Salvage SBRT after Prostatectomy

UCLA has announced a new clinical trial using SBRT for treating recurrent prostate cancer after failure of initial prostatectomy. This is the third such trial in the LA area, adding to the ones at USC and  City of Hope (no longer recruiting). The advantages to the patient are completing salvage radiation in just 5 treatments, and at a lower cost. But there are many issues that the lead investigators, Amar Kishan and Chris King, explored in a very detailed document that they kindly allowed me to see. The hope is that the increased biologically effective dose possible with extreme fractionation will increase cure rates without adding undue toxicity.

Eligibility

Patients are eligible if they had adverse pathological findings (i.e., Stage T3/4, positive margins, Gleason score 8-10, tertiary pattern 5), or PSA rising over 0.03 ng/ml. They are excluding anyone who exhibits distant metastases on a bone scan (M1) or positive pelvic lymph nodes discovered by dissection (pN1). They are allowing patients with non-surgical evidence of pelvic lymph node invasion (i.e., suspected because of a CT or a PET/CT).

Radiation Dose / adjuvant ADT

The treatment plan is:

• All patients will receive 34 Gy in 5 fractions to the prostate bed. 
• There may be a simultaneous boost dose of 40 Gy to any detected tumors in the prostate bed.  
• Optionally, they will also receive 25 Gy in 5 fractions to the pelvic lymph nodes. 
• Optionally, they will also receive 6 months of ADT beginning 2 months before radiation begins. 

While whole pelvic radiation and adjuvant ADT improve salvage radiation outcomes on the whole (see this link), they may not be necessary in all cases. A recent analysis suggested that adjuvant ADT only benefits those with post-prostatectomy PSA ≥ 0.4 ng/ml, Gleason score 8-10, Stage T3b/4, and those with high Decipher scores (> 1 in 3 probability of distant metastases in 10 years).

The prostate bed dose is biologically equivalent to 85 Gy using conventional fractionation (about 1.8 Gy per fraction). It is much higher than the typical salvage radiation dose of 67 Gy - 72 Gy in 37-40 fractions. It also exceeds by about 9% the dose used in a trial of moderate hypofractionation (discussed here). At the last ASTRO meeting, Dr. King presented the rationale for increasing the salvage radiation dose (see this link).  At the time, he proposed a randomized clinical trial using a dose of 76 Gy with conventional fractionation. The new protocol far exceeds that dose on the basis of biologically effectiveness, but they will compare outcomes to historical controls. The goal is to achieve a 5-year biochemical recurrence-free survival rate of 72%, compared to the historical level of 56%.

Toxicity

Salvage SBRT isn't just another form of salvage IMRT; IMRT is more forgiving. With IMRT, if there is a small misalignment, it is not a big deal -- the dose per fraction is small enough that a target miss caused by organ motion will not materially affect outcomes and will average out over time.

• Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid all of the geographic misses. Image guidance is complicated when there is nothing for fiducials to grab onto.  This becomes an important consideration only at higher dose rates.
• Although the biologically effective dose (BED) for oncological control is higher with the SBRT protocol, the BED to healthy tissues (which causes toxicity) is lower. 
• For the tissues that may cause acute toxicity, the BED is a third lower compared to a 72 Gy conventionally-fractionated treatment. In a recent trial of 70 Gy salvage radiation, acute grade 2 and 3 urinary toxicity was 18%; acute grade 2 and 3 rectal toxicity was 18% as well.
• For the tissues that may cause late-term toxicity, the BED is about the same. Serious late-term toxicity was a rare event when 76 Gy was used for salvage in one study, but late term grade 2 toxicity was about 20% urinary toxicity and 8% for rectal toxicity. It is unknown whether the late-responding tissues of the bowels and urinary tract will suffer increased damage from the higher dose rates after longer follow-up.

SBRT as a primary treatment is different from SBRT as a salvage treatment.  There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:

• The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
• The scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
• The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
• Erectile function is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.

We have had a couple of cautionary cases where SBRT toxicity has been extraordinarily high. In one, it was because the delivered radiation dose was too high. In the other, there may have been multiple causes.

There has been a study where conventionally fractionated salvage IMRT with a dose as high as 80 Gy has been used with low toxicity. A recent study using moderate hypofractionation for salvage (51 Gy/ 17 fx) also boasted low toxicity levels among treated patients.

They will monitor both physician-reported toxicity and patient-reported toxicity (urinary, rectal, and sexual). If the rate of grade 3 (serious) toxicity is higher than 20%, accrual will be halted and the study subjected to careful review. If the rate is higher than 30%, the study will be terminated.

