Showing posts with label active surveillance. Show all posts
Showing posts with label active surveillance. Show all posts

Tuesday, March 27, 2018

Should perineural invasion influence active surveillance and radiation treatment options?

Perineural invasion (PNI) is a risk factor detected on a biopsy in 15%-38% of men with a prostate cancer diagnosis. It means that the pathologist saw nerves infiltrated with cancer cells. As they grow, tumors cause nerves to innervate them. The cancer infiltrates in and around small nerves that connect to nerve bundles (ganglia) outside the prostate, becoming a route of metastatic spread (see this link).  The data on whether it is independently prognostic for T3 stage after surgery are equivocal, although PNI is often the mechanism for extracapsular extension.  After considering Gleason score, PSA, stage, and tumor volume, PNI does not seem to add much to the risk of recurrence after surgery. PNI is not associated with higher surgical margin rates, and it is not considered sufficient to preclude nerve-sparing surgery. An open question is whether it raises risk enough to warrant more aggressive radiation options, like brachy-boost therapy, whole-pelvic radiation and long-term adjuvant ADT.

Peng et al. retrospectively examined the records of 888 men who were treated with external beam radiation at Johns Hopkins from 1993 to 2007. 21% of them had biopsy-detected PNI. Compared to men with no PNI, those with PNI had:

  • lower 10-year biochemical failure-free survival (40% vs 58%)
  • lower 10-year metastasis-free survival (80% vs 89%)
  • lower 10-year prostate cancer-specific survival (91% vs 96%)
  • similar 10-year overall survival (68% vs 78%)

It isn't surprising that PNI is associated with higher risk, but does it add any new information not already captured by Gleason score, stage, and PSA (i.e., the NCCN criteria for risk stratification)? After correcting for those other risk factors, PNI was still found to be associated with lower rates of biochemical failure-free survival, but not of metastasis-free survival, prostate cancer specific survival or overall survival.

PNI independently predicted for lower biochemical failure-free survival in low-risk and high-risk patients, but not for intermediate-risk patients.  Although it is a relatively rare finding among low-risk patients, when found, PNI also predicted for lower prostate cancer-specific survival. Biochemical failure in low-risk men with PNI differed according to whether they received adjuvant ADT or not:

  • 33% in men not treated with ADT
  • 8% in men treated with ADT

An earlier analysis of 651 men treated at the University of Michigan similarly found an association between PNI and biochemical failure-free survival, freedom from metastases, prostate cancer-specific survival, but not overall survival at 7 years after radiation treatment. They also found a more marked effect among high-risk patients. A meta-analysis of 5 studies among men who received EBRT found that PNI increased the risk of biochemical recurrence by 70%.

Although PNI may increase the risk associated with an unfavorable intermediate-risk or high-risk diagnosis markedly, brachy boost therapy is the best treatment for any such patient regardless of PNI, according to our best retrospective study and prospective studies like ASCENDE-RT. This study suggests that adding ADT may be beneficial for these patients. Low and intermediate-risk patients with PNI who opt for conventional IMRT may also benefit from the addition of short-term ADT.

(update 4/2020) In a ten-year follow-up of the TROG 03.04 RADAR  randomized trial, Delahunt et al. found that PNI detected at biopsy was independently associated (after adjusting for other risk factors) with later appearance of bone metastases.

Biopsy-detected PNI may have implications for active surveillance. Cohn et al. detected PNI in only 8.5% of 165 men selected for active surveillance. Within 6 months, they were given a confirmatory biopsy. AS was excluded at the confirmatory biopsy due to higher Gleason grade in 57% of men with PNI vs. 13% of men without PNI. PNI should not automatically exclude active surveillance, but it should be recognized as a risk factor in the decision. It would be interesting to know if there is an association between PNI and genomic risk (based on Oncotype Dx, Prolaris, or Decipher tests). It has yet to be determined whether PNI is still a significant risk factor after NCCN risk category, % core involvement, and genomic risk have been accounted for.

