Nadir PSA predicts survival after radiation and androgen deprivation for unfavorable risk patients

If a treatment isn't working, we want to know as quickly as possible so we can try a salvage therapy while it can still make a difference. We want a measure of effectiveness, called a surrogate endpoint, that will predict survival, and we usually turn to PSA as our best early indicator. But there are different ways of defining mortality, and different measurements utilizing PSA. In an analysis of a randomized clinical trial (available here), the researchers sought to answer these questions for unfavorable risk patients who were treated with external beam radiation (EBRT) + androgen deprivation (ADT).

The purpose of the randomized clinical trial (NCT00116220) was to determine whether adding 6 months of androgen suppression improved freedom from biochemical failure over radiation therapy alone. This was a secondary analysis of the data. The details of the study were as follows:

• All patients were "unfavorable risk," defined as PSA between 10 and 40 ng/ml or Gleason score ≥7 or extracapsular extension or seminal vesicle invasion.
• Men were screened for minimal of no comorbidities.
• Median age was 72.
• They all received 70.2 Gy of 3D-CRT at 6 hospitals in the Boston area between 1995 and 2001
• Half (78 men) got 6 months of ADT with the radiation; half (79 men) had radiation without ADT
• PSA was evaluated every 3 months for 2 years, every 6 months for 3 years, and then annually.
• When PSA climbed above 10 ng/ml they received salvage ADT.

In selecting the kind of "mortality" they wanted to use as the gold standard endpoint, the researchers selected "age-adjusted all-cause mortality (ACM)" rather than "prostate cancer-specific mortality." This was a reasonable choice for several reasons:

• It is often difficult to discern whether  prostate cancer was the final cause of death. Men may die of kidney or liver failure or other final causes that are consequences of their prostate cancer. 
• Prostate cancer has been found to be associated with other causes of death. 
• The men in this study were only included if they had no or minimal comorbidities that might contribute to their death. 
• Men were eventually diagnosed with metastatic castration-resistant prostate cancer, and most had received chemotherapy.
• The mortality was age-adjusted for actuarial death rates. 
• Follow-up was long enough (16.5 years, median) so that even slow-killing prostate cancer would be a significant cause of mortality.

They examined 4 PSA-related metrics as potential surrogate endpoints:

1. PSA failure, defined as nadir + 2.0 ng/ml
2. PSA nadir > 0.5 ng/ml
3. PSA doubling time < 9 months
4. Time to PSA failure < 30 months

They had several criteria for inclusion. Basically, they wanted to find metrics that predicted mortality, and that continued to make a difference in survival time after the effect of the adjuvant ADT no longer extended survival. All but "PSA failure" met their criteria. Of the remaining 3 metrics, PSA nadir > 0.5 ng/ml had the largest effect in explaining survival.

The following table shows the percent of 8-year all-cause mortality for each surrogate endpoint, when it was met and when it wasn't, and the percent of the treatment effect (adjuvant ADT) explained by each metric.

	Percent mortality at 8 years		Percent of treatment effect explained by metric
Endpoint achieved:	YES	NO
PSA failure	32.5%	11.8%	NA
PSA nadir > 0.5 ng/ml	47.4%	13.6%	104%
PSA doubling time < 9 mos.	40.7%	14.1%	43%
Time to PSA failure < 30 mos.	39.4%	15.3%	41%

If the PSA nadir was over 0.5 ng/ml, it predicted the biggest difference in mortality. It also explained essentially all of the treatment effect of the added ADT.

Before anyone gets worried that their PSA is over 0.5 ng/ml, we must remember what "nadir" means. Because this analysis was done in hindsight, nadir is the lowest PSA ever achieved after treatment. It was not, in this case, the lowest value achieved so far. It often takes 5 or more years to achieve the nadir after radiation. For those who received adjuvant ADT with their radiation, the nadir will be achieved while they are still on ADT, and the PSA may rise above the nadir as the effect of the ADT wears off.

A nadir of only 0.5 ng/ml among those taking ADT in this clinical trial suggests that the ADT was not working completely. I assume that ADT was begun 2 months before the EBRT, continued during the 2 months of EBRT, and was continued for 2 months after that (6 months total). If the first PSA was taken 3 months after EBRT completion, the effect of the ADT had not worn off yet. Some of the cancer must already have been castration resistant. Patients received a bone scan, but some must have already had metastases that were too small to be detected by it. We see this reflected in how quickly the metric predicted mortality. In as quickly as one year from the start of treatment, mortality was 20% among those who had already reached a nadir, and it was over 0.5 ng/ml vs. 0% in those who hadn't reached it. At year one, the percent who had met the endpoint was negligible for the other endpoints. Clearly, patients with a PSA that never goes down below 0.5 ng/ml after radiation +ADT are at greater risk.

The authors recommend that patients whose PSA never achieves a nadir below 0.5 ng/ml after EBRT plus 6 months of ADT should be recommended for clinical trials of early use of second-line hormonal agents, chemotherapy, and other new therapies. This is a logical implication, but it is not likely to occur very often because standard of care has changed since this clinical trial began.

The DART 01/05 GICOR randomized clinical trial proved that among high risk patients, 28 months of adjuvant ADT was superior to the 6 months of adjuvant ADT that were used in the present study. It is less likely that the nadir will stay above 0.5 ng/ml with the longer course of ADT and with the escalated radiation dose (of about 80 Gy) that is now standard of care. So while a nadir > 0.5 ng/ml in this situation is still an endpoint indicating elevated risk, few patients will be observed to exhibit it.

SpaceOAR hydrogel - is the difference worthwhile?

SpaceOAR hydrogel is spacer injected between the rectum and the prostate that increases their separation. This allows less radiation targeted at the prostate to hit the rectum. They published an interim 15-month report in 2015, and now Hamstra et al. have published their final report based on 3 years of follow-up.

The clinical trial was conducted at 20 participating institutions between 2012-2013 among patients who were to receive IGRT/IMRT as their first-line therapy for low- or intermediate-risk prostate cancer. Additionally, no more than 50% of biopsy cores were positive, ADT was not used, and prostates larger than 80 cc were excluded. The test was "single blinded:" physicians implanted the gel at the same time fiducials were implanted, but patients did not know if they received the spacer. All patients received 79.2 Gy of IMRT with 5-10 mm margins. 149 men were randomly assigned to the Spacer group. The Control group comprised 73 men.

