oligometastasis-directed SBRT

In a recent commentary (see this link), we saw that some clinicians are making unsubstantiated claims of cancer control from treatment of oligometastases (less than 5 detected metastases). Only a randomized clinical trial (RCT) can prove that there is any benefit to such treatment. Johns Hopkins has announced the first such RCT in the US.

Stereotactic body radiation therapy (SBRT) is the treatment of choice because it is precise, as well as convenient for the patient (usually completed in 1-5 treatments). It is important to distinguish between two different situations that may involve oligometastases:

1. Metastasis-directed SBRT after primary treatment (prostatectomy or prostate radiation) and any local salvage radiation has failed. This is sometimes called "metachronous" treatment of recurrent prostate cancer.
2. Radiation to the prostate and oligometastases in newly-diagnosed men, or men who are radiation- or surgery-naive but have progressed to castration-resistance.
3. Radiation to metastases for the purposes of pain palliation, or to prevent fractures or spinal compression.

In addition, the situation may be different depending on whether the oligometastases are in the visceral organs, bones, extra-pelvic lymph nodes, pelvic lymph nodes, or some combination of these.

Phuoc Tran is the lead investigator of the "ORIOLE" RCT (NCT0268058) at Johns Hopkins described at this link. It is a small, Phase 2 trial for men in situation A described above. It has some noteworthy characteristics:

• 36 men will receive SBRT, 18 men will receive standard-of-care treatment
• Oligometastases are diagnosed by bone scan and CT
• Patients will be balanced based on whether initial treatment was surgery or radiation, whether they've had hormone therapy, and whether the PSA doubling time was less than 6 months.
• The primary outcome will be radiographic or PSA progression (by >25% over nadir and by > 2 ng/ml) after 6 months.
• To be deemed successful, the treatment will have to reduce this measure of progression by 50%

There are several interesting secondary objectives of this RCT:

• identification of additional metastases using the DCFPyL PET/CT
• toxicity of treatment reported by doctors
• pain palliation reported by patients
• local control of metastases (see below)
• Number of circulating tumor cells (CTC)
• Genomic analysis of CTCs
• Immune (T cell) response to treatment
• Time until patients have to start life-long hormone therapy

We will see if the radiation activates a systemic T-cell response that may destroy cancer cells beyond the treated tumors (the abscopal effect).

It may seem odd that detection of fewer than 5 metastases by the DCFPyL PET/CT (developed at Johns Hopkins and now in expanded trials) is not a qualifying criterion. Perhaps they will change that for the Phase 3 trial. Or perhaps they want to prove the concept with a bone scan/CT because it will be several years before that PET scan (so far, the most accurate) is widely available and covered by insurance or Medicare. If it works for bone scan/CT-detected oligometastases, it will certainly work for DCFPyL PET-detected metastases.

Update (August 2017): Dr. Tran has made the following change in protocol:

We did change the criteria recently to allow men who had detectable disease on DCFPyL to enroll on the trial, BUT only if the DCFPyL did not show anything more than what is visible on conventional CT-AP and bone scan.  Our thought was that this would allow some patients of the "future" if you will (as PSMA-targeted imaging will be the SOC in 3-5 years) to be included on the trial, but because we do not allow men on the trial with DCFPyL scans that show us more than what is on conventional , we feel that still holds to original concept. 

It is also important to note what is not an objective of this early clinical trial. The outcome we most want to know is whether SBRT treatment of metastases extends overall survival. This 6-month trial will not tell us that. There is no doubt that local control will be excellent, but stopping the progression of 1-3 metastases does not necessarily mean that the cancer has been slowed down systemically at all. Certainly, PSA will fall as an immediate result of treatment. For those who are used to monitoring PSA as a measure of their cancer's systemic progression, this can be confusing. It's worth taking a moment to recall what serum PSA comes from in detectably metastatic disease. PSA is a protein on the surface of prostate cancer cells (and healthy prostate cells too.) It doesn't leak out into the blood from prostate cancer unless a tumor forms with its own blood supply. Tumor blood supply tends to be leaky, and so PSA is detected in the blood serum. Larger tumors with more blood supply put out more PSA. So irradiating those tumors and shrinking them is likely to eliminate the PSA they put out. But what about the micrometastases that do not yet have appreciable blood vessels? If there are thousands of them, will it matter that serum PSA was reduced for 6 months? No one knows the answer to that question and this Phase 2 study will not provide the answer. I hope they will provide radiographic progression-free survival separate from PSA progression-free survival.