It is worth noting that PNI is not always reported on biopsy cores by pathologists, and there is no uniform method for quantifying it. Whether nerve infiltration is small or large, or outside or inside the nerve sheath, it is just reported as PNI, if it is reported at all. It will be difficult to include PNI as part of any risk stratification system until its reporting has been standardized.

Note: Thanks to Daniel Song for allowing me to see the full text of the study.

Thursday, August 31, 2017

The myth that younger men should not pursue active surveillance

In spite of no evidence to back up their assertion, I continue to hear urologists say things like "If you were older, I'd recommend active surveillance. But because you're young, you should have surgery for your low risk prostate cancer now while your recovery will be better." We saw, in a previous article, that immediate surgery rather than active surveillance only resulted in more years of expected misery from impotence and incontinence: see: "Can a man be too young for active surveillance?"

Now, a new study from Memorial Sloan Kettering Cancer Center examines the evidence for potency preservation. The authors, who include John Mulhall, the sexual medicine specialist, demonstrate that the expected loss of erectile function is never compensated for by better recovery in younger men and the age-related decline in erectile function over the years while waiting on active surveillance.

They used a standard questionnaire, the International Index of Erectile Function 6 (IIEF6). It is sometimes called the Sexual Health Inventory for men (SHIM). There are six questions, and the best score (excellent erectile function) is 30. The questions are:

1. Over the last month, how often were you able to get an erection during sexual activity?
2. Over the last month, when you had erections with sexual stimulation, how often were your erections hard enough for penetration?
3. Over the last month, when you attempted intercourse, how often were you able to penetrate your partner?
4. Over the last month, during sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?
5. Over the last month, during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?
15. Over the last month, how do you rate your confidence that you can get and keep your erection?

All men filled out the questionnaire before surgery and periodically for two years. They excluded high risk patients who wouldn't be eligible for active surveillance, and any men who did not have bilateral nerve-sparing surgery. Men who had hormone therapy or salvage radiation were also excluded. There were 1,103 men in their cohort of men treated with RP at MSKCC between 2009-2013. Needless to say, MSKCC has some of the best, most experienced surgeons in the world.

They first looked at the baseline scores by age to get an understanding of how erectile function declines with age. This defines the expected erectile function if there were no surgery. They also looked at actual scores after surgery for each age. The difference between actual and expected shows the true effect of surgery on erectile function, with compensation for age-related decline and for the time delay caused by active surveillance.

They found that:

  • Each year increase in age reduced the IIEF6 score by -0.27
  • Erectile function recovery after RP declined by -0.16 for each year older at the age of treatment

While younger men started with a higher erectile function score, and their recovery after RP was better, it was never good enough to be better than the erectile function of an older man who didn't have surgery. At all time points, they would have been better off if they had delayed treatment and stayed on active surveillance. There was no "window of opportunity" where younger age recovery exceeded what would be expected to happen if they waited.

The authors conclude:
Small differences in erectile function recovery in younger men are offset by a longer period of time living with decreased postoperative function. Better erectile recovery in younger men should not be a factor used to recommend immediate surgery in patients suitable for active surveillance, even if crossover to surgery is predicted within a short period of time.

I hope patients whose urologists spout the myth that "early surgery will lead to better long-term erectile function than delaying until he is older" will email this important study to them and ask for comment.

Saturday, January 7, 2017

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."





Thursday, September 15, 2016

The first randomized clinical trial comparing active surveillance, surgery and external beam radiation tells us little :-(

This was supposed to be HUGE! The first clinical trial ever where patients were randomly assigned to active surveillance (AS), radical prostatectomy (RP) or external beam radiotherapy (EBRT). The results were published in The New England Journal of Medicine (see this link). They started signing up men in the UK in 1999 and continued recruitment for 10 years. By 2009, they screened over 82,000 men for prostate cancer and found 1,643 men with newly diagnosed localized prostate cancer who were willing to be randomized to initial treatment with AS, RP or EBRT, about a third in each. They then followed them for a median of ten years to see how well they did with each therapy. Imagine the effort involved! Sounds good so far -- what could go wrong?