While the researchers report physician-assessed toxicity data, they also collected patient-reported quality-of-life outcomes. Patient-reported outcomes are not subject to reporting bias, and are collected using well-validated questionnaires (EPIC). Patients did not know if they received the spacer. Patients filled out comprehensive questionnaires at baseline, 3 months after treatment, and then at month 6, 12, 15 and 36. On the EPIC questionnaires, a minimally important difference (MID) has been previously found to be a decline of 5 points, 6 points, and 11 points for rectal, urinary and sexual side effects, respectively. The researchers also reported the percent of patients whose quality-of-life scores declined significantly to a level that was at least twice as great (2X MID).

Acute toxicity

The change at 3 months compared to baseline represents the acute effects of radiation. This is the period of maximal deleterious effect of radiation on rectal and urinary quality of life. After 3 months, quality of life typically improves. The exception to this rule is sexual quality of life, which may continue to deteriorate, largely due to age (see this link).

At 3 months, the percent of patients who were bothered by any bowel-related side effect (moderate or big bother) was 9.4% among the Spacer group, and 5.7% among the Control group. The difference was not statistically significant. The only component (components included such morbidities of diarrhea, blood in stools, urgency, frequency, etc.) of bowel bother that was statistically significant was bowel pain, which was reported as a moderate or big bother by 6.8% of the Spacer group and none of the control group. The spacer made bowel pain worse rather than better.

Physician-reported grade 2 acute toxicity at 3 months was exactly the same (4%) for both the Spacer and the Control group. The spacer had no effect on any but the mildest acute toxicity.

Urinary scores were not significantly affected by the spacer. Among the Spacer group, 22.8% evaluated their urinary-related side effects as a moderate or big bother. Among the Control group, 17.1% evaluated it as a moderate or big bother. The difference between the two groups was not statistically significant, nor were any of the components of urinary function (e.g., pain, urgency, waking up to urinate, weak stream, frequency, etc.).

Bothersome sexual effects were also not significantly different between the Spacer and Control group, and at 3 months, were similar to baseline.

Late-term toxicity

At 36 months after treatment, 2.2% of the men in the Spacer group evaluated their bowel function as a big or moderate bother. This compares to 4.4% in the Control group -- not a statistically significant difference. None of the components of rectal bother were significantly better in the men who received the Spacer, although the scores were directionally better in almost every component. Quality of life in the rectal domain for both the Spacer and Control groups were close to their baseline values.

This low rate of bothersome rectal toxicity was confirmed by physician reports of rectal toxicity. Ignoring mild rectal side effects (i.e., grade 1, like blood spots on toilet paper or loose stool) that patients often do not bother to report to their doctors, we see that physician-reported grade 2 or higher rectal adverse events occurred in only 6% of patients, all in the Control group. Only one patient suffered a serious (grade 3) rectal injury in the Control group. It's worth noting that even this small number was an increase from the 15-month report. At 15 months, there was only one patient who had grade 2 or greater rectal toxicity. Late-term rectal toxicity is not a major issue with modern-day radiation.

Late-term urinary scores were not statistically significantly different for Spacer (4.4% big/moderate bother) and Control (8.9% big/moderate bother). Both were improved from baseline. The only component that was significantly worse was urinary frequency (18.2% vs 4.6%). It is unclear why any urinary side effects would be affected at all by a rectal spacer. It may be an artifact of the low sample size at 36 months - just 46 in the Control group, and 94 in the Spacer group.

There were no differences in overall sexual bother between Spacer and Control groups, or in any of its components. In the Control group, big/moderate sexual bother increased from 35.2% at baseline to 41.3% at 3 years. In the Spacer group, big/moderate sexual bother increased from 23.6% at baseline to 28.6% at 3 years. In both cases, sexual bother peaked at 1 year after treatment.

The following table shows the percent of patients in the Spacer and Control groups whose scores in each domain (rectal, urinary and sexual) declined by the minimally important difference (MID) or by at least twice the minimum (2x MID), which would be clinically significant to the patients.

*statistically significant difference between Control and Spacer with 95% confidence

We notice that the spacer moderated the declines in the rectal scores. There was a 16 percentage point improvement in late term rectal evaluations due to the spacer. However, we also saw that the relative decline was not very bothersome to the patients (96% did not find it even moderately bothersome).

What is perplexing here is why the urinary scores would have declined more without the spacer -the clinically notable difference (2x MID) was statistically significant.The dose received by the bladder and urethra was unaffected by the rectal spacer. There was also a rather sudden increase in both urinary and rectal MIDs at the 3-year mark. At all prior time points, there were no statistically significant differences between the Control and Spacer groups. Many respondents were lost to follow-up at 36 months (and over a third were lost) and data may become erratic as sample size gets small.

Is it worthwhile to treat all patients? 

The cost of the SpaceOAR hydrogel injection is about $2,500. IMRT patients should not expect any amelioration of bothersome acute rectal symptoms. A cost/value analysis depends upon which toxicity numbers one wants to focus upon.

1. Even if the difference were statistically significant (and it's not), only 2.2% would avoid bothersome late-term rectal symptoms by using the gel. So to spare one patient bothersome rectal symptoms, 45 patients would have to be treated at a cost of over $90,000. 
2. If we focus on the late-term toxicity improvement, 6% avoided late-term grade 2 or higher rectal symptoms by using a spacer. To spare one patient such symptoms, 17 patients would have to be treated at a cost of $42,500.
3. If we use the 2x MID difference as our guide, 16% would avoid low grade late-term rectal symptoms. So to spare one patient those symptoms, 6 patients would have to be treated at a cost of $15,000. 

Some would argue that even though the symptoms are relatively mild, late-term symptoms are often longer-lasting. Each patient has to decide for himself. Patients who are interested should obtain pre-approval from their insurance. It has been provisionally approved, but Medicare approval is expected in 2018.

Safety must be considered as well. The risks are not large, but neither are they non-existent. In addition to the dangers of anesthesia and infection, there is a small danger that the injection will penetrate the rectal wall or cause a rectal ulcer. Such dangers are small, and undoubtedly diminish with clinician experience.