Dose Constraints

The investigators have put together a set of very tight dose constraints for organs at risk. Organs at risk include the bladder, the front and back of the rectum, the small intestines, the penile bulb and the femoral head. They also included "point dose constraints": the maximum radiation exposure to even a millimeter of the organ at risk. Because of individual anatomy, it may not always be possible to simultaneously meet all dose constraints. In those cases, the physician will decide if the deviation is material, and if it is, he may lower the dose as low as 30 Gy.

Image Guidance

The prostate bed consists largely of loose and highly deformable tissue. Although some radiation oncologists (e.g., at UCSF) use fiducials or transponders for salvage image guidance, most find that they do not stay in place. This has not been a big issue for salvage IMRT because a few "misses" will not contribute materially to toxicity, but it may be a larger issue for salvage SBRT. One way around this is to have the doctor monitor the position of the soft tissue throughout each treatment, and manually realign the beams whenever the position of the tissues deviates from the planning image. The problem is that  manual realignment is time consuming. The patient is lying on  the bench with a full bladder, which may be difficult to hold in. Also, the more time that passes during a treatment, the more opportunity for bowel motion to occur. The lack of intrafractional image guidance remains a concern in this clinical trial that the investigators are well aware of.

A related issue occurs when the pelvic lymph nodes are simultaneously treated. The lymph nodes may move independently of the prostate bed, so it may be impossible to hit both areas simultaneously with pinpoint accuracy. The investigators are using the pelvic bones as landmarks.

Most importantly, all patients must have a full bladder to lift it up and help anchor organs in place. in addition, enemas are required before each treatment, and if the bowels are at all distended, treatment will be discontinued.

Risks

As with any clinical trial, patients take a risk in trying a new treatment. There is also a learning curve that doctors go through in trying out a new therapy.  I, myself, chose to participate in a clinical trial of primary SBRT when there were only 3 years of reported data. I judged the potential benefits worth the risk for me. It was also important to me that the treating radiation oncologist (Dr.King) had been using SBRT for prostate cancer longer than anyone else. Every patient should be well aware of the risks before agreeing to participate in a clinical trial. Patients who are looking for a shorter duration treatment with less toxicity risk may wish to be treated at the University of Wisconsin or in a clinical trial at the University of Virginia (discussed here).

Newly diagnosed, metastatic (M1), but still hormone sensitive - best options

(Frequently Updated)

In the US, only 3% of new patients are newly diagnosed with metastatic, hormone-sensitive prostate cancer (mHSPC). "Metastatic," for the purposes of this analysis only includes distant metastases (Stage M1), but not pelvic lymph node metastases (Stage N1). This group has been the subject of many major randomized clinical trials over the last few years. CHAARTED, in the US, randomized to early docetaxel + androgen deprivation therapy (ADT) compared to ADT alone. STAMPEDE, in the UK and Switzerland,  has published several studies: one on the use of Zometa and Celebrex, one on docetaxel,  one on abiraterone+prednisolone  (updated here) (I'll refer to this combination as Zytiga), and two on debulking the prostate with radiation (one from STAMPEDE and one from HORRAD). They also included men with locally advanced and recurrent prostate cancer, which we will address at another time (see this link). 

LATITUDE was a multinational clinical trial comparing Zytiga+ADT to ADT alone. TITAN was a multinational trial comparing apalutamide (Erleada) +ADT to ADT alone. ENZAMET was a multinational trial comparing enzalutamide (Xtandi) + ADT to early antiandrogens +ADT. ARCHES assessed the effect of enzalutamide on radiographic progression-free survival. TITAN and ENZAMET are discussed in more detail here.

We can look at hazard ratios for overall survival. A hazard ratio (HR) of, say, 0.60 means that the treatment reduced the number of deaths by 40% compared to the standard treatment. Unless it is otherwise noted, the HRs we talk about are all statistically significant with 95% confidence.

Early use of docetaxel

The hazard ratios found for all metastatic men were as follows:
CHAARTED: 0.61
STAMPEDE: 0.81
GETUG-15: 0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
CHAARTED: 0.60
GETUG-15: 0.8 (not statistically significant)
STAMPEDE: 0.81 (not statistically significant)

The hazard ratio for men with low volume mets only were:
CHAARTED: 1.03 (not statistically significant)
STAMPEDE: 0.76 (not statistically significant)

GETUG-15 was a French randomized clinical trial. It has been criticized for including men with more advanced disease than CHAARTED. When STAMPEDE showed similar results to CHAARTED, GETUG-15 was largely ignored, and early use of docetaxel became the new standard of care. Some argued that the  results of STAMPEDE and CHAARTED suggest that docetaxel should be considered for among all metastatic men, but a CHAARTED update suggests a benefit only among those with high volume of metastases. However, a STAMPEDE update showed no difference in overall survival or failure-free survival between the two subgroups. The STAMPEDE authors point to their larger trial and that their analysis applies more to newly diagnosed men, whereas the CHAARTED groups had more previously treated men. They advocate early use of docetaxel regardless of metastatic burden. (High volume was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.)