The bottom line was that all 3 therapies did about the same in preventing death. AS was found to cause higher rates of disease progression and metastases. We will explore why below.

There were several problems that arose.

1. They planned to detect mortality differences, but couldn't.

They thought there would be more deaths in the ten years of follow-up, but almost all the men defied those expectations. That's partly because of all the great new life-prolonging drugs that became available in the 21st century; drugs like docetaxel, Xtandi, Zytiga, and Xofigo. Also, in a clinical trial, patients are very closely diagnosed, treated, and monitored. They get far better care than the average patient in community practice. There were only 17 prostate-cancer related deaths

Men also survived longer because of progress in treating other diseases. But most of all, men lived longer because they frequently visited doctors as part of the study, during which they were  closely monitored for other illnesses. There were only 152 deaths from all other causes, only 9% of the total sample size. Men were 50 to 69 years of age  (62 years median) at the start of the study and were tracked for 10 years. On average, based on US actuarial tables, about 18% should have died from all causes. So the mortality rate was half of what was expected. On the average, men in the UK live two years longer than men in the US - not enough to account for the difference.

No worries. Instead of looking for mortality differences, the researchers had a secondary objective to look for differences in disease progression and rates of metastases. Those are excellent surrogate endpoints. But...

2. The intended treatment wasn't always what patients wound up doing

Although men were randomized to one of the 3 therapies, a lot of the men apparently changed their minds, as was their right. The authors of the study analyzed everything based on the intended treatment at the time they were randomized. This is how they said they would analyze the data, and they stuck with the plan. The switching that occurred was as follows:
  • Of the 545 men randomly assigned to AS,  482 (88%) stayed with it at least for 9 months. The rest decided to have surgery, radiation, no therapy, or dropped out.
  • Of the 553 men randomly assigned to RP, 391 (71%) did have surgery within the first 9 months following randomization. Most of the remainder switched to AS, the rest to radiation or other treatment, and a few chose no treatment or dropped out.
  • Of the 545 men randomly assigned to EBRT, 405 (74%) did have EBRT within the first 9 months following randomization. Most of the remainder switched to AS, the rest to surgery, other treatment, no treatment or dropped out.
  • In all, 22% of the men did not have the therapy they were originally randomized to, yet they are including in the analysis as if they did. It is unknown how this may have skewed the findings.
3. Their AS protocol was nothing like contemporary protocols.

     a. Inclusion criteria were much less restrictive

In contemporary AS protocols, almost all men are in the "low risk" category. "Low Risk" means they are stage T1c or T2a, their Gleason score is 6, and their PSA is less than 10. Some of the more restrictive AS programs, like Johns Hopkins, also include the "Epstein criteria." That means there were no more than 2 positive cores, no more than 50% cancer in any positive cores, and the PSA density must be less than 0.15 ng/ml/g. For the first time this year, NCCN included AS as an option for men with Gleason score 3+4 if no more than half the cores were positive, but only if they were otherwise low risk.

In the ProtecT trial, the only inclusion criterion was that the men had to have localized prostate cancer. See this link for their protocol. This means that they allowed men who were higher stage (T2b and T2c), higher grade (Gleason score ≥ 7), and higher PSA (PSA could be as high as 10-20 ng/ml). In fact, they previously reported that, among the AS cohort:
  • 10% had an initial PSA between 10 and 20 ng/ml
  • 22% had an initial Gleason score≥ 7 (2% were GS 8-10)
  • 25% had a clinical stage of T2 - they do not break that into subcategories, presumably most were T2a
So, many of those higher risk men would have been screened out of a contemporary AS program. The authors did not analyze this higher risk subgroup to tell us how many of the 33 cases of metastases or 112 cases of clinical progression were among them, but they do report (Table 2) that of the 8 prostate-cancer deaths in the AS group, 5 were among men with Gleason score ≥ 7 at diagnosis (vs. 2 each for RP and EBRT). The remaining 3 deaths among those diagnosed as Gleason 6 was similar to the number for RP (3) and EBRT (2). It seems that all extra deaths were attributable to higher Gleason scores in their AS program.

     b. Monitoring of men on AS was below contemporary standards.