Rather than treat all radiation patients, it would be much more efficient to identify the patient characteristics that increase the risk of late-term rectal toxicity. The presence of visceral fat, anatomic abnormalities, medications (e.g., anticoagulants and antihistamines), comorbidities (e.g., inflammatory bowel disease and diabetes), smoking, and the microbiome may play a role. There may also be a genetic component, like mutations in DNA repair genes, that renders a patient more susceptible to lasting damage from radiation. Further analysis may help explain why there was no benefit in terms of acute toxicity, and why even this small benefit took 3 years to show up. Dr Hamstra mentioned that analysis is ongoing, and they plan a follow-up presentation at ASTRO next year.

The researchers are to be congratulated on this very well executed randomized clinical trial. There are too few trials like this. In fact, Daniel Hamstra boasted:

"I think this is better than any other study ever performed for prostate cancer.  I know of no phase 3 trials testing a new technique or study which randomized patients and reported benefits for toxicity and QOL.  IMRT has not done it.  Image guided therapy has not.  Proton therapy has not.  Robotic surgery has not.  Nor has any surgical technique.  If you go back to the original Dutch 3D conformal trial published 15 years ago they showed reduced toxicity with 3D conformal RT as compared to 2D RT (but did not collect QOL).  So, this is really a landmark study in that it was randomized (and blinded in that the patients did not know which arm they were on until the end of the trial).

Note: Thanks to Daniel Hamstra for allowing me to read the full text, and responding to my questions.

What should focal therapy be compared to and how does it compare?

In a recently published randomized trial of a new kind of focal ablation therapy for prostate cancer that was widely misinterpreted in mainstream media, the authors wrote:

"A pivotal comparative study was therefore necessary, but was challenging to design in a manner that would be acceptable to both patients and clinicians and in which the same primary outcome [histologically confirmed progression of cancer] could be assessed for the intervention and the comparator. We had three options for the comparator: surgery, radiotherapy, or active surveillance. For the first two options, a primary outcome that could be applied to both the experimental group and the control group proved difficult to find. Surgery (radical prostatectomy) would not be suitable for a biopsy-based outcome because there would be no prostate from which to take a biopsy. Radiotherapy would be amenable to a protocol-required biopsy, but the histological outcome would be confounded by the necessary neoadjuvant and adjuvant androgen suppression that constitutes the standard of care. Therefore, active surveillance was the only comparator that could reasonably be used over the intended time frame [2 years] of the study.

This is an odd statement, indeed. They rejected surgery as a comparator because salvage treatment is usually given before it is possible to obtain histological (biopsy) confirmation of spread to the prostate bed. This is reasonable. They rejected comparison to radiation because it is difficult to interpret a biopsy on tissue in which the cancer has been shrunk by androgen deprivation. However, all patients were low-risk patients who would almost never receive neoadjuvant or adjuvant androgen deprivation along with their radiotherapy, at least not in the US. Perhaps this is or was standard of care in Europe. That left them with active surveillance as a comparator, but the kind of active surveillance and patient selection for it bears closer examination.

Active surveillance as practiced at the time (2011-2013) in those European centers of excellence was different in some important respects from active surveillance as currently practiced in US centers of excellence. In the US, a confirmatory multiparametric MRI (mpMRI) is often given within a year of the first biopsy, and biopsy cores are obtained from any suspicious areas. The authors state that their study began before this practice became prevalent in Europe. In spite of that, all patients who received focal ablation were given an mpMRI before therapy, while none of the men on active surveillance received it. Certainly, many of the men in the active surveillance cohort had undiagnosed higher grade cancer, and should not have continued on active surveillance. It is impossible to say that any of the cancers progressed in the 2 years on active surveillance, or whether they were simply reclassified because the two repeat biopsies found the cancer that was always there, and which might have been found earlier had the received an mpMRI as the ablation cohort did.

The authors further state:

"The European Medicines Agency agreed that we could reasonably exclude very low-risk patients. Therefore, lower and upper thresholds of risk (defined by Gleason score and tumour burden) were set, below and above which men were excluded.

So "very low risk" prostate cancer patients, who make up most of the patients in active surveillance programs in the US, and all of them in some programs (e.g., Johns Hopkins), were excluded. Focal therapy is compared here to higher risk active surveillance patients than is typical in the US.

Patient selection was also atypical in that no more than 3 positive cores were allowed, and the length of cancer in any one core had to be between 3mm and 5mm. Men with very small (<25 cc and very large (>70 cc) prostates were excluded.

Progression was deemed to have occurred if any of several criteria were met:

1. Gleason pattern≥4
2. > 3 positive cores
3. Cancer core length > 5 mm
4. PSA>10 in 3 consecutive measurements
5. stage T3 discovered

Only the first 3 had a significant effect. It should again be emphasized that many active surveillance programs now recommend radical treatment if a biopsy shows predominant Gleason pattern 4. Under such programs, many, if not most, in their active surveillance cohort would not be deemed to have progressed. This is especially true when mpMRIs are used early to rule out predominant pattern 4.

The procedure

The kind of focal therapy used here (called TOOKAD soluble vascular photodynamic therapy) involves treating the patient under general anesthesia with an intravenous injection of a photosensitizing chemical, called padeliporfin. Optical fibers were inserted transperineally with one end at the tumor to be ablated and the other end attached to a near-infrared laser that delivered an energy dose of 200 J/cm. I believe the authors err when they characterize this as "non-thermal." The operation took about 2 hours, and patients stayed overnight in the hospital. The catheter was removed the next day.

Retreatment was allowed if the 12-month biopsy indicated residual cancer. It's important to keep this in mind when looking at the oncological outcomes. 32% received another treatment on the contralateral side. 6% received retreatment after 12 months. There is no analysis provided showing the toxicity among men who received multiple treatments compared to those who only received a single treatment.

Oncological outcomes

After 2 years of follow-up among the men who received up to two treatments of the focal photodynamic therapy (PDT):

• 28% progressed, mostly with higher Gleason grade
• 58% progressed or were reclassified in their active surveillance cohort
• 51% had a positive biopsy
• 86% had a positive biopsy in their active surveillance cohort

The European PRIAS study of active surveillance found that only 23% had progressed within 2 years, which was even less than the 28% progression rate found here with focal treatment, but PRIAS comprised patients who were very low risk only. In the Klotz study of low-risk patients, 30% progressed in 5 years - about the same as progressed in 2 years here with focal therapy. (See this link.)

