Showing posts with label oligometastatic. Show all posts
Showing posts with label oligometastatic. Show all posts

Friday, July 10, 2020

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.

"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 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:
  • 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
  • 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.

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 (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 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 PLATON RCT (among hormone-sensitive patients) in Canada will have 6 years of follow-up (primary outcome in 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 (recruiting, study completion in 2022) 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 (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.

Tuesday, September 17, 2019

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.

Monday, April 29, 2019

Is there an oligometastatic state for prostate cancer?

The concept of an "oligometastatic state" is that there exists an early stage where metastases are few in number and are in some way different from metastases that develop later. It also means that there are no micrometastases in systemic circulation (in bone and lymph) and in reservoirs like bone, nerve cells, lymph nodes and other organs. If such a state exists, the cancer can be picked off, like dandelions in a lawn, and the person can be cured.

The alternative concept is that cancer spread is always polymetastatic. Thousands of cells are released from the primary tumor. They find their way to sites where they change the tissue they land in, making it amenable to future growth. This is called "seed and soil." A metaphor might be mushrooms growing at the base of an oak tree. The mycelium extends everywhere throughout the soil and into the roots of the tree. Occasionally, a mushroom crops up. You can pick all the mushrooms you want, but the fungus is never destroyed. There is no way to destroy the fungus short of destroying the roots of the oak tree and sterilizing the soil. This is what "systemic" means.

It is well known that tumor cells must undergo a genomic change called epithelial-to-mesenchymal transition (EMT) before they are capable of traveling and living outside of their original environment. Metastasized cells do not look like or behave like the original tumor in its original tissue; they are phenotypically different.

Are all cancers alike?

There are certain "hallmarks of cancer." To qualify as a cancer, it must be malignant, destroying healthy tissue. Most cancers multiply rapidly, losing the ability to self-destruct when its DNA goes awry (apoptosis). They are usually immortal and evade destruction by the immune system. They can travel from one place to another. Solid tumors change the structure of their host tissue and usually generate their own blood supply and nerve innervation (see cancer as a tissue-based disease).

But all cancers are different. Unlike most other solid tumors, prostate cancer is usually originally multifocal in the prostate. While some cancers can be cured by surgically removing the original tumor, the whole organ must be removed (or irradiated) for prostate cancer. Foci may be a centimeter or more apart, so it is known to have a strong signalling mechanism that changes host tissue. It has a predilection for lymph nodes and bone, where it usually creates osteoblastic lesions (bone overgrowth). It is activated by an androgen receptor, which eventually becomes impervious to androgen deprivation. Tumors tend to be hypoxic, and have low immune-cell infiltration. They are relatively radioresistant, and are not appreciably killed off by non-taxane chemotherapy. There are multiple growth pathways - block one and others predominate. It is also abnormally slow growing. It may take many years for EMT cells to originate. The time from the first detectable metastasis to the second may be years apart. Unlike other cancers, prostate cancer metastatic cells generate energy for reproduction from lipid metabolism at first. Many years later, glycolysis may come to predominate (as it does in most other cancers).

To determine if there is such a thing as an "oligometastatic state" it is therefore necessary to show that such a state exists for every kind of cancer. The first step is to show plausibility. With high throughput sequencing it may be able to distinguish the genomics of early metastases from later ones. However, because genetic breakdown is a characteristic of cancer, it is also necessary to show that the early clones are phenotypically different from later clones. If early clones lack the ability to disseminate and prepare the "soil" for metastatic progression, that would create a case for an oligometastatic state.

It is also necessary to show that such a state exists for every type of cancer, or at least to find the cancers in which such a state exists. One cannot just assume that all cancers are alike in this regard.

The SABR-COMET Phase 2 Trial

Palma et al. recruited 99 patients at 10 hospitals in Canada, Scotland, Australia and the Netherlands from 2012-2015. Patients had 1-5 metastases, and were randomly assigned to high-intensity metastasis-directed radiotherapy (SABR or SBRT) or systemic standard of care. After 2 years median follow-up, there were:

  • 66  patients in the SABR group
  • 33 patients in the control group
  • Most had 1-3 metastases: 94% in the control group, 93% in the SABR group
  • SABR dose was most commonly 35 Gy in 5 treatments,  60 Gy in  8 treatments, and 54 Gy in 3 treatments
  • 12% received additional SABR for disease progression


After a median follow-up of 25-26 months:

  • Overall mortality was 36% for SABR, 48% for control (Hazard Ratio = .75)
  • Overall survival (median) was 41 months for SABR, 29 months for control (Hazard Ratio = 0.57; p=0.09) Note: they prespecified that anything above 80% confidence would be sufficient to expand to a Phase 3 study.
  • 39% had metastatic progression in the SABR group, mostly new metastases
  • 61% had new metastases in the control group
  • Grade ≥2 adverse events: 9% in the control group, 29% in the SABR group
  • 5% of the SABR group died as a result of treatment: radiation pneumonitis, pulmonary abscess, and subdural hemorrhage from surgery to repair a perforated gastric ulcer


The authors are cautious about the toxicity, but optimistic that their study provides proof of an "oligometastatic state." They have already announced two Phase 3 randomized clinical trials for people with 1-3 metastases and 4-10 metastases.

