Diagnosing Extraprostatic Extension (EPE)

Extraprostatic Extension (EPE) or "Stage T3a" means the cancer has eaten through the edge of the prostate and is penetrating into the tissue outside. It can be difficult to diagnose before a prostatectomy. Sometimes, it can be felt using a digital rectal exam (DRE) as a bulge or irregular texture, but that is an exception rather than the rule. More often, it is seen on an mpMRI or ultrasound image.

It is important because its presence is a strong predictor of recurrence after treatment. It is one of three risk factors used in the NCCN definition of "high-risk" prostate cancer. That definition is based on the AJCC staging criteria (see this link), which means that it is strictly only based on DRE. DREs almost always fail to detect EPE. If the bulge is so big that one can feel it through the rectum, it adds significantly to the risk. But how much does it add to the predicted risk if it can only be seen on a powerful MRI?

Reisaeter et al. evaluated the Mehralivand EPE Grading System and found it was somewhat more sensitive in clinical practice as the commonly used Likert EPE scoring system. (The interested patient may also wish to read this editorial by Peter Choyke)

The Likert score looks at certain imaging abnormalities (tumor contact length with the prostate capsule, irregularity, bulging, gross extension, and loss of rectoprostatic angle) and summarizes them using five categories:

• 1 = criterion not present
• 2 = probably not present
• 3 = uncertain if present
• 4 = probably present
• 5 = definitely present.

The Mehralivand System uses three grades:

• Grade 1 refers to tumors with a contact length of 1.5 cm or greater or contour bulge or irregularity. 
• Grade 2 refers to tumors with a contact length of 1.5 cm or greater and contour bulge or irregularity, 
• Grade 3 refers to gross visible extension beyond the prostate.

Both systems require very well-trained radiologists - interobserver agreement is only fair.

Mehralivand compared the predictions of the EPE detection system to what was actually detected after the same patients had prostatectomies. Even when the Mehralivand System assigned Grade 3 to a suspected EPE, a third of them were false (positive predictive value (PPV) = 66%). False positives may be caused by inflammation, tumor scar tissue, or biopsy scar tissue. Contact with the capsule may be wholly inside, and a bulge may be wholly contained within the capsule. 

What's worse, the Mehralivand System incorrectly predicted there would be no EPE in 18% of cases where EPE was eventually found (negative predictive value (NPV) = 82%). False negatives are caused by tumors below the size where MRI can detect them. 

• The PPV was 41%, 48%, and 66% for Grade 1, 2, and 3, respectively
• The NPV was 90%, 88% and 82% for Grade 1, 2, and 3, respectively

Since DREs are so bad at detecting EPE, and MRIs are little better, what can be done to better predict EPE, and is better prediction necessary?

Is better prediction always necessary?

It has been found that focal EPE (extensions of less than 3 mm) and EPE comprising low Gleason score tumor tissue are not predictive of treatment failure. In this Johns Hopkins study, 10 year biochemical recurrence-free survival was 76% among men with focal EPE (post-prostatectomy) and 59% among those with more extensive EPE. A surgeon discovering a focal EPE may simply cut wider to get it all. GS 6 tumors have low metastatic potential (see this link). However, a patient who learns in advance that the surgeon will "cut wide" thereby increasing his risk of incontinence or impotence may opt instead for radiotherapy.

mpMRI-targeted transprostatic biopsy

It may be possible to detect clinically significant EPE by detecting suspicious sites using an mpMRI and following up with a real-time ultrasound fusion-targeted biopsy. Some pathologists have argued that needle-biopsy cores that show close proximity to the prostate margin, admixture with skeletal muscle at the apex, or admixture with adipose or other peri-prostatic soft tissue predict for EPE. This suggests that clinically significant EPE may be diagnosed with transprostatic needle-biopsy cores. This is an unusual procedure. Of course, as with any needle biopsy, it may miss the site, and several cores from the suspicious site should be taken. A periprostatic nerve block is required (which imho should be required on all needle biopsies) to prevent any additional pain. There is also some risk of extra bleeding if a blood vessel is nicked. It is worth discussing with the biopsy urologist. It is also important that the designated cores be evaluated by an experienced pathologist like Jonathan Epstein at Johns Hopkins.

(update June 2022) Moroianu et al. reported a "deep learning" algorithm that is better at detecting EPE from an mpMRI than a radiologist.

• Model sensitivity was 80% vs. 50% for radiologists (model predicted more true positives)
• Model specificity was 28% vs. 77% for radiologists (model predicted more false positives)

A combined computational/radiologist approach may be best.

ADT use may have an immunological benefit during the pandemic

The CDC recommends Covid-19 testing for cancer patients who may be immune-compromised by their cancer or chemo treatment.The extra caution is justified only in men with late-stage PC. Those who have already had prostate radiation, may have some immune enhancement, perhaps especially with SBRT (pre-clinical). The exception may be those who have had whole-pelvic radiation. Assuming that Covid-19 (unlike Spanish Flu) is milder in those with better immune systems, it is possible that ADT may improve their immune response to the disease.

Data are showing that men are dying of Covid-19 at greater rates than women. This may be because of genetic effects and hormonal effects. Testosterone was found to be immunosuppressive for influenza.  ADT has been found to be immunoprotective (here and here).

(UPDATE MAY 26, 2022) Lee et al. reported in an observational study of 3,057 US Veterans using ADT:

ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.