Since this is only with 24 months of follow-up, we can conclude that 30% were able to avoid radical treatment for 2 extra years. (Update 6/2018: Even after 4 years of follow-up, the difference was maintained at about 30%). But if the active surveillance group had been initialized with mpMRI detection, it's not clear that this benefit would persist.

It's also worth noting that 52% had no evidence of disease in one active surveillance study on a confirmatory biopsy (see this link), similar to what was seen here with focal treatment. The apparent remission rate was about 40% even using mpMRI-targeted biopsy (see this link). These are much higher than the apparent remission rate of 14% in this active surveillance cohort, again calling into question how active surveillance was defined here. With treatment with Proscar or Avodart, the apparent remission rate has been found to be 54% (see this link), which is equal to that observed here with focal therapy. Could the same rate of apparent remissions be achieved simply by taking a pill?

Morbidity

Side effects of treatment, while seldom serious enough to warrant intervention other than re-catheterization for a period of time, did occur. One in three patients suffered some kind of toxicity from the treatment. Most were low grade (grade 1 or 2) and transient. The ones that occurred significantly more in the treated cohort were (cumulative incidence within 2 years):

• Erectile dysfunction 38%
• Blood in urine 29%
• Painful urination 26%
• Urinary retention 17%
• Perineal pain 16%
• Urinary urgency 11%
• Urinary tract infection 11%
• Urinary incontinence 10%
• Urinary frequency 10%
• Ejaculation failure 8%
• Prostatitis 6%
• Inguinal hernia 4%
• Rectal hemorrhage 4%

There was one case of anaphylactic shock due to the anesthesia. Three men had urinary retention serious enough to require surgical intervention.

Would these men have been better off with radical therapy? We can look at these results side-by-side with some toxicity outcomes of SBRT treatment. The table below shows the highest incidence of side effects reported by both studies. I chose this Georgetown study because they gave 2-year outcomes and because they included Grade 1 toxicity - often only grade 2 or higher toxicity is reported. As with focal therapy, almost all of the side effects were mild (grade 1) and acute, occurring within the first month of treatment, and returning to baseline within 2 years. Potency retention was 79% at 2 years. Similar to focal ablation, only 1% had any serious (grade 3) toxicity. However, none were life-threatening.

In the SBRT study, there were no biochemical failures in the first two years among the low risk and intermediate risk patients in the study. This compares to 51% with evidence of disease, and 28% with higher risk prostate cancer already in the first 2 years for the focal therapy, even with retreatment in some.

It should be clear to patients that the benefits of focal therapy depends on what it is compared to. This analysis should also alert patients to be wary of media hype. For a discussion of the unresolved issues in focal ablation, see this link.

(update 2/2020) FDA Rejects TOOKAD for low-risk prostate cancer

The FDA oncologic drugs advisory committee rejected Steba Biotech's new drug marketing application. The decision may be revisited after Steba presents the results of a longer-running trial expected in 2025. In a Medpage interview, Patrick Walsh, on the committee, said:

"I think most of these patients [treated with TOOKAD] won't be told that at 2 years half of the men will still have cancer and in 28% it will be progressing."

Ipilimumab (Yervoy) fails to increase survival, even when used earlier

Ipilimumab (Yervoy) is a type of immunotherapy that is known as a "checkpoint blocker." It blocks a protein in T-cells (called CTLA-4) that tells the immune system to stand down and not attack the cancer cells. It turns off the off-switch. The hope is that immune response against the cancer will continue longer than it ordinarily would.

A previous trial showed that Yervoy did not extend survival when used in men who were metastatic and castration-resistant  (mCRPC) and who had failed chemotherapy. This is often the first group given a new drug because other options have been exhausted and because it takes less time to prove efficacy. Researchers hoped that it might have some effect if used earlier in disease progression. Unfortunately, it did not.

Beer et al. tested Yervoy this time in men who were metastatic and castration-resistant but who had not yet tried chemotherapy and who were asymptomatic or minimally symptomatic (i.e., no bone pain or organ dysfunction). In this multi-institutional study, there were 399 patients who got Yervoy, and 199 who got a placebo. Neither patients nor doctors knew who got which.

• Patients were given 10 mg/kg of Yervoy or placebo every 3 weeks for up to 4 doses.
• Therapy was repeated every 3 months thereafter to non-progressing patients

The outcomes were as follows:

• Median overall survival was 28.7 months for those who got Yervoy vs. 29.7 months for those who got the placebo (no statistically significant difference).
• Median progression-free survival was 5.6 months or those who got Yervoy vs. 3.8 months for those who got the placebo (a statistically significant difference).
• 23% had a PSA response with Yervoy vs. 8% with the placebo.

The treatment-related adverse responses were:

• Death that was treatment-related in 9 patients (2%).
• Serious or life-threatening immune-related adverse events in 31%
• Serious or life-threatening diarrhea in 15%

While there was a PSA  response, and an increased time during which more patients taking Yervoy were progression free, this did not translate to a lengthening of overall survival. This may be because there was a subset of patients who had a good initial response, but the response was not sustained. This also shows the difficulty of measuring the response to immunotherapy using PSA or other surrogate endpoint. We know that Provenge, the only approved immunotherapy for prostate cancer, lengthens survival without reducing PSA. Here, the converse is true.

Research continues on other checkpoint blockers. Keytruda has been approved for melanoma, lung cancer and head-and-neck cancer. In addition to Keytruda, there are several investigational immunotherapies targeting the PD-1/PD-L1 antigen. It may turn out that checkpoint blockers work better in combination with other immunotherapies (like Provenge or ProstVac), or perhaps they need to be primed with concurrent SBRT radiotherapy or chemotherapy. We need a better understanding about why an immunotherapy may work very well for one cancer, but very poorly for another cancer, We also can't lose sight of the fact that all  immunotherapies may be lethal. There is clearly much to be learned.

Ac-225-PSMA-617 extends survival (update)

The nuclear medicine group at the University of Heidelberg recently reported a complete response in two patients treated with Ac-225-PSMA-617 (see this link). Now they have treated 80 patients with at least 24 weeks of follow-up, and report impressive results (here).

The 80 patients had failed on multiple therapies and were only expected to have 2-4 months of median survival.