Skewed Distribution of Cancers Accounts for the Purported Benefit

The distribution of cancer types was vastly different in the SABR and control groups. Metastatic colorectal cancer, which has an 70% 2-year mortality rate, is twice as likely to appear in the control group as the SABR group; while metastatic prostate cancer, which has a 10% 2-year mortality rate is more than 3 times as prevalent in the SABR group. This skewed distribution accounts for almost all of the difference that the authors attribute to a treatment effect.


Type of CancerControlSABR
expected 2-year survival (approx)
n% of totaln% of total
Breast515%1320%50% (1)
Colorectal927%914%30% (2)
Lung618%1218%10% (3)
Prostate26%1421%90% (4)
Other1133%1827%
TOTAL3366
(1) https://www.nature.com/articles/bjc2015127
(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739317/
(3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096514/
(4) https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32486-3/fulltext


ControlSABR
Expected 2-year survival due to distribution35%48%
Expected 2-year mortality due to distribution65%52%
Hazard Ratio due to skewed distribution80% 
Reported Hazard Ratio75%

Because of the uneven distributions in the treatment and control, the hazard ratio does not reach 80% confidence and the hypothesis should be rejected. The authors believe that just eliminating prostate cancer patients from both groups would correct the flaw, but they would have to eliminate colorectal cancer as well - I doubt the result would be significant with even 80% confidence. I believe the authors of the study erred in accepting the results even with 80% confidence for forging ahead with a Phase 3 randomized trial. The treatment effect, if any, is so small that their Phase 3 trial as specified is insufficiently powered to detect a treatment effect. They do not propose to stratify by type of cancer. Also, much longer follow-up is needed for prostate cancer.

On top of that, they have not made the case for an oligometastatic state, which would have to be true for every cancer type and not just a weighted average sum of them. They would also have to include genomic and phenotypic analysis of biopsied tissue when there are both few metastases and many in order to demonstrate plausibility.

Patients should note the mortality rate attributable to SABR of metastases. There is little risk in irradiating metastases occurring in safe locations, like the pelvic bones. There may be unacceptable risk in irradiating metastases near the heart, lungs, or digestive tract. Since there is no evidence that metastasis-directed therapy for prostate cancer improves survival, patients should not avoid systemic therapy (for which there is convincing evidence). Patients who are interested in SABR of metastases should talk to experienced radiation oncologists in large tertiary-care facilities.

Tuesday, December 19, 2017

Metastasis-Directed Therapy for Oligometastatic Recurrence - the STOMP trial

Metastasis-directed therapy (MDT) for recurrent oligometastatic prostate cancer is a very controversial topic. Researchers who should know better have made unjustified claims (see this link) and have even posted YouTube videos replete with "gee whiz" cases.

Now we have the first randomized clinical trial on the subject. It's a small Phase 2 trial (62 patients randomized to MDT or Surveillance) called STOMP and it only ran for three years (not long enough to detect survival differences in early metastatic patients). The objective of the study was not to see if MDT extended survival (which is what we really want to know), but to determine whether it extended the period before salvage ADT was required. The authors believe that if that more modest claim is realized, then a larger, longer Phase 3 randomized trial to detect any survival improvement would be justified.

"Oligometastatic" was defined as 1 to 3 detected metastases. Metastases were detected using a Choline PET/CT scan. Metastases could be in the pelvic lymph nodes (stage N1) or in distant locations (stage M1). Due to the small sample size in this study, there was a serious disparity in the number of metastases: the MDT group had fewer detected metastases (58% had only one) than the Surveillance group (29% had only one). From the start, the median number of detected metastases was 2 in the Surveillance group vs. only 1 in the MDT -- the Surveillance group started with a significant disadvantage.

"Recurrent" means after primary prostatectomy or radiation therapy has failed, and in some cases, salvage therapies have failed as well. Primary therapy may have included extended pelvic lymph node dissection (ePLND) with prostatectomy or whole-pelvic radiation along with prostate radiation. In this study, most (76%) had prostatectomy and many of them (85%) had failed salvage radiation.

"Metastasis directed therapy" included spot radiation (SBRT) to detected metastases, or surgical removal of lymph nodes or soft-tissue metastases. In this study, 55% of patients had lymph node metastases. If the patient had already had whole pelvic radiation or ePLND and any cancerous pelvic lymph nodes were detected, only those lymph nodes were removed. Otherwise a salvage ePLND was performed. Some patients were treated with SBRT to individual lymph node metastases, but none were treated with radiation to the whole pelvic lymph node field. Bone metastases were treated with SBRT (in 45% of patients), and one lung met was surgically removed. If metastases were detected on follow up in the MDT group, they were treated if there were 3 or fewer (i.e., whack-a-mole).