One should resist the temptation to compare HRs across studies. Each study had different patient characteristics, and PSA screening policies differ markedly in those countries. In fact, a recent analysis of the STAMPEDE outcomes of men who were randomly assigned to either Zytiga or docetaxel found that there was no difference in survival between the two treatments (see this link).

Early use of Zytiga

The hazard ratios found for all metastatic men were as follows:
LATITUDE: 0.66
STAMPEDE: 0.62

An unplanned secondary analysis presented at ESMO 2018 and published in European Urology looked at high volume vs low volume, and found it worked equally well in both situations:

The hazard ratios for men with high volume mets only were:
STAMPEDE: 0.60

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.64

In an 5-year update, there was no difference in mortality depending on whether the patient had many or few metastases:

The hazard ratios for men with high burden patients only were:

STAMPEDE: 0.54

The hazard ratios for men with low burden patients only were:

STAMPEDE: 0.55

Early use of Zytiga+Docetaxel

Overall survival is only available for men with high volume of metastases, but radiographic progression-free survival increased by 2.5 years (from 2.0 to 4.5 yrs) with the addition of abiraterone to docetaxel. Time to castration resistance increased by 1.7 yrs (from 1.5 to 3.2 yrs). 

For men with high volume of metastases, median overall survival increased from 42 months with docetaxel only to 61 months with docetaxel+Zytiga.

See discussion of early results of PEACE1.

Early use of darolutamide (Nubeqa) + Docetaxel

In the ARASENS trial, the "triplet" of ADT+ docetaxel + darolutamide reduced mortality by 32% over ADT+docetaxel (HR= 0.68).

See: discussion of triplet therapy

Early use of Erleada

The hazard ratio for metastatic men was 0.67

Early use of Xtandi

The  hazard ratio for all metastatic men was 0.66

The hazard ratio for men with high volume mets only was 0.74 - not statistically significant

The hazard ratio for men with low volume mets only was 0.48 - statistically significant


Early use of Debulking

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.92  (not statistically significant)
HORRAD:  0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
STAMPEDE: 1.07 (not statistically significant)

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.68 (statistically significant)

Early use of Zometa+Celebrex

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.78 (see this link)

Which is best? 

The early use of Zometa is frowned upon because side effects increase over time. However, if an older man already has osteoporosis, Zometa+Celebrex is a good combination. As long as the patient doesn't have contraindications like heart disease or bad teeth, it is cheap, non-toxic, and reduced risk of death by 22% at the 43-month follow-up. Zometa is usually given along with ADT anyway, so it is hard to argue against including this combination along with Zytiga, Erleada or docetaxel. However, the use of Zometa when one is still hormone-sensitive is controversial. An argument can be made for putting it off until there is evidence of osteoporosis on a DEXA scan - the risk of the worst side effect- osteonecrosis of the jaw - increases with the amount of time taking it.

The hormonal therapies have different modes of action, but without a randomized clinical trial, it's impossible to say that one extends life more than the others. Xtandi and Zytiga are being compared in an ongoing arm of STAMPEDE. (Zytiga prevents the formation of androgens by the adrenal glands and via intra-tumoral synthesis. A recent study suggests that it stops formation of testosterone by the testicles as well. Xtandi and Erleada block the androgen receptor and prevents its translocation into the nucleus, where it can invigorate the cancer even without outside androgens. Erleada also prevents "upgrading" of the androgen receptor - a mode of castration resistance where multiple copies of the androgen receptor appear on the cancer cell, so it can be activated by even the slightest amount of androgen. However, it is unknown whether it slows down castration resistance in clinical practice - the cancer cell evolves many workarounds. A small trial and STAMPEDE found that combining Zytiga and Xtandi did not improve survival in the castration-resistant setting, but side effects were worse. 

Because neither docetaxel nor Zytiga showed a clear survival advantage when men were randomized to one or the other (Sydes et al.), the decision must be made based on other factors.