• The response rate (PSA reduction and tumor shrinkage) was 75%
• Most were still alive 6 months after the therapy
• Dry mouth was the only side effect of treatment

This is a report from a media release, and not a peer-reviewed journal. I will certainly report more details as they become available.

Anyone interested in medical tourism to try this experimental therapy can contact Dr. Haberkorn at the University of Heidelberg (he speaks English):
Email: Uwe_Haberkorn@med.uni-heidelberg.de
Phone: 06221 56-7731

There is a Phase 1 (dose finding) clinical trial of Ac-225-J591(a PSMA ligand) at Weill Cornell in NYC. It involves 8 visits over 12 weeks. Eligible patients must be metastatic and castration-resistant. They must have tried Zytiga, Xtandi and Taxotere or Jevtana. Scott Tagawa is the Principal Investigator.
Email: guonc@med.cornell. edu

(BTW - Scott Tagawa is also leading a trial combining two Lu-177-PSMA radiopharmaceuticals at Weill Cornell)

Recurrent PC (non-metastatic, hormone sensitive) after curative therapies exhausted? Here are some clinical trials to look at.

A perplexing situation is what to do after one has tried one or more potentially curative therapies (e.g., prostatectomy plus salvage radiation including pelvic lymph nodes), and there are no detectable metastases, but PSA keeps rising. The TOAD randomized clinical trial demonstrated that survival is improved by starting on hormone therapy (intermittent or continuous) as soon as recurrence is observed. Chemo has not proved to increase survival until after multiple metastases are detected (CHAARTED). Waiting for metastases to appear and spot treating them  has not proved to be beneficial either (see this link).

There may be hope in participating in clinical trials. There aren't many. There is a trial for the earlier use of Xtandi therapies, as well as trials for novel therapeutics, like apalutamide and Prostvac, which have been very promising in early trials. Here's a current list that you may wish to discuss with your medical oncologist:

Advanced hormonal therapies:

Apalutamide:at University of Texas, Houston (a larger trial is no longer recruiting)
Apalutamide/ degarelix/abiraterone at 8 locations
Xtandi at 172 locations
Xtandi at University of Colorado, Denver

Immunotherapy/PARP inhibitor:

Prostvac at NIH
Durvalumab + Olaparib at MSK
Olaparib - recurrent - Johns Hopkins & Thomas Jefferson U.

MAO inhibitor:

Phenelzine at USC

Small Cell Prostate Cancer Clinical Trials

(frequently updated)

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

Sub-types

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

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

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

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

Chemotherapy

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

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

CHAMP

Nuclear Medicine/ Somatostatin

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

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

213Bi-DOTATOC shows efficacy in targeting neuroendocrine tumors

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

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

These clinical trials include somatostatins:

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

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

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

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

DLL3

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

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

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

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

Checkpoint blockade

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

PD-L1 expression in small cell neuroendocrine carcinomas

Small clinical trials have so far shown little benefit:

Avelumab (Duke)

Pembrolizumab (UCLA)

Focal Ablation: Unresolved Issues

(frequently updated)

Focal ablation is the highly targeted destruction of cancerous prostate tissue, usually with some kind of heat or cold (called “thermal” ablation). There has been a lot of patient interest in focal ablation, spurred on by doctors and institutions promoting it and media reports. There has been much hype in the last year over focal ablation using high frequency focused ultrasound (HIFU) focal laser ablation (FLA), and photodynamic therapy (PDT). Cryoablation has been around for the longest time of any. There have been pilot trials of radiofrequency and microwave ablation as well. Irreversible Electroporation (IRE) may be the only form of ablation that is non-thermal, but so far seems to share characteristics with thermal ablation therapies. The promotional announcements for all of these therapies are often unbalanced, so it behooves anyone interested in pursuing it to get an understanding of the issues involved.

I am sincerely agnostic on this subject, and am very happy to see a potential prostate cancer therapy explored in tightly circumscribed clinical trials where patients are informed of the risks. I do believe that until we have learned more, clinical trials with strict protocols should be the only circumstances under which focal ablation is performed.

I. The Hope

Focal ablation has been touted as “the male lumpectomy.” This is a term borrowed from breast cancer. Breast cancer sometimes starts as a single tumor (called “unifocal”) that may be cured if it is removed with a negative margin. Just as the breast is preserved by such excision, the hope is that prostate function, and especially the function of nearby organs (bladder, rectum, urethra, bladder neck, neurovascular bundles, erectile function, and continence) can be fully preserved. Let’s understand why “lumpectomy” may be very different for the prostate.

II. Multifocality

Prostate cancer is overwhelmingly a multifocal disease. 80-90% of prostatectomy specimens have separate tumors distributed throughout the organ. Removing the largest, highest grade tumor (called “the index tumor”) does not remove all the cancer from the prostate.

III. Hemiablation

One way to get around the multifocality issue is to ablate half the prostate, either the right lobe or left lobe, but not both.This is called hemiablation. The hope is that the damage to nearby organs will be significantly reduced in so doing. Prostate cancer often appears to predominate in one lobe. But appearances are deceiving, even when saturation biopsies have been used to determine that the cancer was unilateral, it turned out to be bilateral in 3/4 of those cases (see this link), and may be as high as 90% (see this link). With traditional TRUS biopsies, unilateral cancer was misidentified in about 80% of men (see this link). Multiparametric MRI is not good at finding small tumors on the contralateral side. Pompe et al. showed that it missed cancer on the contralateral side in 58% of patients. The main issue is that it has not been proven that hemiablation is curative. In a study of 55 men in Belgium who received hemiablative HIFU, a quarter of the men relapsed and required further treatment. In a US study of 100 men receiving hemi-ablative HIFU, followed up with a biopsy after 2 years, a quarter had relapsed with Grade Group 2 or greater prostate cancer.

IV. Index Tumor Theory

Proponents of focal ablation argue that it doesn’t matter if there are small amounts of prostate cancer that remain untreated. Prostate cancer, they believe, spreads by cloning daughter cancer cells from a single “parent” tumor within the prostate. This is called “Index Tumor Theory.” Under this theory, if the index tumor is removed by ablation, the prostate cancer will not spread further. In theory, the small untreated daughter foci of cancer are not malignant and will cause no further problems. In theory, the index tumor is identifiable as the largest, highest Gleason score tumor within the prostate.