For the answers to our most important questions we will have to look forward to the outcomes of some of the other RCTs that have longer follow-up than 6 months.

• The CORE RCT (active, no longer recruiting) at Royal Marsden Hospital in London will have 5 years of follow-up (completion in 2024), and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
• The STOMP RCT at University Hospital in Ghent had 2 years of follow-up looked at time to lifelong hormone therapy as its primary outcome (reviewed here). 
• The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in 2025) and has radiographic progression-free survival as its primary outcome. 
• The French RCT (recruiting, study completion in 2022) will look at radiographic progression-free survival with follow-up up to 3 years. 
• The FORCE RCT at the University of Michigan (primary completion in 2022) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful in among men with mCRPC as it is in men with newly  recurrent disease.

Targeting Bone Metastases with Radiation in Oligorecurrent Men has No Survival Benefit in Mayo Study

Oligometastases in bones

Metastasis-directed therapy (MDT) when there are only a few bone metastases (called "oligometastatic") is controversial. It can certainly relieve pain, and prevent fractures and spinal compression. It can also provide good "local control" (cancer in the irradiated metastasis is permanently destroyed) and reduce the PSA that those metastases put out. But is there any survival benefit?

Patients often ask radiation oncologists (ROs) for radiation of those metastases using targeted radiation (which I'll call "zapping"), and they ask their ROs to treat new metastases as they are detected. This is called "metachronous treatment," but I'll call it "whack-a-mole" Sometimes metastases appear in places where radiation treatment may be problematic, such as near vital organs or deep in the spine. The nagging question is whether such treatment really does the patient any good. With the approval of ever more sensitive PET scans, like the PSMA PET scan approved last week, patients will undoubtedly detect more metastases.

The Mayo Clinic has been one of the cheerleaders for MDT. They have posted a deceptive youtube video featuring their C-11 Choline PET scans showing only how good the local control is. What the video can't show is how those patients would have done without MDT - there was no control group ever used or shown in their video.

Perhaps to partially correct for the misleading video, Boeri et al. at Mayo retrospectively looked at 115 patients who had an oligometastatic recurrence to the bones (1-5 metastases):

• 115 patients were treated with SBRT. They had a median of 1 bone metastasis.
• 47 patients were treated with ADT-only. They had a median of 2 bone metastases.

This was not a randomized study, so it is entirely likely that there was "selection bias" -- those who received ADT-only may be because it was felt they would not be able to benefit from SBRT or that it might be unsafe. Patients who received ADT-only had a higher number of bone metastases and a higher PSA. All of those receiving MDT for bone metastases were also receiving ADT.

• The 5-year prostate cancer mortality was no different between the two groups
• The 5-year radiographic recurrence-free survival was no different between the two groups
• Among those with 5 years of follow-up, the time remaining free of the next significant systemic therapy (e.g., chemo, Zytiga, etc.) was longer for those getting zapped. However, it should be noted that the decision to give an additional significant therapy is a physician decision based on many factors, including patient status, number of metastases, and PSA. Because number of metastases and PSA are changed by MDT, and those receiving MDT started with one less metastasis, the physician may feel pressured to start a new therapy sooner in patients receiving ADT-only.

Pending confirmation from long-term randomized clinical trials of MDT to oligometastases in bones, there is no evidence of oncological benefit.

Oligometastases in Pelvic Lymph Nodes (PLNs)

MDT of oligorecurrent metastases that are only in pelvic lymph nodes (PLNs) is less controversial. Lymph is a slow-moving fluid, and metastatic cancer cells emerging from the prostate might get trapped in the lymph nodes that drain the prostate. So it has been hypothesized that treatment of the PLNs when a few are found to be cancerous may still provide a cure. This has not yet been proven in a randomized clinical trial, but there is observational evidence of a significant benefit to salvage whole-pelvic radiation (see this link).

