Wednesday, September 9, 2020

Adding ADT to external beam radiation only benefits unfavorable risk patients

In 2013, Zumsteg et al. proposed a refinement in the NCCN "intermediate risk" classification into two subcategories, "favorable intermediate-risk (FIR)" and "unfavorable intermediate-risk (UIR)." Based on retrospective studies with short follow-up, they discerned that the two subgroups had divergent prognoses when treated with external beam radiation and adjuvant androgen deprivation therapy (ADT). Since then, others have found that it is also a useful division for deciding whether brachy boost therapy is beneficial (see this link), or whether it is beneficial to add ADT to brachytherapy (see this link). Some FIR patients may be suitable candidates for active surveillance.

It has also been found to be a useful division in terms of prognosis following surgery, brachytherapy, and SBRT (see this link). Some clinical trials use the definition to distinguish  "favorable risk" (low risk or FIR) from "unfavorable risk" (UIR or high risk).  Since 2016, NCCN has incorporated the distinction in its risk stratification system.

The NCCN definitions are as follows:

The NCCN intermediate-risk group is currently defined as having any of the following:
- Stage T2b or T2c, or
- PSA 10- 20 ng/ml, or
- Gleason score = 7 
(If multiple risk factors are present, the clinician may optionally deem it high risk)

Unfavorable Intermediate Risk (UIR):
- NCCN intermediate risk, as defined above, plus
- Predominant Gleason grade 4 (i.e., Gleason score 4+3), or
- Percentage of positive biopsy cores≥ 50%, or
- Multiple NCCN intermediate risk factors

Favorable Intermediate Risk (FIR):
- NCCN intermediate risk, as defined above, but only those with
- Predominant Gleason grade 3 (i.e., Gleason score 3+4 or 3+3), and
- Percentage of positive biopsy cores <50%, and
- No more than one NCCN intermediate risk factor

Now, it has been found to be a useful distinction in an unplanned secondary analysis of a randomized clinical trial, with 17.8 years of median follow-up. Such a long follow-up is unusual for a clinical trial and gives us the ability to see significant numbers of mortality and metastases even in intermediate-risk patients. The trial, RTOG 9408, was originally conducted among 1,068 intermediate-risk patients who received 66.6 Gy to the prostate (low by today's standards) and 46.8 Gy to the pelvic lymphatics. Half the patients received 4 months of adjuvant ADT, and half received none. They lacked biopsy core information on 16%, who are excluded from their analysis. Zumsteg et al. found that adding 4 months of ADT:

  • more than doubled 15-year metastasis-free survival and prostate cancer-specific survival among UIR patients. Mean overall survival was 0.7 years longer with ADT.
  • had no statistically significant effect on 15-year metastasis-free survival, prostate cancer-specific survival, or overall survival among FIR patients
  • it took about 6 years for the differences to start to be noticeable.

Given all the retrospective studies we've seen before that all point to FIR vs UIR as a useful and significant distinction, this is not surprising. It did take a lot of work to review pathology reports on almost a thousand patients, and the authors are to be commended for doing so. If it spares some FIR men from being overtreated, it was a worthwhile effort.

Tuesday, August 11, 2020

PSMA-targeted radiopharmaceutical clinical trials in the US

Now that the VISION trial of Lu-177-PSMA-617 is no longer recruiting, some patients are wondering if they can still get PSMA-targeted radiopharmaceuticals in the US, without traveling to Germany, Australia, India, etc. Here is a list of trials that are active, still open to recruitment, or will soon be recruiting. 

Unless otherwise noted, they are all for men who are: 

  • metastatic
  • castration-resistant 
  • have had at least one taxane chemotherapy
  • at least one of the advanced androgen receptor therapies (e.g., Zytiga, Xtandi, Erleada, or Nubeqa)
  • no Xofigo
  • PSMA-avid on a PSMA PET/CT scan

Links that have contact information are provided.

Radiopharmaceutical

Adjuvant drugs

Extra criteria

Recruitment status/ contact

Locations

Lu-177-PSMA-617

Keytruda

No chemo since castration resistant

recruiting

UCSF

Lu-177-CTT1403

 

No Jevtana

recruiting

UCSF

Lu-177-PSMA-617

 

 

recruiting

•Weill Cornell

•Tulane (not yet)

Th-227-Antibody

(see article)

 

 

recruiting

• Royal Marsden (UK)

• Finland

• Tulane (not yet)

• MSK 

Lu-177-J591

Ketoconazole

Prior RP or RT

Castration-resistant

Non-metastatic

recruiting

• Weill Cornell

• USC

• Georgetown

• IU

• U of Iowa

• UPMC

Lu-177-PSMA-R2

 

 

recruiting

• Stanford

• Yale

• Tulane

• Johns Hopkins

• Mt Sinai

• MD Anderson

• U of Wisconsin

Ac-225-J591

 