In contemporary AS protocols, there is always a confirmatory follow-up biopsy within a year of the first screening biopsy. The repeat biopsy schedule varies from that point on, and may be every year, as it was originally at Johns Hopkins. Some AS protocols utilize mpMRI to search for suspicious areas and only biopsy as suspicion arises, others implement a biopsy schedule that may vary depending on the findings of the last biopsy. Some do TRUS biopsies, some do mpMRI-targeted biopsies, some combine the two, and some do follow-up transperineal template-mapping biopsies. But all good AS programs include follow-up biopsies.

In the ProtecT trial, patients were screened for a high PSA (> 20 ng/ml), emergent symptoms, or a 12-month PSA increase ≥ 50%. So those who had a form of prostate cancer with a low PSA output (such as some of those with predominant Gleason pattern 5) would never be discovered until symptomatic metastases occurred. I don’t know what percent ever got a second biopsy.

We recently saw what happened in Göteborg when there was no pre-determined biopsy schedule: 54 out of 474 men (11%) failed on AS. They used a similar monitoring system as the ProtecT trial: quarterly, and then semi-annual PSA tests, and re-biopsy at the discretion of the doctor.

I sometimes talk to patients who get periodic PSA tests and claim they are on active surveillance. They are putting themselves in danger. Time and again, PSA kinetics have been rejected as a sole indicator of progression for very good reasons, mainly (1) PSA is affected by many non-cancer causes, and (2) some of the most virulent prostate cancer cells put out very little PSA. There is no substitute for confirmatory and follow-up biopsies.

Let's put perspective just how egregious a difference it is when active surveillance does not include follow-up biopsies. Current estimates are that one in three TRUS-guided biopsies (12 through the rectum) will miss a higher grade of cancer. So, if one biopsy failed to detect a higher grade cancer with odds of 33%, then the odds of missing it on two biopsies is (.33) squared, etc. As the following table shows, the odds of missing the higher grade cancer with annual biopsies for ten years is about 1 in a hundred-thousand.







Biopsy
Odds of missing higher grade in ALL the biopsies
1st
33%
2nd
11%
3rd
4%
4th
1%
5th
0.4%
6th
0.1%
7th
0.04%
8th
0.01%
9th
0.005%
10th
0.001%

Now, at Johns Hopkins, for example, it was their active surveillance policy to have annual biopsies, and they used the Epstein criteria discussed above. After 15 years of follow-up, the metastasis-free survival rate was 99.4%. Laurence Klotz at Sunnybrook in Toronto has the longest running trial of active surveillance in North America. They allowed some patients as high as favorable intermediate risk, and while there was always a confirmatory biopsy in the first year, their biopsy schedule was not as rigorous as Johns Hopkins. After 20 years, of follow-up, they report metastasis-free survival of 97.2%. In the ProtecT trial, there were 33 men out of the 545 men in the AS cohort - 6.1% had already been diagnosed with metastases after only 10 years of follow-up. The outcomes of the AS cohort are very out-of-line compared to active surveillance programs that have more rigorous selection criteria and monitoring protocols.


Selection criteria
Biopsy schedule
Active Surveillance Program
Follow-up
Metastasis-free survival
Strictest:
Epstein protocol
Annual
Johns Hopkins
15 years
99.4%
Less strict:
favorable risk only
Confirmatory and periodic thereafter
Sunnybrook
20 years
97.2%
Any localized regardless of PSA or grade

none

ProtecT

10 years

93.9%

4. Their EBRT protocol was below today's standards.

In the years prior to 1999 when they were planning this study, there were very different radiation therapies in place than have now become standard of care. This is a problem with all long-term clinical trials involving radiation technology. By the time we get the results, they are irrelevant because the technology and understanding has progressed so much. For an expanded discussion of this issue, see this link.