Both docetaxel and Zytiga increase toxicity over ADT alone. In the LATITUDE trial, physicians reported grade 3-5 (serious to death) events among 68% taking Zytiga vs 52% on ADT only. Higher rates of grade 3 hypertension and hyperkalemia were observed. In the STAMPEDE trial, physicians reported grade 3-5 events among 47% of those taking Zytiga vs. 33% of those taking ADT only. Higher rates of hypertension and liver enzyme elevation were observed. In the TITAN trial (Erleada), where almost two-thirds had high-volume metastases, Grade 3 (serious) and Grade 4 (life-threatening) toxicities were similar (41-42%) for those who got apalutamide or placebo. In the ENZAMET trial, serious side effects were experienced by 42% of those taking Xtandi vs 34% of those taking an early antiandrogen. The rate of serious side effects is remarkably similar.

In the docetaxel trials, STAMPEDE reported grade 3-5 events among 52% taking docetaxel vs 32% taking ADT only. Neutropenia, lethargy and GI disorders were especially elevated. CHAARTED reported grade 3-5 events among 30% taking docetaxel. Neutropenia, fatigue, gastrointestinal and allergic reactions were elevated.

Based on patient-rated global quality of life after 2 years (see this link), docetaxel and abiraterone were not meaningfully different in patients randomized to one or the other. Abiraterone was better than docetaxel at 12 weeks and 24 weeks. One might expect that the increase in toxic events would have been worse with docetaxel, but while they were different in kind, the incidence of all events requiring medical attention was similar for both treatments. All medicines seem to have lower incidence of side effects when they are used earlier, while patients are healthier.

High volume/low volume of metastases

Planned subgroup analyses of both CHAARTED and STAMPEDE showed that certain different therapies may improve survival depending on the number of distant metastases found using a bone scan/CT. Remember that high volume was arbitrarily defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae; low volume is anything less than that (often referred to as oligometastatic).

For men who are diagnosed with a low volume of metastases (oligometastatic), debulking can add to survival. STAMPEDE recruited participants before the benefit of early Zytiga was known, so it is unknown how the two therapies might interact. It is reasonable to speculate that early Zytiga may be used to radio-sensitize the cancer to debulking with radiation. The role of metastasis-directed SBRT has yet to be proven, but may be considered when safe to do so.

In a post-hoc analysis of LATITUDE data, men with high volume disease benefited from early use of Zytiga, but men with low volume disease did not. In STAMPEDE, there was no difference - Zytiga was equally effective in both groups. Erleada also seems to be equally effective in both groups. However, LATITUDE had mostly high-volume disease men in its sample. For men with a high volume of metastases, docetaxel or Zytiga (but not debulking) may confer a survival benefit). Xtandi seems to benefit most those with low volume of metastases.


Can they be combined or sequenced?

The PEACE-1 trial showed that the combination of docetaxel and Zytiga improved outcomes significantly.

A major clinical trial, ACIS, found that the combination of Erleada and Zytiga increased radiographic progression-free survival in men who were already castration-resistant. That combination improved results (in the AASUR trial) when given as an adjuvant therapy along with prostate radiation to men with very high-risk localized prostate cancer, and will be testedamong high-risk patients with high Decipher scores in the PREDICT-RT trial. The combination is being tried along with salvage radiation in men who have failed prostatectomy in the INNOVATE trial. An ongoing clinical trial is investigating whether Erleada combined with Zytiga extends survival in the relapsed hormone-sensitive setting.

There is a hint that docetaxel may have some efficacy in keeping Zytiga working longer. The androgen receptor always eventually becomes resistant to the effect of Zytiga. Sometimes resistance is attributable to a change in the androgen receptor called "the AR-V7 splice variant." There was a very small (n=14) trial at JH where they were looking at the role of the AR-V7 splice variant in resistance to second-line hormonals (Zytiga or Xtandi). In a few guys (6 out of 14) who were AR-V7 positive after that hormone therapy, they became AR-V7 negative after docetaxel treatment. This is also an effect that they were hoping that supraphysiological doses of testosterone might sometimes create (see this link).

This may work both ways. Hormonal agents may even re-sensitize the cancer to docetaxel after it has become docetaxel-resistant (see this link). It may turn out that alternating the use of chemo and advanced hormonals (and testosterone!) is a good strategy.

For logistical reasons, it may be useful to start with six cycles of docetaxel, which would take 15 weeks. In this way, Zytiga, Erleada or Xtandi can begin 15 weeks later. If one starts with Zytiga, it may take three or more years before it stops working and docetaxel can be tried (Among metastatic men, failure-free survival was about 4 years in STAMPEDE, radiographic progression-free survival was 33 months in LATITUDE). It seems that one can receive more therapies in less time if a patient begins with docetaxel.

It is possible that concomitant early use of Zytiga and docetaxel may have a synergistic effect on the cancer, and in preventing the onset of Zytiga resistance. This is pure conjecture and would have to be proved in a clinical trial. The downside is the cumulative side effects.