Early Covid-19 data are confirming this (here and here)

While normal levels of estrogen seem to be immunoprotective, high levels, as in pregnant women or men on Bipolar Androgen Therapy (because testosterone is metabolized to estradiol), reverses the protection. The implications for ADT use are:

• If you are on continuous ADT, stay on it. This is true even if ADT has been augmented with Zytiga and prednisone, or anti-androgens.Those taking Zytiga with prednisone needn't worry because the prednisone is only a replacement dose, and is not large enough to be immunosupressant. Because of negative feedback, it is more dangerous to take too little prednisone. 
• If you are on intermittent ADT, this might be a good time to end your ADT vacation. 
• Men using Bipolar Androgen Therapy on a clinical trial should discuss the timing with the trial investigator. Anyone taking supraphysiologic doses of testosterone should consider this as well. 
• If you are taking adjuvant ADT after radiation, or neoadjuvant ADT before radiation consider sticking with it a little longer.

(Update 9/23/21) A very small sample size retrospective study found there was no statistically significant difference in Covid-19 death or severity between men who used ADT for PCa  (11 men) and men with PCa and Covid-19 who did not use ADT (80 men).

Also see the recommendations for those getting radiation therapy.

Long-term adjuvant ADT improves results of brachy boost therapy in unfavorable-risk prostate cancer patients

TROG 01.03 RADAR, begun in 2003, was a  (partly) randomized clinical trial to help optimize therapy of unfavorable-risk patients. It explored such topics as use of Zometa, radiation dose escalation, and optimal duration of androgen deprivation therapy (ADT) when given along with ("adjuvant" to) radiation therapy (RT).

• Zometa did not delay progression, which is similar to the STAMPEDE trial finding among men with metastatic hormone-sensitive prostate cancer when it was used without Celebrex. 
• The external-beam radiation (EBRT) doses they explored (66 Gy, 70 Gy and 74 Gy) were below today's standard of care (78 Gy-82 Gy), so have become irrelevant to current practice. 
• The assignment to various radiation doses was not randomized. 
• The benefit of long-term ADT (28 months vs 4 months) with dose-escalated EBRT in unfavorable-risk patients was proved by the DART 01/05 GICOR trial. 

Based on the Kishan et al. study, brachy boost therapy may be the preferred treatment option for high-risk patients So we will turn our focus to the only outstanding question that this major trial can still shed light on - what duration of adjuvant ADT is necessary when unfavorable-risk patients are treated with high dose rate brachy-boost therapy (HDRBBT)?

Joseph et al. reported the 10-year outcomes of the TROG 01.03 RADAR trial conducted at 24 sites in Australia and New Zealand. From 2003 to 2007, patients were randomized on 6 vs 18 months of adjuvant ADT . There were 1,051 evaluable unfavorable-risk patients defined as:

• Stage T2b-4 or
• Stage T2a and Gleason score≥7 and PSA≥10 ng/ml
• NCCN risk groups: 31% unfavorable intermediate-risk, 66% high-risk
• Patients with positive pelvic lymph nodes (stage N1) or distant metastases (stage M1) on a bone scan/CT were excluded

The HDRBBT treatment given to 237 patients consisted of:

• 46 Gy in 23 treatments of EBRT followed by 19.5 Gy in 3 HDR brachy treatments (biologically equivalent to 88 Gy if given as EBRT-only)
• All patients received 6 months of adjuvant ADT (Lupron) starting 5 months before EBRT 
• Half were randomized to get 12 extra months of ADT (total =18 months) 
• Pelvic lymph nodes were not treated

Distant progression (radiographic progression on a bone scan/CT) was the primary endpoint. The 10-year outcomes for those receiving HDRBBT were:

• 20% distant progression (25% less than 74 Gy EBRT)
• 2% local progression (71% less than 74 Gy EBRT)
• 15% bone progression (31% less than 74 Gy EBRT)
• 9% prostate cancer-specific mortality (25% less than 74 Gy EBRT)
• 23% all cause mortality (31% less than 74 Gy EBRT)
• Distant progression was reduced by 39% by the longer ADT treatment. It was statistically significant even after adjustment for potentially confounding risk factors.
• Longer ADT was beneficial independent of RT dose, whether EBRT or HDRBBT
• 13% of men receiving HDRBBT suffered urethral strictures vs 4% of men receiving 74 Gy EBRT (for full toxicity data, see this report)
• The cumulative incidence of transition to castration resistance was significantly lower in men receiving 18 months of adjuvant ADT with RT (in an earlier report)

This establishes the importance of adding long-term (18 months) ADT for all unfavorable risk patients receiving radiation as a primary treatment. The adjuvant ADT gave better outcomes independent of the radiation dose. The Nabid et al trial proved that 18 months is as useful as 36 months in high-risk patients. But rather than slavish adherence to a single number, NCCN recommends 18 months to 3 years of adjuvant, at the discretion of the doctor.

The patient may wish to get more if:

• there are multiple high-risk features (e.g., GS9-10, PSA>20, T3/4, PNI, rare histology, genomic risk)
• there is suspicion of lymph node metastases, especially from advanced PET scans
• side effects are very tolerable

The patient may wish to get less if:

• there are lower risk features (e.g., GS 6-8, PSA<10, T2, no genomic risk)
• advanced PET scans (Axumin or PSMA) are negative
• side effects are onerous
• treatment is entirely extremely hypofractionated (HDR brachy or SBRT monotherapy)
• an additional systemic treatment (e.g., docetaxel, Zytiga, Xtandi, Erleada, or Nubiqa) is used experimentally

In an earlier observational meta-analysis (see this link), adjuvant ADT did not seem to add benefit to brachy boost therapy. This once again shows the limitation of observational studies. Only randomized clinical trials can provide the definitive proof we desire for decision-making.

Some patients think they can delay the transition to castration-resistance by eliminating or reducing the amount of ADT used with their RT. This shows that does not happen. Castration resistance is a consequence of genomic breakdown that always occurs as the cancer evolves. It may be facilitated by eliminating the hormone-sensitive cells and leaving only castration-resistant cells (this is called "competitive release"). By eliminating cancer cells as early as possible (before metastases have been detected) using HDRBBT and long-term adjuvant ADT, there is an opportunity to cure the disease. We are learning that cancer cells signal other cancer cells via extracellular vesicles to become like them. Even if it does not cure the patient, the profound reduction of the cancer load has a bigger effect on castration resistance than drug resistance does. This phenomenon was also noted in the TOAD randomized clinical trial (see this link). After there are metastases, an "evolutionary" personalized strategy (like this one) may be preferable.