They used an older technology (3D-CRT) to deliver only 74 Gy in 37 treatments while adding 3-6 months of hormone therapy before and during treatment. Now, with IGRT/IMRT technology, the patients would safely receive about 80 Gy. Low and favorable risk patients probably do not benefit from adjuvant ADT -- it adds sexual side effects without adding to cancer control in most of them. Some have questioned whether the increase is justified for low or intermediate risk patients (see this link), but, as we saw, 10 years is not long enough to judge that, and there is no consequence to the higher dose in terms of side effects. It is entirely possible that the low dose they gave patients only delayed progression but did not cure the cancer.  If that is true, we may see the EBRT outcomes deteriorate when they present their planned 15-year follow-up.

ProtecT was a vast and expensive undertaking. It will probably never be repeated, and there isn't likely to ever be a US equivalent. Sadly, we can't learn very much from their current analysis of this major study, although it may yield more fruit with some subsequent analyses.

Friday, August 26, 2016

Nanoknife® or irreversible electroporation (IRE) is a promising focal ablation therapy


IRE is unique among focal ablation therapies in that it is non-thermal and precise down to the cellular level. There was a very thorough analysis of IRE on The New Prostate Cancer Infolink in 2013, which interested patients are well advised to read. There is still not enough clinical data to recommend it, but there has been one promising pilot study with published results.

Valerio et al. reported on 34 low and intermediate risk patients treated at two institutions (St. Vincent Cancer Centre in Sydney and Princess Grace Hospital in London) between 2011 and 2013. All patients received multiparametric MRI-targeted biopsies in which 20-30 cores were taken. Patients were selected who had a single significant focus of cancer, either:
  • ·      Predominantly Gleason grade 4, or
  • ·      Core length ≥ 4 mm
Patients had to have good performance status, as the procedure involves full anesthesia and complete muscle paralysis.

Acute complications included blood in urine (18%), urinary tract infection (15%), painful urination (15 %), and urinary retention (6%). All toxicities were low grade - grade 1 (35%) or grade 2 (29%) - and were transient. One patient developed tachycardia and had to be watched for a day after the operation. At 6 months follow-up, all patients were continent and potency was preserved in 95%. One of the potential dangers of focal ablation is recto-urethral fistula, but none have so far been reported for IRE.

With up to 2 years of follow-up with mpMRI, 6 patients (18%) had residual disease:
  • ·      2 stayed on active surveillance
  • ·      3 had a second ablation treatment
o   1 with IRE
o   2 with HIFU
  • ·      1 had a radical prostatectomy
Multiple treatments

As with all forms of focal ablation, residual disease was found in some cases, and multiple treatments may be necessary. With IRE, its sub-millimeter precision is both its greatest strength and its greatest weakness. The strength is in its low risk of harming nearby structures like the bladder neck, urethral sphincter, neurovascular bundles, and rectum. It is also believed to be somewhat sparing of the connective tissue in muscle, blood vessels and nerves. The weakness is that even with our most accurate mpMRIs, it is impossible to discern microscopic amounts of cancer in the prostate. Even leaving a 5 mm margin around the index lesion, it is impossible to know if it ablated all the cancerous tissue.

Heat sink effect

Thermal ablation therapies, like HIFU, cryo or laser, are problematic because heat (or cold) dissipates away from the intended treatment zone. That can result in sublethal ablation of the intended target while causing thermal injury to nearby organs at risk as well as the neurovascular bundles. Tumors may repopulate in the sub-lethal ablation zone with enhanced vigor. With IRE there is no sub-lethal ablation, and no thermal damage to nearby healthy tissue.