The other possibility is starting with docetaxel only and following up with the combination of Zytiga +ADT. By holding off on ADT use, it might delay some of the selective evolutionary pressure that leads to early Zytiga resistance. It is unknown whether early docetaxel without ADT has similar efficacy to the combination. Again, this is a good hypothesis to be tested in a clinical trial.


Will Provenge, Xofigo and Jevtana also be more beneficial if used earlier?

Isn't earlier always better? Not necessarily (see this link). Cancer is a moving target, continually altering its genetic make-up. What works when cancer is in one state may not necessarily work when cancer is in another state. There can be unpredictable interactions. Early and prolonged use of bicalutamide, for example, may actually eventually increase the cancer growth rate; yet, with cancers that have become castration-resistant, adding bicalutamide may sometimes slow it down.

Although Provenge is more effective when the patient's disease is less progressed (see this link), it was not any more effective when used for mHSPC (see this link). Xofigo is in a clinical trial for mHSPC, and Jevtana is in trials for use before docetaxel.

What about nuclear medicines?

An exciting new field is the use of nuclear medicines (alpha-emitters like Xofigo, and beta-emitters like Lu-177-PSMA). Their use has historically been restricted to men with mCRPC. There is a clinical trial of Lu-177-PSMA for men who are castration-resistant but are not yet detectably metastatic (see this link). The PSMAddition trial is for men who are newly diagnosed or metastatic with metastases. The hope is that they can seek out and destroy micrometastases that may be in systemic circulation.

What happens if they are used later?

Most of the advanced prostate cancer medicines were approved for men who were metastatic and castration-resistant (mCRPC). In that setting, docetaxel adds a median survival of 3 months (see this link), compared to a median of 17 additional months among men with high volume metastases in the CHAARTED trial. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). Median (50%) survival was reached at the extended follow-up of the STAMPEDE trial. Median survival was 46 months in the SOC group, and 79 months in the Zytiga group. So, early Zytiga increased median survival by 33 months; In LATITUDE (in which all patients were more progressed), early Zytiga increased median survival by 16.8 months.

We might surmise that if used after metastatic diagnosis but before castration-resistance sets in, the survival improvement might be somewhere in between. However, long-term use of ADT drives changes in the androgen receptor that might shorten the time during which Zytiga is effective. Docetaxel, on the other hand, remains effective even after advanced hormonal agents have been utilized.

What are the other alternatives for metastatic hormone-sensitive prostate cancer (mHSPC)?

Supraphysiological doses of testosterone alternating with ADT (called Bipolar Androgen Therapy or BAT) has shown efficacy in some men (see this link). Expanded trials will tell us which men are most likely to benefit from it.

Treatment of the prostate even after metastases have been discovered  (called "debulking") is an intriguing prospect. However, the most recent reported arm of the STAMPEDE trial showed that prostate-only radiation only provided a survival benefit in oligometastatic men (see this link). There are clinical trials at MD Anderson and Rutgers (not recruiting), and registries at UT Southwestern and MSKCC and the Los Angeles VA that will further explore this opportunity. Princess Margaret Hospital in Toronto is using SBRT for this purpose (see this link). Other trials are ongoing in Europe (this one includes docetaxel and Zytiga): Ghent, and Hamburg.

Other early-use therapies are combined with ADT in clinical trials. These trials are still active:

• apalutamide + Zytiga + debulking (RP or RT). (first results expected Feb 2024)
• Johns Hopkins is testing a PARP inhibitor for potential use instead of ADT in men with germline DNA repair defects(first results expected Dec 2023)
• enzalutamide ± Keytruda  (first results expected in  July 2026)

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.

I-131-MIP-1095, a new radiopharmaceutical, in clinical trials at Memorial Sloan Kettering

There are few radiopharmaceuticals in clinical trials in the US (there are several in use in Germany), so when a new one is announced, we take notice. I-131-MIP-1095 has had a very limited clinical trial in Germany in 28 patients, and will now be tried in the US.

Like Lutetium 177, Iodine 131 is a beta particle emitter (see this link). It's beta particle energy is somewhat higher, so that it can penetrate greater distances through tissue - up to 3.6 mm, compared to 1.9 mm for Lu-177. This is an advantage in that it can destroy larger tumors, but it is a disadvantage in that it may destroy more healthy tissue, causing hematological and renal side effects. It is also similar to Lu-177 in that its uptake in human tissues can be detected using a gamma ray camera or SPECT detector. Because gamma ray detection does not afford the image quality that PET/CT does, it may be combined with a positron emitter, I-124. Lu-177 is sometimes combined with Ga-68 for the same purpose. This combination of therapeutic and diagnostic (sometimes called theranostic) may be useful in tailoring the dose to the patient based on individual uptake characteristics.