"ADT-free survival" is the time from randomization to the time ADT was required for any of three reasons: symptomatic progression, progression to more than 3 metastases (called "polymetastatic progression"), or local progression of baseline-detected metastases. PSA progression was not an adequate reason to start ADT. It is well known that MDT will result in a temporary reduction of PSA that is not sustainable. The goal of any therapy is to treat the disease, not to treat the PSA.

After a median follow up of 3 years, Ost et al. reported that:
  • Median ADT-free survival was 8 months longer in the MDT group
    • 21 months  in the MDT group vs. 13 months in the Surveillance group
    • The difference was not statistically significant with 95% confidence, but was within the pre-specified 80% confidence range*
  • 39% had not started ADT in the MDT group vs. 19% in the Surveillance group
  • 61% started ADT for polymetastatic progression (half of them within one year of treatment) in the MDT group vs 55% in the Surveillance group
  • Location of metastases did not affect ADT-free survival
  • 58% had only 1 metastasis (median=1) at baseline in the MDT group vs 28% in the Surveillance group (median=2).
  • There was no significant difference in ADT-free survival (even at 80% confidence) among those who had a PSA doubling time (PSADT) at baseline of >3 months (only 10 men in each group had a PSADT ≤ 3months)
  • Treatment toxicity was mild
* The authors pre-specified an 80% confidence interval for this pilot study. This is unusual. Ostensibly, this was because they knew they would be implementing an expanded Phase 3 study and only wanted to check for gross differences in this Phase 2 pilot study.  In a more conventional statistical analysis, the hypothesis that MDT affected ADT-free survival would have been rejected. Also, at 80% confidence, they should have accepted the hypothesis that the higher number of metastases in the Surveillance group made a difference - but the authors seem to ignore the inconsistency. Because of this, patients and clinicians are cautioned to not make changes in treatment decisions based on this.

Because "polymetastatic progression" was the endpoint used to determine whether ADT was indicated for treatment, and 39% of the Surveillance group were already starting with 3 metastases at baseline, it is surprising that it took 13 months for a single new metastasis to become detectable in that group, and that for 19% of the Surveillance group, a fourth metastasis never became detectable throughout the 3 years of follow up. In the MDT group, four new metastases had to become detectable after the first ones were eradicated by treatment. 31% (11 of 31) had a second round of treatments, and 6% had a third round of treatments before the sudden appearance of four or more detectable metastases all at once. By setting "ADT-free survival" as the endpoint and making it conditional upon the simultaneous detection of four metastases, they guaranteed that the endpoint would be reached earlier in the Surveillance group. What is surprising is that even with that built-in bias, the difference was not significant with 95% confidence. It is also worth noting that in a pre-planned subgroup analysis, there was no significant difference in ADT-free survival (even at 80% confidence) among those who had a PSA doubling time at baseline of >3 months. Patients with "indolent" metastases did not benefit from MDT. This study does not show that metastatic progression was slowed by MDT. Only an improvement in overall survival time can show that.

This study used a Choline PET (F18, I presume) scan to detect metastases. We recently saw that there is a clinical trial at Johns Hopkins to detect and treat oligometastases using the more accurate PSMA PET scan. While outcomes may be improved with a more accurate scan, it will undoubtedly eliminate many patients from the oligometastatic pool of patients.

This study did not investigate whether salvage radiation to the entire pelvic lymph node field would have had better outcomes than spot SBRT treatment. We are still not very good at finding cancerous lymph nodes (see this link) and the treatment field is inadequate most of the time (see this link).

Importantly, this study does not address whether it is beneficial or detrimental to delay start of ADT. The 8-month delay in the start of ADT may result in 8 months that the cancer is systemically multiplying and evolving. The TOAD trial suggested that early amelioration of the micrometastatic burden in recurrent patients may have a greater influence on survival than any selective evolutionary pressure that starting earlier may exert. It furthermore showed that overall quality of life was unaffected by the earlier ADT start. ADT is the standard of care when metastases have been discovered. Clinical trials of oligometastatic MDT should include ADT use in both arms to give a realistic appraisal and to be ethical.

While this trial was done among recurrent patients, the STAMPEDE trials (see this link and this link), the CHAARTED trial, and the LATITUDE trial among newly-diagnosed patients proved that aggressive systemic therapy, as early as possible after metastases are discovered, provides a significant survival advantage.

It is important that patients understand the very real risk of avoiding systemic treatment when there are known metastases. While it risks little to treat those oligometastases that can be safely treated, we must understand that there is no known survival benefit to doing so. There is a known risk to delaying systemic therapy. Dr. Ost wrote to me, "MDT does not replace ADT and our results should not be interpreted in that way."


Thursday, July 6, 2017

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.





Wednesday, May 3, 2017

Unwarranted conclusions about oligometastatic treatment

Some patients wonder, if they just have a couple of metastases, why can't those be "zapped" by a few quick SBRT treatments and thereby be cured of their prostate cancer? Or, even if they can't be cured, can't the cancer's progression be slowed down?