Fexapotide Triflutate (FT) injection - a new kind of focal treatment to extend time on active surveillance

FT for Prostate Cancer

A new medicine may be able to help men on active surveillance stay on it longer. The medicine, called Fexapotide Triflutate (FT), is administered just once with a thin (#22 gauge), reportedly non-painful, needle, in the prostate quadrant where GS6 cancer has been detected. It causes prostate cells, both benign and cancerous, to undergo "apoptosis" (programmed cell death). It only kills prostate tissue and not blood vessels or nerves, does not leak outside of the prostate into systemic circulation, and does not affect adjacent tissues of the rectum, bladder, urethra, or periprostatic tissue.

Shore et al. reported the results of a Phase 2 randomized clinical trial in 148 patients at 28 sites.  They were randomized to get low-dose FT (2.5 mg), high dose FT (15 mg), or active surveillance (AS). Patients and investigational staff were blinded as to FT dose, with no sham injections for AS patients. The FT patients received a single injection only into the quadrant with the cancerous core. Patients were all excellent candidates for active surveillance:

• Gleason score 6
• Stage T1c (nothing felt on DRE)
• Only 1 core with cancer
• ≤ 50% cancer in the core

They were all followed using the same protocol:

• Follow-up biopsy on Day 45 and at 18 months, 36 months, and 48 months
• PSAs every 6 months
• After the first biopsy, 18 of the 49 AS patients were allowed to opt for FT injections

After 4 years of follow-up:

• 42% of AS patients progressed, and 39% were treated for progression
• 19% of high-dose FT patients progressed, and 11% were treated for progression
• 37% of low-dose FT patients progressed, and 21% were treated for progression.
• Median biopsied tumor grade was Gleason 3+4 among those assigned to AS or low-dose FT vs Gleason 3+3 among those who received high-dose FT. At 18 months, the median tumor grade for the high-dose group was benign (no cancer detected) vs GS 3+3 in the other two groups.
• At 18 months, estimated tumor volume in the quadrant with cancer increased by 69% for AS vs decreased by 59% for FT.
• The effect of high-dose FT was greatest at 18 months, and still had an effect at 48 months.
• The effect of low-dose FT was greatest at 18 months, but was insignificant at 48 months.
• PSA reduction was maintained in both FT groups (-21%) 
• There were very few and transient side effects attributable to the injections (blood in urine, sperm or stool), diarrhea or nausea from antibiotic.
• There were no serious adverse effects - no increase in urinary symptoms
• There were no significant sexual problems associated with FT treatment

It is entirely possible that injections across the entire prostate might have improved results.

For comparison, at 5 years after AS, Johns Hopkins (which had similar stringent requirements) reported progression in only half as many patients (21%), about the same percent as in the high-dose FT group. It is unclear why progression among the AS control group was so much higher in the Shore trial.

Comparison to 5αri therapy

Dutasteride has also been used in an effort to slow progression among men on AS. Fleshner et al. reported that after 3 years, 38% of treated patients and 48% of their more liberally-assigned AS patients progressed or were treated. In the Shore trial at 3 years, 10% of high-dose FT-treated patients and 30% of the AS patients progressed and were treated. It's hard to compare these trials because the AS criteria were so different.

At one year after 5αri therapy (finasteride or dutasteride) for BPH in very-low-risk men on AS for prostate cancer, Shelton et al. reported that no cancer was found on biopsy in over half (54%) of the treated men, similar to the finding of the high-dose FT group at 18 months. Only 5% progressed to Gleason 7, similar to the high-dose FT group  (6%) at 18 months.

• 5αris are known to have sexual side effects in 20-25% of men taking them. Sexual side effects may include reduced libido, difficulty in having an erection or orgasm, or gynecomastia. 

• Hair growth is a beneficial side effect for many men. 

• They have to be taken every day. 

• They shrink benign prostate tissue, and may cut PSA in half if the PSA is due to enlargement of the entire prostate. However, in men who have BPH due to enlargement of the transition zone-only (with normal-sized prostates), their effect on BPH and PSA is unclear. Whereas PSA as a biomarker for active surveillance is already problematic, using 5αris may increase confusion and anxiety.

• FT, on the other hand, has no sexual side effects

• works well for transition zone tumors, and 

• has a smaller effect on PSA (-21%)

• is a pain-free, "one and done" treatment. 

• It is unknown what the relative costs will be.

Other potential therapies

In a retrospective study at Cleveland Clinic, statin use was not associated with reduction of progression among men on active surveillance.

There are other medicines in ongoing clinical trials to delay progression in men on AS:

• 2-hydroxyflutamide (intra-tumoral injection)
• apalutamide
• green tea catechins
• curcumin
• Prostatak
• Provenge
• Proscavax

Patients are cautioned against using supplements that may be masking their true PSA (see this link) in the hope of prolonging AS. "Treating PSA" rather than treating the underlying cancer can lead to mismanagement.

This small study suggests that FT injections can delay progression for men on AS, without any side effects. This is different from focal ablation therapy (see this link).  There must still be periodic biopsies, although their frequency may be safely reduced. The cost and whether insurance will cover that cost may be a consideration. If it gets approved for BPH (see below), and considering that many men with prostate cancer also have symptomatic BPH, this may be available "off-label" within the next couple of years.