The molecule (or ligand) that the I-131 is attached to is MIP-1095. MIP-1095 is attracted to the PSMA protein on the surface of 95% of prostate cancer cells. Although it is highly specific for prostate cancer, there are other tissues that express PSMA, especially the salivary glands and lacrimal glands. It is excreted by the liver and kidneys, and may show up in the intestines, and the lower urinary tract. The dose to the kidneys may limit the amount of the pharmaceutical that may be given to the patient.

A group from the University Hospital Heidelberg, Zechman et al., treated 28 metastatic castration-resistant patients with I-131-MIP-1095 with the following results:

• In 61%, PSA was reduced by >50%. This is better than the response seen with Lu-177-PSMA-617 in these trials and in this one.
• PSA decreased in 21 of 25 patients, increased in 4.
• 85% had complete or moderate reduction of bone pain. 
• 25% had a transient slight to moderate dry mouth, which resolved in 3-4 weeks.
• White blood cell count, red blood cell count and platelets declined during treatment, but there were only 3 cases of grade 3 hematologic toxicity, often in patients with low blood counts at baseline.
• No renal toxicity was observed.
• The effective dose to cancer cells was higher than for Lu-177-PSMA-617, red marrow and kidney doses were similar, and liver dose was lower.

The clinical trial that is now recruiting at Memorial Sloan Kettering, is a Phase 1 trial to find the best dose of I-131-MIP-1095 among patients with metastatic castration-resistant prostate cancer. Doses will be administered 12 weeks apart for up to 5 cycles or until dose-limiting toxicity is observed (monthly assessments). Interested patients in the New York City metropolitan area should call the contacts listed on the bottom of this trial description.

Small Cell Prostate Cancer Clinical Trials

(frequently updated)

Small Cell Prostate Cancer (SCPC), and more generally Neuroendocrine Prostate Cancer (NEPC), are thankfully rare types of prostate cancers. They are not responsive to hormone therapy, to taxanes (Taxotere or Jevtana), or to radiation. They are difficult to detect and monitor with the kinds of imaging used to detect prostate adenocarcinoma (mpMRI, bone scans, PSMA PET scans), but may show up with FDG PET (see this link). They do not put out PSA, PAP or bone alkaline phosphatase. Special biochemical tests or biopsies for chromogranin A, neuron-specific enolase (NSE), synaptophysin,  DLL-3, CD56, and other biomarkers are required. It often appears at a "mixed type." 

Sub-types

Not all neuroendocrine prostate cancers carry the same prognosis. Aggarwal identified a sub-type that became prevalent in 17% of patients who were heavily pretreated with enzalutamide (Xtandi) and abiraterone (Zytiga). He calls this "treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC). The pre-treatment probably selected for this subtype that may be partially responsive to familiar therapies. The "treatment-emergent" subtype and the small amounts sometimes detected initial biopsies do not appear to be as virulent (see this link). There are some studies that indicate that they may appear spontaneously in later stages of normal prostate cancer development. Aggarwal commented:

“Although long term androgen deprivation therapy may be associated with the development of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) in a minority of patients, multiple studies have confirmed the long-term benefit of abiraterone and enzalutamide for prostate cancer patients in various disease settings. Use of these agents should not be limited by concern for the subsequent development of t-SCNC.”

Aggarwal has announced a clinical trial where he will be testing a combination of Xtandi, Keytruda, and ZEN-3694 in (among others) a group of men identified with the t-SCNC subtype. ZEN-3694 is an experimental medicine that inhibits a gene called MYC, which is often over-expressed in advanced prostate cancer. 

Aggarwal is also testing FOR-46 targeting the CD-46 protein that often is expressed in neuroendocrine tumors.

Chemotherapy

Because of the "mixed type," chemo often includes a taxane. More often, a platin is mixed in a cocktail with another chemo agent, like etoposide. A couple of case reports from Japan (see this link and this one) reported some success with a platin combined with irinotecan.

This clinical trial at Duke has two chemotherapies (cabazitaxel and carboplatin), as well as two checkpoint blockade-type immunotherapies (nivolumab and ipilimumab):

CHAMP

Nuclear Medicine/ Somatostatin

The Urology Cancer Center in Omaha, Nebraska has announced a clinical trial of 225Ac-FPI-2059 for neuroendocrine cancers. FPI-2059 is a small molecule that attaches to the neurotensin receptor 1 peptide that is expressed by neuroendocrine cancer cells.