To address those questions, we have to understand what is called the "natural history" of prostate cancer progression. Even high-risk prostate cancer is quite a different sort of thing from metastatic prostate cancer. High-risk prostate cancer cells, for example those with Gleason score 5+5, are incapable of thriving outside the prostatic environment. At some point they undergo a genetic transition called epithelial-to-mesenchymal transition (EMT), after which they can freely move throughout the body in the lymph, blood or the spaces around nerves, and plant themselves and accumulate in distant locations. Sometimes those microscopic metastases can circulate for a long time before planting themselves somewhere new. Sometimes they can plant themselves but do not proliferate appreciably for a long time. Sometimes they can alter the tissue environment in a new place (especially bone tissue) so it is more amenable to clumping and proliferation. Sometimes those cells get caught in lymph nodes (lymph nodes may be thought of as filters to catch cellular debris, including cancer cells) and proliferate there. All of these processes occur simultaneously.

Let's try to gain an understanding of how many cancer cells are in systemic circulation at a given time. We have found that a count of 5 or more circulating tumor cells (CTC) per 7.5 ml of blood is associated with metastatic progression (the prostate is also always shedding cells, healthy and cancerous, that are not capable of metastatic progression). So a 200 lb. man with no detectable metastases and with a CTC count of 5, who has 6.5 liters of blood, will have at least 4,300 circulating tumor cells. In addition, there will be many thousands more lodged in and between tissues. Now, to be detectably metastatic with today's best imaging technology, a clump of tumor cells must be at least 4 mm long. The cancer cell may be about 10 μm, so there are at least 200,000,000 of them before the smallest metastasis becomes detectable. All of those cancer cells are constantly shedding and forming new daughter metastases elsewhere. So cancer cells may be circulating, clumping, and growing for a long time before they form a big enough clump to be detectable.

It should be clear that there is no possibility of a cure without systemic treatment. Currently, we have no systemic treatments that can cure metastatic prostate cancer.

How long does it take to go from the first microscopic metastasis to the point where it is detectably metastatic? That's impossible to know with any accuracy for a given individual. What we do know is that on average it takes 8 years from the time a man is biochemically recurrent after prostatectomy to the time when the first bone metastases are detected on a bone scan (see this link). That represents the accumulation of perhaps a billion cells in one place. It may be years more before the next bone metastasis is detected. Lymph node metastases are the slowest progressing of all the kinds that prostate cancer causes. It is not unusual for many years to pass between new detectable lymph node metastases. The new PET scans detect metastases much earlier, when the tumors are 80% smaller.

Now we can come back to the question of whether early detection and treatment of metastases can at least slow progression and increase survival. A C-11 Choline PET/CT may be able to reliably detect metastases when the PSA is only about 2 ng/ml, rather than 20 ng/ml for a bone scan. The newer PSMA-based PET/CTs may detect metastases even earlier, say at about 0.5 ng/ml. So, if any treatment is given when metastases are detected this early, and then we find that it takes a very long time - many years - to detect subsequent metastases, did the treatment delay progression? This effect is called "lead-time bias."

Adding to the confusion is the fact that those big clumps of detectable cancer cells are the source of much of the PSA. When those detected metastases are "zapped," the cancer cells in them no longer secrete PSA and the cancer is controlled locally. We also know that old clumps of cancer are a rich source for new tumor cells. Is it possible that reducing at least that local source of metastatic cells will slow progression?

The only way to answer this question with any assurance is to conduct a randomized clinical trial. Some patients will get the treatment, in this case SBRT to the detected metastases, and the other patients will get standard of care -- hormone therapy. Then we will be able to see how long it takes for new distant metastases to be detected for the treated group as compared to the control group; and more importantly, did the treated group survive longer?

Triggiani et al. retrospectively report on patients at several centers in Italy (for some reason, most of these studies have been done in Italy) who had 3 or fewer detected metastases treated with SBRT.

  • About 100 patients with a recurrence after primary treatment with metastases detected by Choline PET scan (the oligo-recurrent group)
  • 41 castration-resistant patients with metastases detected by bone scan/CT (the oligo-CRPC group)

After a median of 20-23 months of follow-up, distant progression-free survival was:

  • 43% after 2 years for the oligo-recurrent group
  • 22% after 2 years for the oligo-CRPC group

The authors conclude:
"Stereotactic body radiotherapy seems to be a useful treatment both for oligo-recurrent and oligo-CRPC."

We are now ready to understand why this is an unwarranted conclusion. There is no way to know, based on the data they provided, whether the treatment was "useful" or not. We have no way of knowing what the distant progression-free survival would have been had they not received the SBRT treatment. Inexplicably, several groups from Italy also reached such unwarranted conclusions.