What is controversial about the way they are treated at the Mayo Clinic is that only those cancerous PLNs and a small margin around them were surgically removed, and whole pelvic salvage radiation wasn't routinely given. They were treated in any of three ways:

1. Salvage Pelvic Lymph Node Dissection (sPLND). Jeffrey Karnes at Mayo is one of the few top surgeons in the US who does this difficult surgery. It is difficult because PLNs detected on a PET scan can be very small. They are invisible, can be hidden in fat deposits, and are very difficult to find. There are innovative techniques like fluorescent or gamma-ray PSMA indicators that can facilitate detection. Patients treated with sPLND also received 6 weeks of bicalutamide.
2. External Beam Radiotherapy (EBRT) to PLNs as part of salvage radiation treatment (SRT). At Mayo, 72% received salvage IMRT to the identified PLNs plus a large margin around them, while 28% received SBRT to just the identified PLNs plus a small margin around them. This was typically done along with 12-18 months of ADT.
3. ADT-only, Patients treated with either of these two forms of MDT were compared to patients who received ADT-only, which is the current standard-of-care. Again, this was not part of a randomized clinical trial, so it is likely that the ADT-only patients were not offered MDT for a reason. Most importantly, about half had cancerous LNs in the retroperitoneum or abdomen (Stage M1a) - already outside of the prostate drainage area (Stage N1), and they had more positive LNs. In contrast, only 9% of the sLND group  and 19% of the EBRT group had cancerous LNs outside the pelvis. The ADT-only group had much further progression at the time of treatment.

After a median follow-up of 47 months:

• Prostate Cancer-specific mortality was 13.5% for ADT-only, 9.5% for EBRT, and 6.3% for sLND (the difference between ADT-only and sLND was statistically significant)
• Radiographic recurrence was 65% for ADT-only, 40% for EBRT, and 61% for sLND.
• Castration-resistance was 39% for ADT-only, 19% for EBRT, and 21% for sLND.
  • The median time until castration-resistance set in was 59 months for ADT-only, 73 months for EBRT, and 98 months for sLND.
• Second-line systemic therapies were offered to 43% for ADT-only, 29% for EBRT, and 24% for sLND.
  • The median time until the therapies were offered was 28 months for ADT-only, 32 months for EBRT, and 44 months for sLND.
• Inexplicably, the percent of cancerous lymph nodes outside of the pelvis (% M1a) was not included as a variable to correct for in their multivariable analysis, and was largely ignored.

The authors found an association between MDT and radiographic progression in their retrospective sample of patients. However, it leaves unanalyzed how much of that association is due to the extraordinarily high rate of out-of-pelvis progression already present in the ADT-only treated patients. In fact, it seems likely that that is the reason they didn't receive MDT. 

They also make the same error with respect to castration-resistance and use of second-line therapies that they made in their bone MDT analysis; i.e., they "treated PSA" with their MDT, so they can't use castration-resistance and time to second-line therapy as useful endpoints. Tellingly, radiographic recurrence is similar for ADT-only and sLND, while EBRT is lower, possibly only because of the longer use of adjuvant ADT with EBRT.

Another open question is whether whole pelvic salvage radiation might have been more effective than the limited margins they used at Mayo. With the more accurate PSMA PET scans, ROs are able to treat the entire PLN area with radiation boosts given to the detected ones. The RTOG-consensus treatment area has recently been expanded (see this link). It's important that patients understand the detection limits of even the best PSMA PET scan: metastases smaller than 4 mm, and those that put out only small amounts of PSA remain invisible.

(Update 12/30/2020) Farolfi et al. reported on 16 patients who received sLND based on PSMA PET scan detection, and still had persistently detectable PSA 6 weeks later. They were given a second PSMA PET scan. Additional cancerous PLNs were found in 56% (in an additional 31%, cancer was found in non-pelvic LNs). In 63% of patients, the PLN cancers were in at least one of the same sites. This shows how poor surgical dissection is for PLN metastases, even with PSMA PET guidance.

Other articles about studies of oligometastatic prostate cancer:

Treating PSA

ORIOLE RCT

STOMP RCT

SABR-COMET RCT

Unwarranted Claims

Whole pelvic salvage radiation may be better than precisely targeted lymph node salvage radiation

Debulking the prostate in newly diagnosed oligometastatic men