Index tumor theory relies on the findings of two studies. Liu et al. and Mao et al. showed that metastases arise as clones from a single parent cancer cell. The Liu et al. study was based on cancers from 30 men who died of prostate cancer. The Mao et al. study confirmed the earlier study in a sample of 16 men. While both studies showed that metastases arose from a single prostatic parent cell, they did not show that the parent cell was in an index tumor. In fact, a case report from Johns Hopkins showed that lethal metastases at least sometimes could arise from a small, low grade tumor within the prostate, rather than from an index tumor. Adding to the complexity, Cheng et al. found that multiple tumors had independent origins. In 15/18 tumors, they found that they arose independently rather than from a parent tumor within the prostate, and in only 3/18 tumors they arose through intraglandular dissemination from an index lesion. Similarly, Wei et al. looked at prostate tumors taken from 4 patients, and found there was considerable genetic diversity within their index tumors as well as their other cancer foci. Ibeawuchi et al. discovered that a unifocal tumor could be as genetically diverse as multifocal tumors. Løvf et al. found that the various tumors in the same prostate only rarely shared genetic mutations, suggesting independent origins. Kneppers et al. found among 30 men with lymph node metastases that for 23%, their metastases were not clonally derived from the index tumor.

All of the above-mentioned genetic studies have been conducted in small numbers of patients. Genetic studies are tremendously difficult to conduct and interpret. Genetic breakdown is a characteristic of cancer, which complicates the subjective determination of what constitutes a clone from the index tumor.

None of this disproves index lesion theory entirely. In fact, there must be some truth to it or focal ablation would never be effective. Focal ablation trials with 5 years of follow-up demonstrate that focal ablation seems to halt progression in most men. However, because the studies have not been randomized, we cannot rule out that those mostly low risk patients were caught early and would not have progressed appreciably in that time frame anyway. We also know from long-term active surveillance trials that about half of all men with confirmed low-risk tumors will eventually progress – the smaller Gleason 6 tumors must be monitored. The most likely scenario is that there are index tumors in some men but not others. Unfortunately, we have no easy way of predicting which patients have index tumors and which have multiple tumors that are capable of malignant spread.

V. Targeting the index tumor

Assuming there is an index tumor, the next question becomes: can we precisely locate the tumor for targeted ablation? Our best current tool for doing so is using a multiparametric MRI (mpMRI) to target what seems to be the index tumor, and to confirm the location with a biopsy (either ultrasound fusion or in-bore). This poses special challenges.

Most patients who choose focal ablation are those who have predominant Gleason pattern 3 (either Gleason score 3+3 or 3+4). mpMRI is not at all sensitive at finding such low grade tumors if they are small; in fact, it is no better than a standard TRUS biopsy. In a study of mpMRI and Ga-68-PSMA PET/CT, both imaging techniques missed more than half the prostate tumors found after prostatectomy. Perhaps Color Doppler Ultrasound or transperineal template mapping biopsy perform better (see this link), but they are seldom used. However, mpMRI is a good tool for finding larger and higher grade tumors. In a study at UCLA, 80% of “index tumors” were found using mpMRI. In another UCLA study, mpMRI found that half of all men with intermediate or high-risk prostate cancer had satellite tumors in addition to their index tumor, but 2/3 of those same men were found to have satellite tumors when their prostates were surgically removed. Over half of the satellite tumors were Gleason score ≥ 3+4.

While mpMRI may detect index tumors, it is not a good tool for delineating even higher grade tumors. Priester et al. compared the dimensions of tumors found via mpMRI in 114 men to the dimensions of their same tumors determined via post-prostatectomy pathology. They found that the actual tumors were 3 times larger than their MRI estimates – they missed 80% of the tumor’s volume by relying on the MRI. It is worth noting too, that these MRIs were read by arguably the best radiologist in the business, Daniel Margolis at UCLA. He literally wrote the book (PIRADS 2.0) for interpreting mpMRIs. In a study of 461 lesions in 441 men, the average size of tumors was only 1.6 cm on the mpMRIs but was 2.4 cm after prostatectomy. The correlation between MRI and actual size was poor (0.13- 0.65). Pompe et al. found that mpMRI could not detect extracapsular invasion, and missed cancer in 58% of patients who had cancer in the contralateral lobe from the index tumor. Brisbane et al. found that only 65% of biopsied clinically significant prostate cancer was within the MRI-defined region of interest. Aker et al. found that neither MRI nor PSA were good indicators of recurrence after cryo.

If satellite tumors are to be ablated as well as the index tumor, mpMRI performs even worse in finding them. Hollmann et al. found that satellite tumors were a median of 1 cm, and up to 4.4 cm, away from the index lesion, so they would not be destroyed within the ablation zone of the index lesion, and it would be difficult to locate them. (Update 5/2019) Stabile et al found that mpMRI missed 30% of the significant (Gleason score≥3+4) cancer outside of the index lesion, and the missed tumors had a median length of 2.6 mm, which is smaller than anything an mpMRI can detect.

VI. Incomplete ablation in the ablation zone

Now let’s assume you do indeed have an index tumor, and you were able to accurately delineate it somehow, the next question becomes: Can focal therapy be used to completely ablate the tumor? So far, the answer seems to be – not completely. In some studies, treated patients had MRI-guided biopsies of the ablation zone within 6 months of treatment. Cancer was found in the ablation zone:

A. Focal Laser Ablation (FLA):  

(Update 5/2020) Feller et al. reported on the 10-year outcomes of 158 men and 248 cancer foci treated with MRI-guided FLA. All men had low or intermediate-risk prostate cancer. 122 had an MRI-targeted biopsy of their treatment sites after 6 months.

• 26% were positive with clinically significant cancer
• 15% were positive with clinically insignificant cancer
• 59% were negative

(Update 5/2021) Mehrahlivand et al. reported that 3 years after MRI-guided FLA of 15 low and favorable intermediate-risk patients, almost half had residual cancer in, adjacent to, or in close proximity to the treatment area.