 

recruiting

• Weill Cornell

• Tulane (not yet)

Ac-225-J591

 

 

recruiting

• Weill Cornell

• Brooklyn Methodist

Lu-177-PSMA-617

(VISION)

 

 

Active, not recruiting

• 84 locations

Results expected August 2020

I-131-1095-MIPS

(see article)

Xtandi

Chemo naïve

Failed Zytiga

Active, not recruiting

• 17 locations

Results expected December 2021

 



Friday, July 10, 2020

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

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

"Treating PSA"


I. Selecting for low PSA subtypes


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

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

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

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

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

II. Supplements that interfere with PSA tests


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

III. SBRT of oligometastases


1. Exponential growth


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

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


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

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

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

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


2. PSA-based Endpoints


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

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

The earliest endpoints that can be used to measure the success of a prostate cancer therapy are PSA based. All of the following surrogate/secondary endpoints are PSA based:
  • PSA50 - the percent who had a reduction in PSA by 50% or more
  • Nadir PSA - the lowest PSA reached after therapy (see this link)
  • PSA doubling time (PSADT) - whether the therapy slowed PSA growth
  • Biochemical recurrence (BCR) - depending on initial treatment, and there may be multiple salvage therapies, each with a PSA failure defined for it (see this link)
  • Biochemical Recurrence-Free Survival (bRFS)
  • Biochemical failure (BF)- rise in PSA by a pre-specified amount post-therapy
  • Biochemical No Evidence of Disease (bNED)
  • Time to BCR/ BF
  • Time to start of lifelong ADT (based primarily on a pre-defined PSA failure benchmark)
  • Failure-free survival (FFS) or Progression-free survival (PFS) or Event-free survival (EFS) - defined as BF or radiological progression or clinical progression or death. 
The following surrogate endpoints are not PSA-based:
  • Clinical Progression-Free Survival (cPFS) - worsening of symptoms or performance status (see this link)
  • Radiographic Progression-free Survival (rPFS) or Disease-free survival (DFS)- progression on scans or death
  • Objective Response Rate (ORR) - tumor size or number reduction using RECIST criteria
  • Change in Bone Scan Index
  • Time to radiographic progression or failure
  • Metastasis-free survival
  • Clinical progression - pain, bone fracture, spinal compression
As an example of circular reasoning, we can see in the ORIOLE trial that 6-month Progression Free Survival (PFS) was chosen as the primary endpoint. PFS was defined as  PSA progression (by >25% over nadir and by > 2 ng/ml) or radiographic progression or death. As we can readily see in the exponential growth curve, the odds of a new metastasis on a bone scan/CT are very low and there are not likely to be any deaths. Therefore, PFS was almost entirely PSA progression. But the protocol "treated PSA." It is therefore illogical to conclude, even for a Phase II trial, that oligometastatic treatment slowed progression.

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

3. Danger of Withholding Early ADT


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

Some patients (and doctors) believe that by delaying ADT, they can increase their quality of life, and delay castration resistance. Neither is true. Contrary to popular belief, decreasing the intensity of hormone therapy and delaying its use brings earlier castration resistance and death. The strongest evidence for this comes from the STAMPEDE (on Zytiga and Xtandi), LATITUDE, and SPARTAN trials. Among men who were newly diagnosed with metastatic prostate cancer:
  • Overall survival was longer if men used Zytiga + ADT.
    • No difference based on the number of metastases
    • Failure-free survival was longer if they used Zytiga  + ADT
  • Overall survival was longer if men used Xtandi+ADT
    • Survival was especially lengthened if there were fewer metastases 
    • PSA progression-free survival was longer if they used Xtandi+ADT
  • Overall survival was longer if men used Erleada+ADT
    • PSA progression-free survival was longer if they used Erleada+ADT
A clear pattern emerges: early use of intensive hormone therapy prolongs survival and prolongs the time to castration resistance. Men who were oligometastatic benefited from early, intense hormone therapy.

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

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

Maha Hussain reported the results of a randomized clinical trial comparing intermittent vs continuous ADT in recurrent men with metastases. She found that:
  • Time to castration resistance was not different for the two protocols (Figure S5)
  • For men with minimal disease, overall survival was 6.9 years for those on continuous therapy vs 5.4 years for those on intermittent therapy. The trial was underpowered for this difference to reach statistical significance.
  • It took 4-5 years for the survival curves to start separating - long follow-up is needed to detect survival differences.
Taken together, all these major randomized clinical trials show that the best way to use ADT in the oligometastatic setting is to use it early and heavily. Reducing the number of cancer cells as quickly and effectively as possible, even reducing those cells that haven't begun to measurably contribute to PSA, extends survival. The effect of evolutionary selection pressure allowing castration-resistant cells to survive is dwarfed by the reduction in sheer numbers. Circular reasoning may harm patients.