In fact, in a meta-analysis with longer-running follow-up data, Ost et al. (commented on here) found that for oligo-recurrent patients, distant progression-free survival was:

  • 31% after 3 years, and only
  • 15% after 5 years

In other words, the vast majority (85%) of men with SBRT-treated oligometastatic recurrence had detectably relapsed within 5 years. Given the lead-time bias and the slow rate of detectable early progression anyway, it is impossible to say that the radiation treatment accomplished anything. Until we have some proof, patients should approach metastatic treatment for anything but palliative purposes with caution. There is currently no evidence, none, that treatment of metastases has any effect on survival.

In spite of the lack of evidence, if a radiation oncologist looking at the patient's anatomy finds metastatic radiation to be safe, then there is little reason other than cost to abstain from it. However, a patient is taking a survival risk if he puts off hormone therapy in order to find metastases, especially in light of early evidence from the TOAD study.

Treatment of pelvic lymph nodes is a special case. If a patient is able to detect any metastatic pelvic lymph nodes, and he is convinced that he should have treatment at all, he should consider treatment of the entire pelvic lymph node field rather than isolated pelvic lymph nodes. One has to treat what one can't see as well as what one can see; again, provided that it is safe to do so. Safety may be questionable because of anatomy, lack of visceral fat, history of bowel inflammation, and previous pelvic radiation. The evidence for efficacy is mixed. Some retrospective data analyses (Rusthoven, Abdollah, Jegadeesh) found a survival benefit, while some did not (Kaplan and Johnstone). These retrospective studies are notoriously confounded by selection bias (i.e., the patients who got the therapy were the most likely to improve anyway). We await the outcomes of the randomized clinical trials before we have a more definitive answer.

There are currently several randomized clinical trials that have begun. Few are large enough or scheduled to run long enough to detect a survival benefit for prostate cancer. So far, the trials are in London, Montreal, France, Ghent, Italy and at Johns Hopkins.




Sunday, December 11, 2016

PET scans for prostate cancer

In the last few years there has been an explosion in the number of new PET scan indicators. I thought it a good idea to provide some background and an update.

Bone scans

PET scans may be understood as an improvement over bone scans. The traditional way of finding distant metastases is to use a technetium bone scan and CT. There are several problems with bone scans:
  • they show bone overgrowth, which may be bone metastases, but may just be arthritis or old injuries
  • only a bone biopsy can tell for sure, and it's not often feasible when the suspected mets are small or inaccessible
  • they reveal few mets when PSA is below 10-20 ng/ml or when PSA is stable
  • they only show bone mets, not soft tissue
The main advantage is that they are relatively inexpensive.

The principal uses are: 
  • to rule out bone mets in high risk patients prior to curative treatment
  • to diagnose metastases that may respond to chemo, Xofigo, or spot radiation
  • to track response to treatment among metastatic patients.

PET SCAN USES

Inherent limitations

The new PET scans are better than previous ones in terms of the size of the metastases they can detect, but they do not detect all metastases.

  • A cancer cell is many times smaller than the resolution of the CT or MRI. 
  • The activity of the cancer cell seems to influence whether it is detectable on any of the scans. 
  • There is "noise" in even the most specific tracer, with no sharp delineation between signal and background.

Salvage Radiation

The most important use of these new PET scans is to rule out salvage treatment when it would be futile. For men who have persistently elevated PSA after prostatectomy, or who have had a recurrence (nadir+2) after primary radiation treatment, a PET scan showing distant metastases can spare the man the ordeal and side effects of salvage treatment.

For salvage after primary radiation failure, it is necessary to locate areas within the prostate where the cancer may still be localized.  Memorial Sloan Kettering and the Mayo Clinic have effectively used PET scans to target areas within the prostate for salvage focal ablation or brachytherapy.

For salvage radiation after prostatectomy, it may be possible to identify areas of the prostate bed where spread is evident. While the entire prostate bed must be treated (most of the prostate cancer is below the limit of detection of even the most accurate PET/MRI scan), some radiation oncologists like to provide an extra boost of radiation to the detected cancer foci.

There has been accumulating evidence in the last few years (see this link) that very early salvage radiation treatment may improve salvage radiation outcomes over waiting until the PSA has risen above 0.2 ng/ml. Unfortunately, none of our PET indicators are any good at detecting metastases when PSA is below 0.2 ng/ml. It is unlikely that there are any distant metastases when PSA is that low, but there are some relatively rare forms of prostate cancer that metastasize without putting out much PSA. This leaves the patient without any assurance that salvage radiation will be successful. Perhaps the new PORTOS genetic test will be able to detect distant metastases biochemically, but this remains to be proven.

Pelvic Lymph Node (LN) Treatment

For men diagnosed with high risk prostate cancer, a difficult question is whether the pelvic lymph nodes ought to be treated, either with radiation or with pelvic lymph node dissection. Nomograms based on disease characteristics are used to determine whether the pelvic LNs merit treatment, but such nomograms are often inaccurate. A CT scan can sometimes identify lymph nodes enlarged (>1.2 cm) due to cancer. However, some LNs are only slightly enlarged (0.8-1.2 cm), and some cancerous LNs are not enlarged at all (<0.8 cm). LNs are usually enlarged by infection, so size alone is not a good indicator of cancer. An advanced PET scan can sometimes detect cancerous LNs. This may aid the decision on whether to have whole pelvic treatment for men with high risk cancer. Men who have already had radical prostate therapy that may have included radiation (primary or salvage) to other areas (i.e., the prostate or prostate bed) may face a similar decision as to whether to treat the pelvic LNs with radiation.