FT for BPH

Benign Prostatic Hyperplasia (BPH) plagues most older men with Lower Urinary Tract Symptoms (LUTS). LUTS symptoms include getting up many times at night to pee (nocturia), bothersome urinary frequency and urgency, urinary retention (incomplete emptying), weak/interrupted stream, and dribbling. Cialis, alpha blockers, and Proscar or Avodart are effective in some men. The most invasive therapies are radical prostatectomy and Trans-Urethral Resection of the Prostate (TURP). TURPs sometimes have to be re-done and carry risk of erectile dysfunction (ED), incontinence, and retrograde ejaculation. Somewhat less invasive is Holmium Laser Enucleation of the Prostate (HoLEP), with perhaps diminished risks. Both require catheterization during healing. Both may make future treatments for prostate cancer problematic. Several mechanical solutions have been tried (see this link) with varying degrees of success.

The advantage of FT is it is minimally invasive - only two injections with a thin needle are given, one in each side of the transition zone of the prostate. It can be easily re-done, if needed. And it has no effect on non-prostatic tissue (e.g., nerves or blood vessels) so side effects are expected to be minimal.

Shore et al. (and here) reported on a trial of 995 men with BPH treated at 72 sites in the US. The treatment consisted of:

• 5 ml of FT solution injected in each lobe (2.5 mg FT in 10 ml total)
• using a thin (22 G) needle 
• into each lobe of the transition zone 
• under transrectal ultrasound guidance.

The Phase 3 trials were randomized and double-blinded. Follow-up was double-blinded, and continued for up to 6.5 years. From 18-39 months after the first blinded injection, 344 patients received an (unblinded) injection of FT (half had a second injection, half a first).

Adverse Events

• There were no cases of infection or sepsis
• Mild side effects of the injection (blood in semen, urine or stool) were transient and similar for treatment and placebo.
• Transient side effects attributable to the antibiotic were the same for treatment and placebo.
• No FT detected in plasma.
• No anti-FT antibodies were created
• No differences in semen.
• Improvement in patient-reported sexual function of FT-treated vs worsening of placebo group
• Improvement in patient-reported urinary function of FT-treated vs worsening of placebo group
• In the first year, peak urine flow rate was no different in the FT group compared to the placebo, but the placebo (buffered saline+antibiotic) itself created a significant improvement
• Reduced use of TURP among FT-treated vs placebo group
• Reduced use of TURP among FT-treated vs placebo group who used oral medications 
• Acute Urinary Retention in 1% of FT-treated vs 5% of placebo group

Other Measures

• PSA did not change
• Exterior prostate volume reduced by 2% in treatment group only. 
• Prostate cancer detected in 1% of FT-treated vs 5% of placebo group

Unlike systemic treatments like 5αris, alpha blockers, and bladder anti-spasmotics, FT has no global effects. It requires only a single pain-free, non-invasive, treatment, and it may allow one to postpone, perhaps indefinitely, more invasive treatments. 

When used for BPH, it does not interfere with PSA as a biomarker for prostate cancer. It reduces the need for prostate cancer treatments, and probably does not add to the side effects of those treatments if needed.

With these large phase 3 trials completed, the FDA may approve its use within the next couple of years.

Radiation in the Time of Covid-19

A panel of top radiation oncologists in the US and UK addressed the question of putting off or shortening various kinds of radiation treatments for prostate cancer at a time when it is best to maintain distance from institutions that treat patients.

Their recommendations depended on the disease setting. For detailed recommendations, see this table. They recommend:

• Consultations and return visits post-RT should be handled by telephone or online if possible.
• The preferred therapy for all favorable risk prostate cancers (very low, low, favorable intermediate risk) is active surveillance during the pandemic.
• 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.) should be used prior to primary RT for all unfavorable-risk patients (unfavorable intermediate risk, high risk, and lymph node positive). If there must be treatment during the pandemic, a shortened course of external beam RT using moderate (20 treatments) or extreme hypofractionation (5 treatments) is recommended.
• Brachytherapy should be avoided during the pandemic, and delayed until afterwards if desired,  due to high exposure of anesthesiological medical staff.
• Adjuvant/Salvage RT should be delayed. 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.) may be used during the delay.
• De-bulking the prostate with RT in patients with low volume metastases can be delayed with 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.).
• Treatment of oligometastases with one to three RT treatments may be delayed with 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.).

I only take issue with the recommendation for non-palliative oligometastatic RT. (They specifically excluded palliative RT from their guidelines.) They state that they recommend delaying treatments that fall into the category of "non-essential procedures that do not have evidence to support their impact on overall survival rates." Treatment of oligometastases is definitely in that category. Yet they state that RT±ADT is the preferred treatment during the pandemic. Anyone with metastases  (any number) should be on ADT or advanced ADT anyway. Painful metastases and those at danger of spinal compression should receive SBRT+ADT.

ProtecT Randomized Clinical Trial: Patient outcomes by treatment received - active monitoring, prostatectomy, or radiation

In an earlier article (see this link), we looked at the only trial that randomized men with localized prostate cancer to either "active monitoring" (AM), radical prostatectomy (RP), or external beam radiation (EBRT). AM was less restrictive than today's active surveillance protocols (it included men who were not low risk) and it did not include mpMRI or follow-up biopsies. EBRT was lower dose than contemporary guidelines, included short-term ADT for everyone, and used a more toxic technique (3D-CRT) than IMRT prevalent today. RP was open and nerve-sparing. The earlier analysis categorized patients according to the treatment they were randomized to receive, rather than the treatment they actually received. They did this because it eliminates "selection bias" - patients switched to the treatment that they or their doctors believed would benefit them most. Now, the authors report patient outcomes according to the treatment they actually received.

1. Treatment choice/ oncological outcomes

In the first year, 78% of patients received the treatment they were randomly assigned. Higher risk men chose radical treatment rather than AM. Conversely, men with low-risk PC were less likely to opt for EBRT.