Another radiopharmaceutical has been tried by the nuclear medicine department at the University of Heidelberg. I suggest that anyone who is interested email or call (they all speak English) Uwe_Haberkorn@med.uni-heidelberg.de Phone: 06221/56 7731. With the euro now at close to parity with the dollar, this medical tourism is an especially attractive option:

213Bi-DOTATOC shows efficacy in targeting neuroendocrine tumors

A similar radiopharmaceutical using Lu-177-DOTATATE (called Lutathera) has been FDA-approved for small cell cancer affecting the digestive tract. DOTATOC (and also DOTATEC and DOTATATE) binds to somatostatin receptors on the small cell digestive tract cancer surface, where it is highly expressed. It is rarely expressed in small-cell prostate cancer, but there have been some isolated case reports like this one or small trials like this one. This means that treatment with a somatostatin analog (octreotide, lanreotide, or pasireotide) may be somewhat effective even without the radioactive emitter attached to it. These drugs are available now in the US, are not toxic, and your doctor can prescribe them without a clinical trial. there is a clinical trial of it in London for any solid tumor:

https://clinicaltrials.gov/ct2/show/NCT02236910

These clinical trials include somatostatins:

https://clinicaltrials.gov/ct2/show/NCT01794793
https://clinicaltrials.gov/ct2/show/NCT02754297

This clinical trial at Johns Hopkins uses Lutathera to treat neuroendocrine prostate cancer, specifically:

https://clinicaltrials.gov/ct2/show/NCT05691465

While the presence of somatostatin receptors in the tumor can be determined by pathological analysis (immunohistochemical (IHC) staining for SSTR2), there is an FDA-approved PET scan that uses Ga-68-DOTATATE that can detect it without a biopsy. It is used to detect neuroendocrine tumors that are often non-prostatic. Researchers at Emory found that Ga-68-DOTATATE uptake is higher even in neuroendocrine tumors of prostatic origin, which suggests that somatostatin-based therapy may be beneficial. (One patient who was positive for a BRCA2 mutation but negative for NEPC had high uptake as well.)

DLL3

DLL3 is a protein that is expressed on the surface of neuroendocrine cells regardless of the cancer of origin, and has been identified in two-thirds of neuroendocrine prostate cancer (NEPC) cells. An antibody linked to a chemotherapy, called Rova-T, against DLL3 has been developed and has shown some promise against NEPC in a preclinical study. Unfortunately, AbbVie discontinued R&D after it failed to meet goals for small cell lung cancer (SCLC). A Phase 2 trial that included NEPC was discontinued. Misha Beltran at Dana Farber has tried an antibody-drug conjugate (rovalpituzumab teserine) targeted to DLL3 on a single patient. After two treatments, his metastases shrank and stabilized.

Harpoon has announced a clinical trial of HPN328  for people with advanced cancers that express DLL3. HPN328 is a bispecific T-cell engager (BiTE) that targets DLL3 and also promotes T cells to attack those cells exhibiting it. AMG757 is also a BiTE. Amgen has announced a clinical trial of AMG 757 for advanced prostate cancer. Phanes Therapeutics has a BiTE clinical trial targeting DLL3.

AMG119 is a CAR-T therapy that targets DLL-3. CAR-T involves treating one's own T-cells by sensitizing them to DLL3. Both of these create a T-cell and a cytokine response in environments that otherwise have low immune cell activity. That response may kill bystander cells, and through a phenomenon called "antigen spreading," may be able to kill other cancer cells that do not exhibit DLL3. (BiTE and CAR-T therapies that target PSMA are  in clinical trials noted at end of this article)

The Wang Lab at Duke has specific expertise in morphological analysis of NEPC and IHC staining for DLL3. It may be a good idea to get a second opinion from them.

Checkpoint blockade

Another recent discovery is that PD-L1 is highly expressed in SCPC. This opens the door to immunotherapies that target the PD-1/PD-L1 pathway, like Keytruda.

PD-L1 expression in small cell neuroendocrine carcinomas

Small clinical trials have so far shown little benefit:

Avelumab (Duke)

Pembrolizumab (UCLA)

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.

The FDA has approved Ga-68-PSMA-11 PET/CT for detection of recurrences after prostatectomy or radiation. They have also approved Axumin PET scans and C-11 Choline PET scans (at Mayo) for this purpose.

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.

For salvage radiation after primary radiation therapy, whether focal or whole gland (see this link), a PSMA PET scan combined with an mpMRI may be able to detect areas within the prostate that still have cancer. PSMA PET scans may cause false positives if used alone to detect cancer in and around the prostate, because they are excreted in the urine. Some of the newer PSMA PET scans (e.g., F18-PSMA-1007 and F18-rh-PSMA-7) have less renal clearance.