Index tumor theory

Another issue that applies to all focal therapies is the theory of index tumors. There is a theory that the spread of prostate cancer is from a primary, relatively large and often higher-grade tumor called an index tumor. According to this theory, all metastases are clones from the original index tumor. If true, ablating the index tumor will stop the cancer. Prostate cancer is known to be multifocal (lots of little tumors) in 80% of men, but if the index tumor theory is correct, the multiple tumor foci will not seed any spread -- only the index tumor can do that.  Liu et al. and Mao et al. showed that metastases arise as clones from a single parent cancer cell, but did not show that the parent cell was in an index tumor. Several studies provide evidence to the contrary:
  • ·      A case report from Johns Hopkins showed that metastases arose from a small, low grade tumor rather than an index tumor.
  • ·      Cheng et al. found that multiple tumors had independent origins. In 15/18 tumors, he found that they arose independently within a single gland, and in 3/18 tumors they arose through intraglandular dissemination from an index lesion.
  • ·      Ibeawuchi et al. showed that there was as much genetic diversity in a unifocal tumor as there were in multifocal tumors.
Clinical evidence for the index tumor theory is based on the fact that a single focal therapy treatment is effective much of the time, at least in the short term. Most likely, it is true in some men but not in others, and it may be true of some, but not all, of the cancer within a single man. The other issue raised by the multifocal nature of prostate cancer is that the satellite tumors, whether they arise independently or are spawned from the index lesion, may be outside of the treatment range of the focal therapy. Hollmann et al. found that satellite tumors were a median of 1 cm, and up to 4.4 cm, away from the index lesion.

Active Surveillance

It has not yet been established that immediate focal ablation has any advantage over active surveillance. In low risk men, active surveillance is certainly safer. Active surveillance is increasingly being used by men with favorable intermediate risk prostate cancer. Arguably, there is a window of time during which focal ablation is possible, but we really don’t know that with any certainty. Men who have focal therapy must be closely followed for recurrence because we don’t know whether residual tumors may become active. Focally treated patients are effectively on lifetime active surveillance anyway.

Clinical Trials

There is obviously much to be learned from clinical trials. There is a second small-scale clinical trial (NEAT) that has been completed and should have results soon. NEAT included patient-reported quality-of-life outcomes, and allows for adaptive surgical technique to optimize treatment. They treated increasingly larger margins unless toxicity increased. To avoid risk of recto-urethral fistulae, only anterior zone tumors were treated.

There is an on-going full-scale clinical trial (NCT01835977) in Amsterdam. They are also running a registry and expect to treat 2,000 patients before 2020.

In the US, there are a few practitioners who are experimenting with IRE: Jaime Wong (Jenkins Clinic, Atlanta, GA), Gary Onik (Carnegie Mellon University), and  Jonathan Coleman (Memorial Sloan Kettering Cancer Center) have done over a dozen cases each. There is a pilot trial of 6 cases at Duke University (NCT01972867).





Thursday, August 25, 2016

Can a man be too young for active surveillance?


There is a “conventional wisdom” that active surveillance (AS) is only for older men, and that younger men are better off having immediate radical treatment, typically prostatectomy (RP). By “better off” we mean that there is a better chance at cancer control, or that the side effects of treatment, particularly incontinence and impotence, will be milder if treated earlier. Let’s turn a spotlight on that conventional wisdom, and see if it holds up under scrutiny.

The screening protocol for men under 50 years of age that is advocated by Memorial Sloan Kettering (see this link and this one), and recently discussed here, has important implications for active surveillance. Autopsy studies have demonstrated prostate cancer incidence of 20-30% in men under 50, mostly low grade and indolent. With increased screening of this young cohort, there will be an increase in the current incidence rate (now at about 10%). These men will increasingly be urged by their urologists to seek radical treatment, primarily surgery. If their screening protocol is widely adopted, there is great danger of over-treatment for this age group.


Oncological Control

With up to 20 years of follow-up, the Klotz Active Surveillance Trial has demonstrated the safety of that protocol. Klotz reported that of the 993 patients, there were only 15 deaths (1.5%) due to prostate cancer. When he pooled together several active surveillance studies, he found that the combined disease-specific survival rate was 99.7%. A Gleason score of 8-10 on confirmatory biopsy and a PSA doubling time of less than 3 years were associated with mortality, indicating the importance of close monitoring and follow-up biopsies on any active surveillance protocol.

It is worth noting how long men entering the Klotz study were able to stay on active surveillance before their progression characteristics indicated that radical treatment was required. Most of the progression was found in the first 5 years after entering the program, and reached a plateau by 15 years.