(Update 5/2019) Chao et al found that 8/32 (25%) had an mpMRI suspicious for cancer in the ablation zone within 2 years after FLA (Median time to positive mpMRI in the ablation zone was 6 months). All were confirmed by biopsy. Only one of those patients had low volume GS 6. 24/32 (75%) had an unsuspicious mpMRI, but biopsy at 2 years after FLA was nevertheless positive in 9 of the 14 men (64%) who had a biopsy. So 17/22 men (77%)  had a positive biopsy in the ablation zone after 2 years. Change in PSA did not predict a positive or negative mpMRI or a positive or negative biopsy.

In this study, MRI-detected cancer was found in 10/27 patients after 12 months, with cancer found in the ablation zone via biopsy in 3 patients. Cancer was found in the ablation zone in 2/9 patients (22%) in this study, 7/10 (70%) patients in this study that used a targeted biopsy, and 4/12 (33%) in this study. In one study, 2/13 (15%) had residual cancer within the ablation zone, but only 13 of 23 patients had a targeted biopsy. Knull et al. compared the pre-operative mpMRI images with MRIs obtained immediately after FLA in 23 lesions. They found that FLA did not completely overlap the intended ablation zone in about half of the lesions, and those tumors extended a median of 0.9 mm past the edge of the ablation zone.

B. High Intensity Focused Ultrasound (HIFU): 

Cancer was found in the ablation zone in 36% of the patients who had biopsies for cause in this study. In a hemi-ablation study, 28% had biochemical recurrence and 3/8 biopsied patients (38%) had cancer in the treated lobe. In another hemiablation study, 16% had cancer in the ablated lobe. In a large study of whole gland HIFU, 29% were given a repeat treatment. Cancer was found in 42% of high-risk men in the ablation zone in this study - 10% were given a repeat treatment. In a US hemiablation study, 17% had Grade Group 2 or greater cancer in the treated lobe.

(Update 3/2020) Klotz et al. reported the 1-year outcomes of an MRI-guided and MRI-thermometry HIFU-ablated kind of thermal ablation called TULSA-PRO. The favorable risk men were all biopsied a year after whole gland treatment. Cancer was found in 35% of the treated men even though they barely had a prostate left (3 ccs.) and their PSA was very low (0.5 ng/ml). Full article here.

(Update June 2022) Ehdaie et al. reported on 2-year biopsies of 101 intermediate risk men treated with MRI-based HIFU. 20% still had cancer in the ablation zone, 12% GS≥3+4. 60% still had cancer in the prostate, 40% GS≥3+4.

(Update 6/21/20) Lumiani et al. reported the 16-month outcomes of 52 consecutive TULSA-PRO patients, mostly focal. 27% were positive for recurrence on follow-up MRI, and the recurrence was confirmed by biopsy in all those who had a biopsy. Recurrence rates were similar for focal and whole-gland.

(Update 3/16/23) Duwe et al. reported the 2-year outcomes of 29 favorable risk men 

treated with focal (38%) or hemi-ablation (62%) at a single center in Mainz, Germany. After 2 years, 38% had biopsy-proven recurrence, a third of those with cancer in the ablation zone, and one with numerous pelvic lymph node metastases. The trial was stopped early because of the high failure rate.

C. Photodynamic Therapy (PDT) /TOOKAD: 

In a hemiablation study, 11/21 men (52%)had a positive biopsy in the treated lobe.

D. Cryo: 

In a whole-gland study of cryoablation, 37% had residual cancer in the ablated prostate. In a study of focal cryoablation,  23/50 (46%) of patients undergoing re-biopsy were positive for PCa. Baskin et al. reported that neither MRI or PSA were adequate indicators of progression. On biopsy, 10% of patients had residual GS≥7 cancer on the treated side, and 10% had GS≥7 cancer on the untreated side. Aker et al. reported that on biopsy 18 months post-treatment, 35% still had clinically significant prostate cancer (only 46% had no prostate cancer), and that neither MRI nor PSA were good indicators.

E. Irreversible Electroporation/NanoKnife (IRE): 

In a study of focal IRE, which is largely a non-thermal form of ablation, 4/25 patients (16%) were found to have residual cancer in the ablation zone. In another study that used mpMRI to detect residual cancer up to one year after treatment, 9/30 patients (30%) were found to have residual cancer in the ablation zone. Colletini et al reported in-field treatment failures by 18% of low and intermediate-risk patients detected via mpMRI-targeted biopsy after 6 months. Valerio et al. reported that 6/34 patients (18%) had residual disease. Guenther et al. reported that the recurrence rate at 5 years was 5.6% for Gleason 6, 14.6% for Gleason 7, and 39.5% for Gleason 8–10. Gielchinsky and Lev-Cohain reported that 4/13 patients had biopsy-detected recurrence. Zhang et al. reported that 6-months after focal IRE, 46% of low- and intermediate-risk cancer still had biopsy-detected cancer outside of the ablation zone and 17% still had cancer inside the ablation zone.

So we observe that ablation is sometimes incomplete within the treated area. There are thermodynamic and biochemical reasons that may explain those failures.

VII. Heat Sink Effect

Most kinds of ablation (e.g., FLA, HIFU, cryo & PDT) are thermal, which means they rely on the local application of heat or cold to ablate the tumor tissue. The second law of thermodynamics guarantees that heat (or cold) will never stay exactly where it is put. This is true for the thermal energy generated by laser beams, by ultrasound, contact with cold, or by any kind of electromagnetic energy. Water is a very good conductor of thermal energy, and prostate tissue is mostly water. The thermal energy always flows away from where it is placed, leaving the ablation zone with less ablative energy, and areas around it with more ablative energy. This translates to sub-lethal killing of cancer cells within the ablation zone, and killing of healthy tissue outside of the ablation zone.

VIII. Urethral Proximity

Because of the need to avoid damage to the urethra, tumor proximity to the urethra precludes use of focal ablation. A study at UCLA found that 72% of candidates had tumors within 5 mm of the urethra on whole-mount pathology. An MRI correctly predicted proximity (positive predictive value) in 84%. This would screen out most patients. However, an MRI correctly predicted there were no tumors (negative predictive value) nearby in only 52%. This error in imaging can be a source of in-field recurrence.