Just as it is necessary to irradiate the entire prostate bed and not just the detected foci when giving salvage radiation after prostatectomy, it is probably necessary to treat the entire pelvic LN area, and not just individual LNs, when cancer is detected anywhere in the pelvic LN area. Of course, such a decision must be balanced against the risk of side effects. There are ongoing clinical trials (RTOG 0534 for salvage therapy and RTOG 0924 for primary therapy) to determine whether such treatment provides any survival advantage when LN involvement is suspected. The STAMPEDE trial included an arm where patients were node positive (but negative for distant metastases) and were treated with radiation. Short term follow-up demonstrated an improvement in failure-free survival of 52% among those who had treatment.

Oligometastatic radiation of distant metastases

Although some have theorized that there is a stage in prostate cancer metastatic progression where the cancer is still curable, or where it can be delayed by removal of 1-3 detectable metastases, this theory has never been proven. In fact, a meta-analysis this year (see this link) showed that metastatic progression continues in almost all men despite such treatment. The possibility remains that progression may be slowed by spot treatment, although this remains uncertain as well. The natural history of metastatic progression is often very slow in early stages, with years between the first few metastases. The reason for this may be because the tissue in metastatic sites must first be biochemically transformed by signals from micrometastases in order to accommodate the growth of larger metastases. This preparation of fertile "soil" in which metastatic "seeds" can grow may take some time. PET scans for detection undoubtedly introduce lead-time bias into the calculation; i.e., the time between the first and second detected metastasis is certainly longer because a more sensitive PET scan was used, and not necessarily because the first detected metastasis was spot-treated.

In spite of the uncertainty concerning efficacy of spot treatment, patients often want to treat whatever can be detected. When such metastases are detected with sensitive PET scans and are in locations amenable to spot treatment with SBRT, and there is minimal risk of radiation damage to nearby organs, it is hard to argue against such use. However, the patient should understand that there is so far no evidence that such treatment will provide any benefit. He should also understand that detectable metastases in distant sites means that his cancer is systemic. There are thousands of circulating cancer cells and undetectable cancer cells already lodged in tissues. For this reason, it is never a good idea to delay systemic therapy (e.g., hormone therapy) in order to wait for PSA to increase to a point where metastases become detectable on a PET scan. The TOAD randomized clinical trial suggested that immediate hormone therapy at the first sign of recurrence after curative options were exhausted cut 5-year mortality in half compared to waiting for PSA to rise and metastases to become detectable.

Palliative treatment of metastases

Metastases can cause pain and interference with organ function. Bone scans can find larger bone metastases, and they are the ones most apt to cause pain, fracture, or spinal compression. Metastases in weight-bearing bones may be spot-radiated with SBRT to prevent such problems and to relieve pain. In the unusual event that a bone scan can't locate them accurately enough for SBRT treatment, a PET scan may be used.

Bone scans do not detect metastases in soft tissue, while most PET scans (other than the NAF18 PET) can. A PET scan may locate metastases in organs that may be biopsied or treated with radiation or other therapies, like embolization or ablation.

Multiple metastases

The CHAARTED study has taught us that prostate cancer with multiple distant metastases behaves in a different way and reacts to different therapies compared to prostate cancer with a low metastatic burden. Although the metastatic burden in the CHAARTED study was based on bone scan and CT, there may be a potential to identify patients who may respond to earlier systemic therapy if a PET scan were to be used. This use has yet to be explored.

Tracking success of treatments (radiographic progression)

PSA is not always the best measure of whether a treatment is successful and ought to be continued. Because they destroy cancer cells, some therapies may actually raise the PSA level for some time immediately following treatment. Chemotherapy does not always immediately reduce PSA, but the patient wants to know whether the potentially toxic treatment should be continued. Most of the time, serial bone scans can provide an adequate radiographic assessment. However, in patients with low PSA or low metastatic burden, serial PET scans may sometimes provide a more accurate assessment.

Initial detection, active surveillance, focal therapy, dose painting

Just as multiparametric MRIs can be used to detect significant prostate cancer when suspicion remains after a first negative biopsy, a PET scan can conceivably be used for such a purpose (as in this clinical trial). PET scans can also be used to track progression of prostatic foci in patients on active surveillance. It is hard to justify the cost for such purposes, and there is as yet no evidence that it is any better than a multiparametric MRI. In light of the recent evidence that multiparametric MRI may fail to delineate up to 80% of detected prostatic index tumors, they may find future use of PET/MRI in contouring treatment areas for focal ablation and for dose painting (see this link).