In the ten years of follow-up, there were only 17 prostate cancer deaths out of 1643 men randomized in the trial. The pooled, adjusted risks and the percent of the AM group that suffered each oncological outcome after 10 years of follow-up were:

• 69% lower risk of prostate cancer death for radical therapy (RP or EBRT) vs AM 
• 1.8% PC deaths among AM
• 64% lower risk of metastases or death for radical therapy (RP or EBRT) vs AM 
• 6.0% metastases or death among AM
• 77% lower risk of progression for radical therapy (RP or EBRT) vs AM 
• 24% progression among AM
• 47% lower risk of salvage ADT for radical therapy (RP or EBRT) vs AM 
• 8.8% salvage ADT among AM
• No statistically significant differences between RP and EBRT

The inferior performance of their AM protocol was predictable (see this link - Section 3). Their AM protocol did not include mpMRI confirmation, biopsy follow-up, and allowed some higher-risk patients.


2. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AM or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 24% were incontinent by the end of two years, with little improvement from that point. Incontinence increased slowly in the AM group as they elected to have radical treatment.


Table 1. Incontinence: The percent who used one or more pads per day

Time point	AM	RP	EBRT
Baseline	0%	1%	0%
6 months	0%	55%	1%
1 year	1%	32%	2%
2 years	3%	24%	2%
3 years	3%	23%	2%
4 years	5%	20%	2%
5 years	5%	20%	2%
6 years	7%	21%	2%

b. Nocturia

The researchers examined the question of whether nighttime urination was more frequent after therapy. On this dimension, only EBRT had a clinically detectable effect, and it was only at the 6 month mark. After that, it returned quickly to AM levels. RP returned to baseline level.

Table 2. Nocturia - Twice or more per night

Time point	AM	RP	EBRT
Baseline	20%	22%	20%
6 months	24%	35%	65%
1 year	23%	26%	36%
2 years	28%	23%	32%
3 years	31%	25%	32%
4 years	33%	25%	33%
5 years	35%	23%	36%
6 years	38%	25%	34%

3. Rectal Adverse Outcomes

The researchers asked the trial participants whether they had blood in their stools half the time or more. There were no discernable effects of AM or RP. Blood in stools peaked at a low level (8%) of those who had EBRT.

Table 3. Blood in stools more than half the time

Time point	AM	RP	EBRT
Baseline	1%	1%	1%
6 months	1%	1%	4%
1 year	1%	0%	4%
2 years	0%	1%	7%
3 years	1%	1%	8%
4 years	1%	1%	8%
5 years	2%	1%	8%
6 years	1%	2%	6%

4. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AM. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was possible for 5% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 13% at 2 years but did not recover appreciably beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AM cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they aged and elected to have radical therapies, predominantly surgery. 

For the EBRT cohort, erectile function had dropped to a minimum value of 18% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 34% at 3 years. At 6 years, potency was twice ads high as those who had RP. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point	AM	RP	EBRT
Baseline	68%	66%	63%
6 months	59%	5%	18%
1 year	60%	6%	34%
2 years	54%	13%	32%
3 years	49%	14%	34%
4 years	43%	15%	31%
5 years	40%	16%	28%
6 years	35%	15%	29%

Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation

Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.

Myth #3: Over time, erectile function is about the same for surgery and radiation. 

Beyond PSMA - FAPI theranostics

(frequently updated)

Ideally, a new diagnostic and therapy ("theranostic") will have the following qualities:

• it will be theranostic for all cancer (high sensitivity)
• it will not be theranostic of anything that isn't cancer (high specificity)

In my previous article (see this link), we saw how PSMA heterogeneity can lead to treatment failure. PSMA is pretty specific, except for the salivary glands, the kidneys, and a few other places where expression is low. There is an opportunity to create ligands that are more sensitive and more specific.

Cancer is a tissue-based disease too

We often think of cancer as a cell-based disease: some rogue cells go wild, become immortal, and replicate out of control (see "The Hallmarks of Cancer"). In 1889, Stephen Paget put forth the "seed and soil" hypothesis: the cancer (the seed) thrives in "congenial soil." Not only does the seed find such soil, we have since learned that it actively creates its soil. This led to a new understanding of cancer as a tissue-based disease (see this link). What we call the "microenvironment" of the cancer is not just a passive player supporting the cancer cells; it actively sends signals to some cells (via extracellular vesicles - small "bubbles" containing microRNAs, enzymes, and essential proto-oncogenes) that cause them to become cancerous, and other cells to become supportive tissue - collagen, fat, blood vessels and nerves (collectively called stroma). They also suppress immune infiltration, attract regulatory T cells and certain kinds of macrophages that prevent immune response, and release cytokines that may cause or suppress inflammatory  response. The "reactive stroma" allows the tumor to grow and expand. This starts a positive feedback loop that enables the tumor (a collection of cancer cells and their stroma) to grow relentlessly.

Cancer-Associated Fibroblasts (CAF)

Fibroblasts are the most common cells in our connective tissue, which is the most prevalent tissue in our bodies. They create the collagen, fibronectin, the ground substance, adipose tissue, cytokines, growth factors, and other proteins that makes up the extracellular matrix that supports tissue architecture. When one cuts one's fingers, fibroblasts are activated and create the structure needed for the wound to heal. Fibroblasts are involved in cell adhesion, growth, migration and differentiation. Because they give rise to many different kinds of cell-precursers and proteins, they may be thought of as stem-cell-like (mesenchymal). The interested reader may wish to read this.

When cancer cells in the prostate go awry, they may, at some point go from being normal epithelial cells to being mesenchymal cells (called the epithelial-to-mesenchymal transition or EMT). EMT cells are capable of traveling outside of the prostate, where they can grow and clump into metastatic tumors, replete with cancer-associated fibroblasts (CAFs). The tumor can be thought of as a wound that doesn't finish healing and continually creates more wounds. In some cancers, 90% of the tumor volume is the stroma.