4. Future Clinical trials

We have learned some lessons about clinical trials for oligometastatic treatment:
  • It has to have long enough follow-up, depending on the setting: at least 5 years for  newly diagnosed or recurrent men to allow time to get to the steep part of the exponential curve. It will take longer if more sensitive imaging is used.
  • It must use radiographic progression-free survival, or similar, as its primary endpoint
  • It must not use a PSA-related endpoint
  • ADT must be used in at least the control group. It would be unethical to withhold the standard of care (see AUA Guidelines for Advanced Prostate Cancer (mHSPC 14-18)) .
  • It should preferably use a PSMA PET/CT to locate metastases. The ORIOLE trial only found an advantage if patients were oligometastatic on both a PSMA PET/CT and a bone scan/CT. The use of more sensitive imaging will move the starting point to the left on the exponential curve, so it will take that much longer to detect a benefit.
These randomized clinical trials (RCTs) are currently active:
  • The CORE RCT (active, no longer recruiting) at Royal Marsden Hospital in London will have 5 years of follow-up (completion in 2024), and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
  • The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in 2025) and has radiographic progression-free survival as its primary outcome. 
  • The PLATON RCT (among hormone-sensitive patients) in Canada will have 6 years of follow-up (primary outcome in 2025) and has radiographic progression-free survival as its secondary outcome. Oligometastatic men who have never had their prostates treated with RT will have prostate radiation too in both arms. ADT is given in both arms, advanced hormonals and chemo at the physician's discretion.
  • The STEREO-OS RCT (recruiting, study completion in 2022) in France will look at radiographic progression-free survival with follow-up of up to 3 years. 
  • The FORCE RCT at the University of Michigan (primary completion in 2022) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful in among men with mCRPC as it is in men with newly recurrent disease.

Wednesday, June 10, 2020

Testosterone Therapy Does Not Increase the Risks of Prostate Cancer Recurrence or Death After Definitive Treatment for Localized Disease

In the largest observational study so far, Sarkar et al. reported that men in the US Veterans Administration (VA) database who received surgery or radiation for localized prostate cancer and then received testosterone replacement therapy (TRT) for low testosterone were at no greater risk for recurrence than a matched sample of such men who received no TRT.

The VA database included 28,651 men treated with prostatectomy (RP) and 41,333 men treated with primary radiation (RT) between 2001-2015. Of those men:
  • 469 of the RP group received TRT
  • 543 of the RT group received TRT
  • Median follow-up was 7 years
Comparing the men who received TRT to a matched group of men who didn't, they found:
  • There was no difference in biochemical recurrence
  • There was no difference in prostate cancer mortality
  • There was no difference in overall mortality
The database did not include data on serum testosterone levels or duration of TRT.

This confirms a couple of smaller (sample size about 100) retrospective studies at Baylor College of Medicine on men who had received RP and RT.

Before treated men rush out to supplement testosterone, we should acknowledge that all of these studies are retrospective. Although the authors of the VA study made an effort to match the patient and disease characteristics of men who received TRT and those who did not, it is entirely possible that there were characteristics that were not included in the database. In other words, doctors may have been biased by other factors to select patients for treatment.

We should also acknowledge that in the Baylor studies and others, PSA did increase after TRT in both groups, although usually not to the extent that a biochemical recurrence was declared. This is expected in men who received RT because they still have intact prostates that may still secrete PSA from benign sources. However, it is more concerning in men who have had RP because benign prostate tissue should have been eliminated, and even Gleason score 6 prostate cancer may progress, albeit slowly (see this link).

Until we have a prospective randomized trial (like this one with results expected in 2024), patients and their doctors must make this decision based on available data and judgment. While it is undoubtedly true that castration levels of testosterone (below 50 ng/dl) discourage prostate cancer progression, Morgentaler's testosterone saturation theory says that above some minimal testosterone level (around 120 ng/dl), adding more testosterone does not further encourage prostate cancer progression. Many urologists now believe this. However, testosterone sold in the US is required to have a black box warning against its use in men who have had prostate cancer. Getting one's doctor to prescribe it may be challenging.