How PET scans work

Positron Emission Tomography (PET) is a way of creating a 3D anatomical image. Instead of using X-rays, as a Computerized Tomography (CT) scan does, it detects positrons, which are positively charged electrons (which do not exist in nature). When a positron encounters a normal negatively-charged electron, they annihilate each other and release 2 gamma rays in opposite directions. When the machine detects such a pair of gamma rays, it extrapolates their source position, putting an image together. The PET scanner is combined with a CT scanner in the same device in order to provide anatomic detail.

As a cautionary note, PET scans do expose the patient to significant amounts of ionizing radiation from both the PET indicators and the simultaneous CT scan. It is not something one wants to do frequently.

PET emitters are short-lived radioisotopes that are created in a nearby cyclotron. Commonly used ones include carbon 11 (C11), fluorine 18 (F18), gallium 68 (Ga68), copper 64 (Cu64), zirconium 89 (Zr 89), and iodine 124 (I124). The choice of which one to use is based on cost, access, half-life, strength of signal, and ease of integration with the ligand. C11, for example, has an extremely short half life of only 21 minutes. This means it has to be manufactured very nearby where it will be incorporated into a ligand (like acetate or choline), and must be used immediately. F18 has a longer half-life (118 minutes) and has excellent detectability, but interferes somewhat with metabolism of acetate or choline. I124 has a long half-life (4.2 days) which may be too long for a patient who may have to remain isolated for the duration.

PET emitters are chemically attached (chelated) to molecules, called ligands, that have particular affinity for prostate cancer cells. Some ligands are metabolically active, meaning they are food for the cancer cell, but not as much for healthy cells. Other ligands are created to attach to specific binding sites on the surface or inside prostate cancer cells. Sodium fluoride (NaF18) replaces hydrogen with positronic fluoride when hydroxyapatite, the mineral that constitutes our bones, is actively accumulating in bone metastases.

Metabolic ligands

Because rapidly growing cancer cells metabolize a lot of glucose, fluoro-deoxy-glucose (FDG) has long been used in PET scans for cancer. Prostate cancer in its early stages does not metabolize glucose readily, so FDG can't be used until later stages.

Prostate cancer cells do metabolize fats, consuming choline and acetate. C-11 choline and acetate overcomes the interference problem of F-18 choline and acetate, but is very difficult to work with. Although the FDA has approved the C-11 Choline PET, only the Mayo Clinic offers it in the US. A few sites offer the C-11 Acetate PET, but it is expensive. It also requires a fairly high PSA, ideally ≥ 2.0 ng/ml, or fairly large metastases, to detect anything.

Fluciclovine has recently been FDA approved. It is incorporated into prostate cancer cells as part of amino acid metabolism. It can detect somewhat smaller metastases at lower PSAs.

PSMA ligands

95% of prostate cancers express a protein called Prostate-Specific Membrane Antigen (PSMA) on the surface of cells. There are a variety of ligands that are attracted to it. Some of the ligands are antibodies (like J591), some are shortened antibodies (called minibodies, like Df-IAb2M), and some are small molecules (peptides, like PSMA-HBED-CC or DCFPyL). PSMA-targeted ligands may accumulate in salivary glands, tear glands and kidneys, and urinary excretion may interfere with readings in the prostate area. PSMA has also been found on the cell surface of some other kinds of cancer. New PSMA ligands are still being developed and tried. So far, the one that seems to have the highest specific affinity for PSMA is called F18-DCFPyL. It detects more metastases at lower PSA than the others. 

Other ligands

There are other prostate cancer-specific molecules for which ligands have been developed and to which positron emitters have been attached.  One of the most promising is the bombesin or RM2 ligand that attaches to the gastrin-releasing peptide receptor (GRPR) on the prostate cancer cell. In pre-clinical studies, it outperformed C-11 Choline. Clinical trials have started. Clinical trials have begun on several PET ligands that are designed for other receptor sites: human kallikrein-related peptidase 2 (hK2), FMAU, Ga-68-Citrate, I-124-Prostate-Stem-Cell-Antigen, Ga-68-DOTATATE (Somatostatin receptor), F18-DHT (androgen receptor), Cu-64-DOTA-AE105 (uPAR receptor), Cu-64-TP3805 (VPAC receptor). or multiple radiotracers.

The winner (so far) is...

Based on clinical trials, below are various PET indicators in approximate rank order of their sensitivity to detect prostate cancer, and their specificity for detecting it exclusively:
  1. F18-DCFPyL
  2. F18-DCFBC
  3. Ga68-PSMA-HBED-CC (Ga68-PSMA-11)
  4. Fluciclovine (F18 - FACBC)/ Axumin
  5. C11-Choline/ C-11-Acetate
  6. F18-Choline
  7. NaF18
  8. F18-FDG
The following table shows the percent of patients who had metastases detected at various PSAs. F18-DCFPyL is much better than Ga68-PSMA at low PSA.  At PSAs between 0.5-3.5 ng/ml. it detected prostate cancer in 88% of recurrent patients, while Ga68-PSMA-11 only detected prostate cancer in 66% of the same patients - an improvement in sensitivity by a third. Next in line is fluciclovine, which was recently FDA approved. In 10 patients screened for recurrence at a median PSA of 1.0 with both Ga68-PSMA-11 and fluciclovine, the PSMA scan detected cancer in 5 of the 10 men that were negative on fluciclovine. In addition, positive lymph nodes were detected in 3 of the men using the PSMA scan that were undetected with fluciclovine (see this link). Most other PET indicators, like C-11 Choline or Acetate, or NaF18 are not at all reliable when PSA is less than 2.0.