The tumor stroma can impair drug deliver, participate in drug resistance, and change the very nature of the cancer within (its phenotype). The stroma is where immunological agents and vascular-targeted agents have their effect (or lack of effect in the case of prostate cancer). See this link for a detailed discussion. It is also potentially targetable if it has a specific characteristic protein.

Fibroblast Activating Protein Inhibitor (FAPI)

There are several characteristic proteins in CAFs. One called Fibroblast Activating Protein (FAP) seems to be particularly useful. It is highly specific - it has only been found in cancers of epithelial origin (like prostate cancer), and never in healthy tissue. Immunohistochemical analysis of tumors has demonstrated a strong correlation between high FAP expression and worse prognosis. It has also been found in damaged tissue: inflamed tissues as in rheumatoid arthritis, myocardial infarction, liver cirrhosis, and atherosclerosis.

Uwe Haberkorn and researchers at the University of Heidelberg have synthesized a FAP inhibitor (FAPI) that seems to inhibit production of CAFs specifically and thoroughly.  Not only does it inhibit progression in mouse models, but it seems to "fix" the problems associated with the cancer stromal compartment - imperviousness to immunotherapies and angiogenesis inhibitors. They are fine-tuning the ligand to be more sensitive and specific, and to last long enough in clinical use for theranostic applications.

Kratochwil et al. reported on the Ga-68-FAPI uptake in 28 different tumor types in 80 patients, in whom FDG, PSMA or other PET scans failed to detect much cancer. Good uptake was seen for almost all solid tumors. Above average uptake was seen for sarcoma, salivary, esophageal, cholangiocellular carcinoma, breast, lung, prostate, pancreatic, thymus, head and neck, ovarian, desmoid, chordoma, and colorectal cancer.

Lindner et al. reported on two metastatic breast cancer patients treated with Y-90-FAPI-04 as a proof of concept. They both reported an immediate reduction in pain. Dr. Baum at Bad Berka has treated 10 patients with a single low dose of Lu-177-FAP-2286. It accumulated in tumors, and had no associated toxicity. There was some symptomatic relief in some patients, and he plans to give them a second injection.

It is also possible to target fibroblast growth factors using inhibitors rather than radioactive agents, as described in this article.

Recently, we saw how two PET indicators were more sensitive than one. In that study, a GRPR-targeted ligand was paired in the same molecule with an integrin-targeted ligand. Integrins are created downstream from fibroblasts. GRPR is found in prostate cancer cells but is also highly expressed in gastrointestinal and CNS tissues. This limits its usefulness as a therapeutic target. However, the concept of double therapeutic targets is potentially useful for prostate cancer, where both PSMA and FAPI may be targeted.

Clinical Trials

In the US, preliminary clinical trials of FAPI-targeted PET indicators have begun.

• This one  at Stanford
• This one and this one at UCLA

So far, there are no therapeutic trials of Lu-177-FAPI that I am aware of, although the Haberkorn group may well be doing exploratory work. Big Pharma has taken notice; Lantheus, Novartis, Clovis, and Avacta have announced investments.

There is also a fibroblast inhibitor, erdafitinib, being explored in clinical trials:

• This one at M.D. Anderson
• This one at UW Seattle

Why Lutetium-177-PSMA treatment sometimes may not help, and may even harm

(updated)

Lu-177-PSMA usually improves survival

We've seen in a couple of small trials in Germany and Australia that Lu-177-PSMA seemed to provide better than expected survival. In Germany, median overall survival was 12.9 months across 104 patients. In Australia, median overall survival was 13.3 months across 50 treated patients. In both trials, all or almost all patients had already received taxane chemotherapy and either enzalutamide or abiraterone. There was no control group in either trial, so we can only guess at what overall survival would have been without the therapy.

In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link),  median overall survival was 14.4 months with Xofigo vs. 11.3 months with placebo. The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival.

In a recent trial of Jevtana as a third-line therapy, after docetaxel and either abiraterone or enzalutamide, median overall survival was 13.6 months for Jevtana vs. 11.6 months for the other second-line hormonal. 

So, in heavily pre-treated patients, Lu-177-PSMA seems to improve survival about as well as Xofigo or Jevtana when used as a third-line therapy. The VISION trial  found that LuPSMA treatment increases survival by 5 months in heavily treated patients (similar to Xofigo).

PSA is not always a good indicator of effectiveness, as has been found for Xofigo and Provenge. Lu-177-PSMA reduced PSA in about 2/3 of treated patients in most studies. That leaves about 1/3 of patients who derived no benefit (even though they had PSMA-avid tumors), and waterfall plots showed that a few patients had large increases in PSA following PSMA-targeted therapy.

It is worth noting that the PSMA protein contributes to the survival of the cancer, and just the PSMA ligand that attaches to it has some activity in delaying progression, even without a radioactive component (similar to the way an anti-androgen attaches to the androgen receptor, delaying progression). It is also worth noting that ADT initially increases PSMA expression, but decreases its expression with continued use.

The opportunities are:

• to select patients who are likely to benefit
• give alternative therapies (like Jevtana) to patients who are unlikely to benefit
• provide adjuvant therapies that may increase survival

PSMA avidity - optimal point in time

It has long been known that PSMA is a moving target. The advent of PSMA PET scans has enabled us to track PSMA expression. Cancers that express a lot of PSMA (called PSMA-avid tumors) can be distinguished from cancers that express very little. Radiologists determine avidity by comparing the uptake of the tracer in cells that express PSMA to the uptake of the tracer in cells known to not express PSMA. Early low-grade prostate cancer does not express PSMA at all. Higher grade prostate cancer may express some PSMA. PSMA expression really starts to take off when the cancer metastasizes, although it is highly variable between patients. About 90-95% of metastatic men express at least some PSMA on their prostate cancer cells. At some point, however, as genomic breakdown continues, PSMA is no longer expressed by metastases. Treating when PSMA is not adequately expressed can cause a lot of toxicity to healthy tissues (especially kidneys and salivary glands) and little therapy (see this link and this one). Thus, there is an optimal point for treating each patient with PSMA-targeted therapy. Treatment too early or too late, may exert selective pressure on the predominant non-PSMA-types, allowing them to take over.