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.

Ruling out distant spread where it seems to be localized

PSMA PET scans have been approved to detect prostate cancer in high-risk patients. PSMA PET scans provide a critical decision-making tool because it may be able to answer the following questions for the first time:

1. Is the cancer still confined to the prostate capsule?
2. Has the cancer spread to the prostate bed or to surrounding organs?
3. Has the cancer spread to pelvic lymph nodes?
4. Has the cancer spread to non-local lymph nodes, bone, or visceral organs?

Giving extra radiation to known tumors

While modern dose-escalated doses of radiation of very good at eradicating tumors, results can be improved even further if focused boost doses are given to areas in the prostate, the prostate bed, and pelvic lymph nodes that are proven to be cancerous with a PET scan. The excellent results are described here.

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. 

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).

The FDA has approved Ga-68-PSMA-11 PET/CT at UCLA and UCSF for unfavorable risk prostate cancer.

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 often 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. 

NaF(18) PET for bone metastases

Sodium fluoride (NaF18) replaces hydroxide with positronic fluoride when hydroxyapatite, the mineral that constitutes our bones, is actively accumulating in bone metastases. It is our most sensitive tool for detecting bone metastases. Fourquet et al. found that in the same patients, NaF18 detected 91% of bone metastases while DCFPyL detected only 46%.

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 are the F18-based ligands (F18-DCFPyL, F18-PSMA-1007, and F18-rh-PSMA-7). They detect more metastases at lower PSA than the others. 

As prostate cancer progresses, PSMA expression reduces and the cancer metabolizes glucose to a greater extent. Then, it will be detected by FDG PET scans.

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 recurrent prostate cancer, and their specificity for detecting it exclusively:

1. F18-PSMA-1007
2. F18-rhPSMA-7
3. F18-DCFPyL
4. F18-DCFBC
5. Ga68-PSMA-HBED-CC (Ga68-PSMA-11)
6. Fluciclovine (F18 - FACBC)/ Axumin
7. C11-Choline/ C-11-Acetate
8. F18-Choline

• NaF18 (note: best for detecting bone metastases)
• F18-FDG (note: better in late-stage PCa)

The following table shows the percent of patients who had metastases detected at various PSAs. F18-PSMA-1007 and F18-rhPSMA-7, are experimental PET indicators that are cleared quickly from the bladder, and are the best so far. 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)		(1)
Ga68-PSMA-HBED-CC			66%  (0.5-3.5)
F18-rh-PSMA-7 (experimental)		71%	86% (0.5-1.0) 86% (1.0-2.0)	95%	(11)
F18-PSMA-1007 (experimental)		86%	89% (0.5-1.0) 100% (1.0-2.0)	100%	(12) (13)
F18-DCFPyL		48%	50% (0.5-1.0) 89% (1.0-2.0)	94%	(9)
F18-DCFPyL		38%	63% (0.5-1.0) 83% (≥ 1.0)		(14)
Ga68-PSMA-HBED-CC	31%	54%		88%	(2)
Ga68-PSMA-HBED-CC		58%	73% (0.5-1.0) 93% (1.0-2.0)	97%	(3)
Ga68-PSMA-HBED-CC		50%	69%	86%	(4)
F18-FluoromethylCholine		12.5%	31%	57%
Ga68-PSMA-HBED-CC			36% (PSA<1, PSADT>6 months)	95%  (PSADT<6 months)	(5)
Ga68-PSMA-HBED-CC	11.3%	26.6%	53.3% (0.5-1.0) 71.4% (1.0-2.0)	95.5%	(6)
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)	(7)
Ga68-PSMA-HBED-CC	43%	58%	72% (0.5-1.0) 84% (1.0-2.0)	90% (2.0-5.0)	(13)
Fluciclovine		37.5% (0.2-1.0)    77.8% (1.0-2.0)		88.6%	(8)
C-11 Choline		28%	46% (0.5-1.0) 62% (1.0-2.0)	81%	(10)

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 Ga-68-PSMA-11, 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, while FDA-approved at UCLA and UCSF so far, costs $3,000  out of pocket. Hopefully, Medicare/insurance will reimburse soon.

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 NIH for free 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  Northwestern University.

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, There are several studies in Canada: in BC.

Ga68-PSMA-11 is approved at UCLA and UCSF and is available in a clinical trial in the US, including one with a PET/MRI, at  Cleveland Clinic. 

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.

See also;
F18-PSMA-1007 -  the latest PSMA-based PET indicator