Percent of patients in whom prostate cancer was detected by the PET indicator, broken down by the PSA of the patients



PSA range
Source
PET Indicator
<0.2 ng/ml
0.2- 0.5 ng/ml
0.5 -2.0 ng/ml
> 2.0 ng/ml

F18-DCFPyL


88% (0.5-3.5)


Ga68-PSMA-HBED-CC


66%  (0.5-3.5)

Ga68-PSMA-HBED-CC
31%
54%
88%
Ga68-PSMA-HBED-CC

58%
73% (0.5-1.0)
93% (1.0-2.0)
97%
Ga68-PSMA-HBED-CC

50%
69%
86%
F18-FluoromethylCholine

12.5%
31%
57%
Ga68-PSMA-HBED-CC


36% (PSA<1, PSADT>6 months)
95%
(PSADT<6 months)
Ga68-PSMA-HBED-CC
11.3%
26.6%
53.3% (0.5-1.0)
71.4% (1.0-2.0)
95.5%
Ga68-PSMA-HBED-CC
33.3%
41.2%
69.2% (0.5-1.0)
86.7% (1.0-2.0)
94.4%(2.0-5.0)
100% (>5.0)
Fluciclovine

37.5% (0.2-1.0)    77.8% (1.0-2.0)
88.6%


PET/MRI

PET scans are usually combined with simultaneous CT scans for image resolution. Siemens has a device that simultaneously provides a PET scan and an MRI. This enables  greater image resolution and the detection of smaller metastases than is possible with a PET/CT. (GE and Philips manufacture dual scanners rather than an integrated single scanner). The PET/MRI exposes the patient to a much lower dose of ionizing radiation than the PET/CT. These devices are expensive, and are only available at a few large tertiary care facilities. In one PET/CT vs. PET/MRI comparison using Ga-68-PSMA, the PET/MRI was able to detect 42% more metastases in recurrent patients, 10% more lymph node metastases, and 21% more bone metastases. In the US, PET/MRIs are in use at Mass General, Johns Hopkins, Stanford, UCSF, Washington University, Cleveland Clinic, and Memorial Sloan Kettering and several others.

Cost/Availability

So far, only FDG, C11-Choline, and Fluciclovine are FDA approved for prostate cancer detection. NaF is approved for clinical trials and registries only. FDA approval opens the way for Medicare and private insurance to approve and pay for them. Sometimes, insurance plans will agree to pick up the cost. Otherwise, patients who want them must pay out of pocket, if they are available. Ga68-PSMA-11, for example, is available for purchase in a clinical trial at UCLA for recurrent prostate cancer and costs $2,650 for each infusion. 


Clinical trials

All of the newer PET tracers require validation with larger sample sizes. While there are some diagnostic tests that have a "gold standard" against which performance can be evaluated, this is problematic for detecting metastases. A positive finding can often be confirmed with a biopsy, so a PET scan's positive predictive value (true positives and false positives) can be ascertained. But there is no easy way to determine whether negatives were true or false in live patients.

F18-DCFPyL is available for free in a trial at 15 sites in the US and Canada. It is only for patients who are recurrent after a prostatectomy (PSA>0.2) or after primary radiation (PSA> nadir+2.0). They must also be negative on a bone scan/CT and not be using hormone therapy.  Contact details are available here. NIH is also doing a free clinical trial among any men who are (1) high risk or (2) recurrent (see this link). It is available as a PET/MRI for specific purposes at the University of Wisconsin, Northwestern University, and at Princess Margaret Cancer Centre in Toronto.

It is also available at Johns Hopkins, where it was first developed, for a wide range of indications if ordered by any of their physicians Contact details are available here, here, and here. Johns Hopkins is also utilizing it in a study to determine whether there is any benefit to SBRT treatment of oligometastases (see this link).

There are several studies in Canada: in BC, Ontario (and this one and this one).

Ga68-PSMA-11 is available in several clinical trials in the US, including several with a PET/MRI, at UCLA, UCSF, Stanford, and Cleveland Clinic. UCSF is testing a new PSMA indicator called CTT1057.

Fluciclovine is available almost everywhere in the US, and is covered by Medicare for recurrent patients.

If you are interested in one of those PET scans for an indication outside of the clinical trial, call the contact anyway. Some are planning clinical trials for expanded indications shortly, and some may make the PET scan available for purchase outside of the clinical trial. Inquire about cost and get pre-authorization from your insurance company if you can. These can be very expensive.