Michael Hofman and others at the Peter MacCallum Cancer Center in Melbourne (see this presentation and this link) have initiated several clinical trials using Lu-177-PSMA at earlier stages of disease progression:

• #lutectomy trial (Declan Murphy,  PI) is treating PSMA-avid high-risk patients with Lu-177-PSMA, followed by prostatectomy and pelvic lymph node dissection
• #upfrontPSMA (Arun Asad, PI) is treating patients first diagnosed with high volume metastases with Lu-177-PSMA + ADT + docetaxel vs ADT + docetaxel.

Other opportunities for early use include Lu-177-PSMA treatment for those in the following settings:

• active surveillance
• persistent PSA after prostatectomy
• salvage treatment after first recurrence
• salvage treatment after second recurrence
• metastatic CRPC before docetaxel or advanced hormonal therapies
• non-metastastic (on bone scan/CT) CRPC before docetaxel or advanced hormonal therapies

Centers in Germany may be willing to treat patients per protocol (i.e., outside of a clinical trial) in some of those situations.

Repopulation

In radiobiology, one of the ways in which radiation can fail to destroy cancer is called repopulation. It means that when radiation kills some cancer cells but leaves many behind, the remaining ones now have access to space in which to expand and access to nutrients and oxygen that the other cancer cells had deprived them of. Paradoxically, the tumor can then grow faster than it ever would have before the treatment. This is sometimes seen with rapidly growing tumors, as some head and neck cancers. They sometimes irradiate those cancers multiple times a day to prevent repopulation.

Repopulation is never seen with X-ray (or proton) treatment of relatively slow-growing prostate cancers. X-rays penetrate throughout the prostate and kill all the cancer there. If there is any survival of an oxygen-deprived tumor core, it will be killed by the next fraction of X-rays in a day or two. However, Lu-177 emits beta rays that may only penetrate to about 125 cells around each target. Ac-225 (also sometimes used in PSMA therapy) only kills about 8 cells around each target. With such short-range killing, there is a real danger of repopulation if there are insufficient PSMA targets within the tumor. Multiple treatments are usually not given for several weeks, and the tumors may have changed by then.

PSMA heterogeneity

What we have learned recently is that not only does PSMA expression change over time, but in a given patient, some tumors may express PSMA and some may not. Moreover, even within a single tumor, some cells may express PSMA and some may not.

Paschalis et al. looked at the degree of PSMA expression of 60 patients with metastatic castration-resistant prostate cancer (mCRPC). They also looked at tissue samples of 38 of them taken when they were diagnosed with hormone-sensitive prostate cancer (HSPC). To detect the amount of PSMA expressed, they used an antibody stain that attaches to the part of the PSMA protein that lies above the cellular membrane. They rated the tumors "0" if there was no PSMA up to "300" if all cells expressed PSMA. They also performed a genomic analysis, looking for mutations in over 100 genes associated with DNA-repair defects.

Among the tumor samples from men with HSPC they found:

• 42% of the 38 men with HSPC  had no PSMA at diagnosis - it only emerged later
• 5 of the 6 HSPC men diagnosed with Gleason score 6 or 7 had little or no PSMA expression at that time
• About half of 30 HSPC men diagnosed with Gleason score 8-10 had little or no PSMA expression at that time
• Those who expressed PSMA had a worse prognosis
• Expression of PSMA varied greatly (heterogeneous) between patients
• Expression of PSMA varied greatly between biopsy samples from the same patient
• The higher the PSMA expression in a patient, the greater the amount of PSMA heterogeneity

Among the tumor samples from the 60 men with mCRPC they found:

• PSMA expression had increased from when they were diagnosed with HSPC
• Half of the tumors with no PSMA at HSPC diagnosis continued to have no PSMA
• 73% expressed PSMA; 27% did not - only 1 of whom had neuroendocrine prostate cancer
• 84% of those expressing PSMA exhibited marked PSMA heterogeneity
• Heterogeneous patterns were identified:

• PSMA positive and negative cells interspersed in a single area
• PSMA-positive islands in a sea of PSMA-negative cells
• PSMA-positive regions separated by >2 mm from PSMA-negative regions
• Some metastases wholly PSMA-positive, some wholly PSMA-negative in the same patient

• Bone and lymph node metastases had similar PSMA expression; liver metastases (none neuroendocrine) had lower PSMA expression

Analysis of DNA-repair defects revealed:

• mCRPC patients with DNA-repair defects had higher PSMA expression
• HSPC patients without DNA-repair defects were less likely to become PSMA-positive
• Patients treated with PARP inhibitors were more likely to respond if they were PSMA-positive
• For validation, in a separate sample of tumors, those with DNA-repair defects were found to have much higher PSMA expression than those without such defects. This was especially true for somatic mutations in BRCA2, ATM, and dMMR.
• PSMA was downregulated in androgen-independent basal cancer cells (resistant to advanced anti-androgens) and neuroendocrine cells.

The significance of this study is that it may explain why about a third of PSMA-avid patients do not respond to Lu-177-PSMA therapy. The emitted beta particles may kill cells within about 125 cells from where they are attached at the PSMA site. Thus cells that do not express PSMA that are more than 2 mm from a PSMA-avid site will not be killed (see "Repopulation" above).

The authors hypothesize that DNA-damage repair defects cause PSMA to proliferate. If they are right, a PARP inhibitor (like olaparib), which has also been found to be effective when there are DNA-repair defects (see this link), may be able to increase the efficacy of PSMA treatment. This is the subject of an ongoing clinical trial.