Time on AS
Percent for whom no treatment was recommended
5 years
75.7%
10 years
63.5%
15 years
55.0%
20 years
55.0%


Age was not a risk factor for prostate cancer mortality. Klotz said, “Younger patients were not at increased risk of prostate cancer mortality.” In fact, in younger men, the risk of non-prostate cancer mortality was almost six times higher than the rate of prostate cancer mortality.

It’s important to understand how slowly low-risk prostate cancer typically progresses in young men, even without active surveillance; that is, even without an intention to treat if the cancer progresses. Based on the Memorial Sloan Kettering Nomogram, we can see that for a 45 year-old man in excellent health diagnosed with a Gleason score of 3+3, PSA of 4 ng/ml, and nothing felt on a digital rectal exam, he has a zero chance of dying of prostate cancer in the next ten years, and a 4% chance of dying of something else. Even if he lets it go for 15 years, he only has a 3% chance of dying of prostate cancer, and an 8% chance of dying of something else.

It has been observed that there are rare and virulent forms of prostate cancer that are more prevalent in men under 50, and particularly among younger African-American men (see this link and this link). This is irrelevant to the discussion of active  surveillance  because those men will seldom be good  candidates for active surveillance from the outset. And if they do get in, clinical progression will be noticed in any active surveillance protocol at a very early time. Still, it is a reasonable precaution to screen men under 50 for genetic markers when there is a family history of early prostate cancer; for example, Oncotype Dx, Prolaris, TMPRSS2-ERG fusion, PTEN loss, or BRCA2 mutations.

Advancing age at the time of diagnosis is associated with a worse prognosis. In an analysis of 205,551 cases in the SEER database (see this link), 15-year prostate cancer mortality rates increased steadily with age at diagnosis.

Age Group
15-year PC mortality
≤50
2.3%
51-60
3.4%
61-70
4.6%
≥71
6.3%

Once again, this observation is irrelevant to a discussion of active surveillance. Age was not found to be a prognostic factor after accounting for Gleason score, tumor stage and PSA. The higher risk older men would probably not meet the entry criteria for active surveillance (although, depending on co-morbidities, they may be good candidates for watchful waiting). Those older men with more virulent disease that do get into an AS program would most likely be soon found to progress and be safely treated in time.

Based on oncological prognosis, younger age should not be used to decide between active surveillance and radical therapy.

Continence

An argument for treatment for younger men has been that there is a higher chance of continence preservation after surgery among younger men who already have better continence. Let’s see what the real-world numbers look like.

Continence naturally declines with age. Population-based continence statistics on younger men is scarce, but we can reasonably assume that moderate to severe incontinence is a rare occurrence in a 45 year-old man, and for our purposes, let us suppose that a 45 year old, just diagnosed with low-risk prostate cancer, is fully continent. What decision maximizes his lifetime expected continence?

Age
A. No natural moderate or severe incontinence
B. Expected lasting continence for men treated at that age
C. Percent losing continence due to RP at that age
D. Probability of staying on AS if started at 45
E. Expected loss of continence due to decision to initially have RP rather than AS
F. Life expectancy (years)
45
100%
80%
20%
100%
20%
34
50
92%*
79%
13%
76%
10%
30
55
84%
74%
10%
64%
6%
25
60
81%
70%*
11%
55%
6%
21
65
79%
66%
13%
55%
7%
18
70
74%
63%
11%
55%*
6%
14
75
74%*
59%
15%
55%*
8%
11

Sources:
B.     Younger cohort is from Johns Hopkins prostatectomy patients, older cohort is from University of Chicago: http://www.jurology.com/article/S0022-5347(06)01930-6/abstract http://www.jurology.com/article/S0022-5347(10)00017-0/abstract
C.     Column A – Column B
D.    Klotz, assuming plateau continues
E.     Column C x Column D
F.     Social Security actuarial tables
* extrapolated figures

Our fully continent 45 year-old man has about an 80% chance of retaining his continence if he has an immediate RP.  So, about 20% of 45 year-old men will lose continence if they decide for RP rather than AS. Those 20% will live with that loss of continence for 34 years.