Also, see the following articles about the experimental use of high-dose testosterone for metastatic prostate cancer:





Thursday, June 4, 2020

Importance of Adding ADT to Brachy Boost Therapy for Men with Unfavorable-Risk Prostate Cancer

Last month, we looked at Level 1 evidence (highest level, superseding all previous studies) that for unfavorable risk patients, brachy boost therapy (BBT) [external beam therapy (EBRT) with a brachytherapy boost to the prostate] has better results when accompanied by 18 months of androgen deprivation therapy (ADT). (see this link)

Now a meta-analysis has reaffirmed that finding. The two studies were probably submitted for publication at about the same time, which explains why the meta-analysis doesn't include data from RTOG 01.03 RADAR. In the Jackson et al. meta-analysis (and Medpage summary), there were:
  • 6 randomized trials of EBRT with or without ADT comprising 4,663 patients.
  • 3 randomized trials of EBRT with or without a BBT comprising  718 patients.
    • One of those trials included ADT, the other two did not
Their analysis found that ten-year overall survival was:
  • improved by 30% by the addition of ADT to EBRT
  • not improved by the addition of BBT to EBRT (at least when ADT was not included)
  • The addition of ADT had a bigger impact than the addition of BBT
  • The trial that included both ADT and BBT had the best results
Because this meta-analysis included trials with men from different risk levels, it gives no direction about which therapy is best for favorable- vs unfavorable-risk men. DART 01/03 GICOR proved that adjuvant ADT only provides an added benefit to EBRT in high-risk men (vs intermediate risk men). Furthermore, BBT did not benefit and did add toxicity to favorable-risk patients (see this link).

Some of the trials did not include radiation doses now considered curative. It also did not look at ADT duration.


Sunday, May 31, 2020

Lu-177-PSMA-617 vs Jevtana (cabazitaxel): which should I do next?

We saw recently (see this link) that of chemo and hormonal medicines for metastatic castration-resistant prostate cancer (mCRPC), Jevtana (cabazitaxel) is the preferred third treatment after Taxotere (docetaxel) and Zytiga (abiraterone) or Xtandi (enzalutamide). But when should radiopharmaceuticals, either approved ones like Xofigo (Ra-223), or prospective ones like Lu-177-PSMA-617, be used in the optimal sequencing?

Michael Hofman reported some early results of the TheraP randomized clinical trial (RCT) at the recent ASCO meeting. They randomized some well-selected patients to receive either Lu-177-PSMA-617 or Jevtana. Patients were selected according to the following criteria;
  • mCRPC (PSA≥20 ng/ml and rising)
  • must have had docetaxel
  • must had either Zytiga or Xtandi or both
  • healthy, with good liver, kidney and blood function
In addition, all patients received both an FDG PET scan and a PSMA PET scan. They were excluded from the trial if either:
  • Their metastases were insufficiently PSMA-avid - (10% excluded)
  • There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) - (18% excluded)
  • 85 patients were treated with Jevtana
  • 98 patients were treated with Lu-177-PSMA-617

The endpoint used was the percent of patients whose PSA declined by at least 50% (PSA50) from baseline after the treatment. After a median follow-up of 13 months:
  • Lu-177-PSMA-617 had a PSA50 of 66% vs 37% for Jevtana
  • The percent who had PSA progression was 31% less in those getting Lu-177-PSMA-617 relative to those getting Jevtana
  • It is too early for data on overall survival
  • Serious/life-threatening adverse events occurred in 35% of those taking Lu-177-PSMA-617 vs. 54% of those taking Jevtana
  • The most common adverse events reported by those taking Lu-177-PSMA-617 were fatigue, dry mouth/eyes, low platelets, nausea, and anemia. Only 1 patient discontinued for toxicity.
  • The most common adverse events reported by those taking Jevtana were fatigue, diarrhea, nausea, loss of taste, neuropathy. dry mouth, and neutropenia, 5 patients discontinued for toxicity
Given the comparatively low toxicity, it seems like Lu-177-PSMA-617 should usually be the preferred third treatment, over Jevtana, although longer follow-up will be needed to see if there will be a survival difference.

This study further highlights the importance of getting both an FDG and a PSMA  PET scan at about the same time.

PSMA expression is highly variable. It is not expressed in low grade cancer in the prostate. Expression increases as metastases develop, reach a peak, and then decrease. PSMA expression also increases when second-line hormonals are first used, but then decreases with continued use. Given this variation over time and treatment, several questions about PSMA-targeted therapy remain unanswered:
  • Should it be used soon after second-line hormonals?
  • Should it be used before or soon after docetaxel?
  • Would the problem of heterogeneity be minimized if Jevtana and Lu-177-PSMA were given simultaneously?
  • Should it be used in minimally metastatic patients?
  • Should it be used in newly diagnosed metastatic patients?
  • Should it be used with immunotherapies (e.g., Provenge, Checkpoint inhibitors)?
  • Will PARP inhibitors enhance the cell-kill rate?
  • Is PSA the best biomarker of effectiveness?
  • What are the best radionuclides to use (e.g., Ac-225, Th-227)?
  • What are the best/most specific ligands to use? (e.g., PSMA-617, PSMA-I&T)
  • Are there better surface proteins to target, perhaps simultaneously (e.g., FAPI)
  • How do they compare to PSMA BiTE therapies?
  • How does it compare to Xofigo for bone metastases?

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.

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).

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.

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.