(update 2/24/23) Sayar et al. report the results of a PSMA autopsy study.

• 25% had no detectable PSMA
• 44% had heterogeneous PSMA expression in multiple metastases
• 63% had at least one PSMA-negative metastasis
• Loss of PSMA expression was linked to epigenetic changes on the FOLH1 gene
• Treatment of cells (in vivo and in vitro) with HDAC inhibitors restored PSMA expression
  

HDAC inhibitors are available off-label and include: Valproic Acid (Depakote), Zolinza (vorinostat), Beleotaq (belinostat), Faridak (panobinostat), and Buphenyl (phenylbutyrate).

Practical detection of heterogeneity/ clinical trials

Now that we know that heterogeneity can impact Lu-177-PSMA effectiveness, it behooves us to find a way of determining the degree of heterogeneity without doing a biopsy of every single metastatic site. One way is to give each patient two PET scans, so they could see the sites that exhibited PSMA expression as well as the sites that exhibited high uptake on an FDG PET scan.

It is futile to offer PSMA-targeted therapy if there are many sites that show up only on an FDG PET scan but few sites that display uptake of PSMA. It also may be futile to treat patients that show some sites where PSMA and FDG sites do not overlap - "discordant." On the other hand, where there is a high degree of overlap between FDG and PSMA - "concordant" - the PSMA radiotherapy will kill both cancers simultaneously. Of course, the ideal candidate would display only highly PSMA-avid sites.  Thang et al. reported on the survival of 30 patients who were treated with Lu-177-PSMA (who were either high PSMA/low FDG or concordant, compared to 16 patients who were excluded based on lack of PSMA (8 patients) or a high degree of discordant sites (8 patients). All patients were heavily pretreated.

• Treated patients survived 13.3 months (median)
• Untreated patients survived 2.5 months (median)

(update 12/2020) Michalski et al. looked at 54 patients. Some had at least one tumor that was positive on FDG, but negative on PSMA (FDG+/ PSMA-). They compared outcomes to patients that had only PSMA+ tumors. They found:

• A third of patients had at least one FDG+/PSMA- tumor
• Overall survival was FDG+/PSMA- patients was 6 months
• Overall survival for PSMA+only patients was 16 months

(update 2/16/22) A secondary analysis of the TheraP trial of Jevtana vs LuPSMA looked at patient response depending on whether their cancer showed up also on FDG PET scans. They looked at the percent of men whose PSA reduced by 50% or more (PSA50) in the cohort that received cabazitaxel vs the cohort that received Lu177PSMA. Each cohort was analyzed according to whether they were highly avid on a PSMA PET scan (SUVmean≥10) "high PSMA" and whether their metabolic tumor volume on an FDG scan was greater than 200ml (MTV≥200) "high FDG". They required high PSMA (SUVmax≥20), and excluded men who were FDG+ and PSMA-.

• In men with high PSMA, the PSA50 was 91% for Lu177PSMA vs 47% for cabazitaxel
• Among men with high PSMA, the odds ratio of responding to Lu177PSMA was 12.2 vs 2.2 for cabazitaxel 
• In men with low PSMA, the PSA50 was 52% for Lu177PSMA vs 32% for cabazitaxel
• In men with high FDG, the PSA50 was 57% for Lu177PSMA vs 20% for cabazitaxel
• Among men with a high FDG, the odds ratio of any response to either treatment was 0.44
• In men with low FDG, the PSA50 was 70% for Lu177PSMA vs 44% for cabazitaxel

It is unknown whether the survival of untreated patients might be longer or shorter had they received treatment. It is possible that discordant patients may benefit from sequenced (before or after) or concomitant treatment with:

• chemotherapy- 
• for non-discordant, newly diagnosed, with high-volume metastases in Australia
• for patients who have progressed after an advanced hormonal and docetaxel, this Australian trial combines it with cabazitaxel.
• immunotherapy: 
•  trials of adjuvant Keytruda in UCSF and Melbourne
•  trial of combo with Keytruda and Yervoy in Australia
•  trials of a bispecific PSMA/ T cell-recruiting antibody (BiTE) in: 
1. Los Angeles, Europe & Australia (AMG 160) (early results)
2. AMG 160 + Xtandi/Zytiga + PD1i
3. City of Hope, LA AMG 509
4.  NY (REGN5678) -> trial ended for toxicity
5. Germany AMG 212 (CD3/CC1) (Phase 1 results)
6. various US sites (HPN 424) (early results) -> trial ended
7.  various sites in N. America (JNJ 63898081)
8. TNB-585 (5 US sites)
9. CB-307 (UK)
10. LAVA1207 (4 US sites)
11. JNJ-80038114 (Nashville, France, Germany, UK)
• trial of a CAR-T/PSMA therapy at UOP, Thomas Jefferson U & Columbia and Shanghai and City of Hope
• Phase 2 trial (completed) of Progenics' antibody-drug conjugate  (PSMA ADC 2301)
• Xofigo for bone metastases - trial of a therapy that may include both
• With EBRT to oligomets in recurrent patients in Australia
• PARP inhibition - trial in Melbourne
• Enzalutamide (Xtandi) randomized trial in Australia
• Adding a systemic radiosensitizer: Veyonda (idronoxil) suppository. A phase I/II trial  found it was safe, with only anal inflammation attributable to the suppository. Results were no better than trials without the radiosensitizer; however, unlike those other trials, almost all (91%) patients had already received Jevtana.
• other novel non-PSMA targeted treatments

It is possible that such adjuvant treatment may decrease the population of discordant sites, and minimize repopulation effects.

Based on this new knowledge, it is recommended that patients who are good candidates for Lu-177-PSMA therapy have both a PSMA PET/CT scan and an FDG PET/CT at around the same time. FDG PET scans are generally covered by insurance; PSMA PET scans are not covered by insurance yet.