IX. Biochemical Effects

Human cells, especially cancer cells, have self-preservation mechanisms that may defeat efforts to ablate them. One such mechanism is “heat shock protein (HSP).” Whenever cells are threatened with heat, they enlist HSPs to protect themselves. (There are actually separate “cold shock proteins” that have been identified.) HSPs play an important role in protecting cancer cells, and scientists are developing HSP inhibitors that may one day help other medicines to treat cancer. HSPs are known to play a special role acting as chaperones in bringing the androgen receptor to a more protected place inside the cell. They also encourage cells to enter a dormant phase where they are less subject to destruction. Cell cycle dormancy may play a role in ablation therapy. It is possible that in malignant cells that are not destroyed, cell cycle arrest may delay cell replication for some time. Paradoxically, activation of HSPs may turn cancer cells more aggressive. (See this link and this one). This has not been studied in regard to focal ablation, but should be.

We are coming to recognize the effects that cancer cells may have on nearby “bystander” cells. In a recent lab study, prostate cancer cells stressed by PDT released nitric oxide that caused bystander cells to become more aggressive. The role of extracellular vesicles/proteasomes in promoting malignancy in nearby cells under ablation conditions has yet to be elucidated.

X. Organ-at-risk damage/toxicity

Because of the heat sink effect, there will always be some impact on surrounding healthy tissues. Depending on where within the prostate the index tumor is, and how large the ablation zone is, ablation may damage the urethra, the rectum, the bladder neck, or neurovascular bundles. In most modern trials of focal ablation, side effects have been low, but are not zero.

At the same time, there has been much progress made in reducing the toxicity of radical (whole gland) radiation therapy. Take for example, a report of HDR brachytherapy as a monotherapy for treating intermediate risk patients, and compare it to the recent report by the Ahmed/Emberton group of (mostly) intermediate risk patients treated with focal HIFU in the UK, the largest study of focal HIFU. Both studies had 5 years of follow-up.

	HDR brachy	HIFU
Recurrence-free survival	94%	72%
Potency preservation	82%	84%
Percent pad-free	97.5%	97.6%
Serious rectal injury	none	2 patients

Oncological control was 30% better with HDR brachy and only required a single treatment. Sexual, urinary, and rectal late-term side effects were equivalent for both treatments. What is the advantage of focal ablation, then?

XI. Re-do rates

As we’ve seen, some recurrences occur within the ablation zone, but most recurrences occur outside of the treated area. In the above-cited report on HIFU, 28% of patients had a recurrence. This is typical for focal ablation. An advantage often cited for focal ablation is that patients who have a recurrence can be retreated with a second round of focal ablation therapy. In the Ahmed/Emberton HIFU study, 25% of all patients were treated with HIFU multiple times (others chose radical salvage therapy (7%) or permanent hormone therapy (1%)).

In a UCLA trial of focal ablation in 170 intermediate-risk men who were treated with partial gland cryo or HIFU, 22% had a recurrence within 2 years. Among those who were re-treated, half had a clinically significant recurrence.

“Re-do’s” incur extra costs and may increase morbidity of treatment. There’s no guarantee that they will be effective. As we’ve seen, recurrences are common even when the whole gland is ablated.

XII. Lack of long-term data

The longest running studies of focal ablation, other than cryotherapy, have only 5 years of follow-up. While 5 years may be enough for therapies that are simply an improvement over existing therapies, focal ablation requires longer follow-up because of all the open questions that may affect long-term results. Because many of the focal ablation patients so far have been low risk patients who are likely to enjoy long progression-free times anyway, it is not at all clear that the remissions are lasting ones. Both the AUA nor the EAU consider focal ablation to be experimental and unproven.

XIII. Tracking progression after therapy

After radical prostatectomy, we hope that PSA will become undetectable permanently. If it rises afterwards, we suspect recurrence. After radical radiation therapy, PSA reaches a nadir, usually less than 0.5 ng/ml. If it rises 2 or more points above that, we suspect recurrence. However, with focal ablation, there is no reasonably expected PSA nadir, and there is no rise in PSA we can label as a biochemical recurrence. The PSA changes will be different for every patient. Because only the index tumor has been ablated, we don’t expect PSA from small foci of cancer outside of the ablation zone to vanish, nor PSA from BPH or prostatitis. The Chao et al trial showed that change in PSA is not a good predictor of recurrence. Because PSA cannot be used to monitor remission, we have to use imaging and periodic biopsies. Such imaging and biopsies requires experienced radiologists and pathologists because ablated tissue is qualitatively different from unablated tissue. Again, the Chao et al trial showed that while a positive mpMRI always predicted a positive biopsy, a negative mpMRI led to a positive biopsy in most cases treated with FLA. If found to be true of other kinds of focal ablation, periodic biopsies will have to be part of routine follow-up.

XIV. Salvage after ablation

If ablation doesn’t succeed and further ablation is either futile or dangerous, what are the salvage options? Salvage prostatectomy is complicated by the ablative tissue alterations, and may lead to increased morbidity. There is no reliable data on whether or not salvage radiation is effective after ablation failure. There are no experts in such salvage therapies.

XV. Comparison to active surveillance

Focal ablation is often put forward as a middle ground between active surveillance and radical treatment. However, unlike active surveillance, there is some risk of morbidity after focal ablation. There is no long-term clinical evidence for the index tumor theory, and we have learned from long-running active surveillance trials that up to half of all Gleason 6 cancers eventually progress. Because of this, the patient is actually on a lifelong active surveillance protocol anyway: he must continue to have periodic imaging and biopsies to track progression, but is disadvantaged by not being able to use PSA to track progression.

Some focal ablation proponents, notably Ahmed and Emberton, argue that focal ablation should only be offered to intermediate risk patients and to those low risk patients who refuse active surveillance. This seems reasonable.

XVI. Inexperienced practitioners and practices

Focal ablation is still very new in the US, there are few practitioners who have adequate experience, and the learning curve is steep. There are no standard protocols. It may be years before there is consensus on best practices.

XVII. Danger of procedures

Ablation often requires anesthesia, local or general. IRE, for example, requires artificial paralysis and respiration throughout the high-voltage process.

XVIII. Cost/Insurance

No form of ablation is covered by insurance or Medicare, and out-of-pocket costs are typically in the $20,000 range. Because “re-do’s” are often required, future costs are unpredictable. There will be ongoing costs of periodic imaging (usually mpMRIs) and biopsies.

As with all new therapies, methods and outcomes will undoubtedly improve over the years. This first wave of practitioners and brave patients are taking risks that may eventually benefit many others. It is important that patients understand those risks before making their treatment decision.