Monday, April 27, 2020

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 marginadmixture 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.

Monday, April 20, 2020

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.

Sunday, April 19, 2020

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.

Sunday, April 12, 2020

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:
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.

Wednesday, April 8, 2020

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.