If he chooses AS instead of RP, what happens in the next 5 years? He has some small natural deterioration of continence, roughly an 8% expected loss. If he has an RP 5 years from now, his expected continence is about the same at 79%. Therefore, his net expected loss of continence will be 13% if he remains on AS for the full 5 years. But he has only a 76% chance of staying on AS for the first 5 years. Therefore, his expected loss of continence due to the decision to go on AS at 45 and get treated at 50 is 10% - only half as much as if he had the RP at 45. And he will expect to live with that incontinence for fewer years.

If he chooses AS at 45 and manages to stay on it for the next 25 years without treatment (a 55% probability), his expected loss of continence (incorporating the probability of being able to go that long without treatment) is minimized, at only 6%. And he will only have to suffer the loss for 14 years.

With respect to preserving continence, the 45 year old man is better off going on AS and staying on it as long as he can. What’s more, it can be easily shown with a similar continence analysis that a man diagnosed with low risk prostate cancer at any age, is better off choosing AS over immediate treatment.

We have ignored the stress incontinence that persists even after “full” continence is restored. 34 years is a long time to worry about leakage every time a man coughs, sneezes, laughs or plays sports.

Potency Preservation

Potency is better preserved by prostatectomy while the patient is younger and fully potent. Is our 45-year old man, newly diagnosed with low risk prostate cancer and fully potent, better off having a prostatectomy immediately, or choosing AS? Let’s run the numbers.


Age
A. Expected potency without prostatectomy
B. Expected lasting potency for men treated at that age
C. Percent losing potency due to RP at that age
D. Probability of staying on AS if started at 45
E. Loss of potency due to decision to initially have RP rather than start with AS
F. Life expectancy (years)
45
100%
55%
45%
100%
45%
34
50
94%*
49%*
45%
76%
34%
30
55
87%
43%
44%
64%
28%
25
60
82%
35%*
47%
55%
26%
21
65
74%
27%
47%
55%
26%
18
70
60%
18%*
42%
55%*
23%
14
75
45%
8%
37%
55%*
20%
11


Sources:
B.     http://jama.jamanetwork.com/article.aspx?articleid=1104401 Supplemental content: eTable3 (97% had nerve-sparing surgery)
C.     Column A – Column B
D.    Klotz, assuming plateau continues
E.     Column C x Column D
F.     Social Security actuarial tables
* extrapolated figures

Our fully potent 45 year-old man has a 55% chance of retaining his potency if he has an immediate RP.  So, about 45% of 45 year-old men will lose potency if they decide for RP rather than AS. Those 45% will live with that impotence for 34 years.

If he chooses AS instead of RP, what happens in the next 5 years? He has some small natural deterioration of potency, roughly a 6% expected loss. If he has an RP 5 years from now, his expected potency will be a less too, at 49%. Therefore, his expected loss of potency nets out exactly the same (at 45%) if he remains on AS for the full 5 years. But he has only a 76% chance of staying on AS for the first 5 years. Therefore, his expected loss of potency due to the decision to go on AS at 45 and get treated at 50 is 34% - 11 percentage points less than if he had the RP at 45. And he will expect to live with that impotence for fewer years.

If he chooses AS at 45 and manages to stay on it for the next 25 years without treatment (a 55% probability), his expected loss of potency (incorporating the probability of being able to go that long without treatment) is only half of the expected loss due to immediate treatment, at only 23%. And he will only have to suffer the loss for 14 years.

With respect to preserving potency, the 45 year-old man is better off going on AS and staying on it as long as he can. What’s more, it can be easily shown with a similar potency analysis that a man diagnosed with low-risk prostate cancer at any age, is better off choosing AS over immediate treatment.

This analysis ignores other important sexual side effects that would certainly weigh against immediate prostatectomy. Those sexual side effects include loss of penile length and girth, climacturia, Peyronie’s, venous leak, dry orgasms, anorgasmia, and dysorgasmia. Baseline erectile function is seldom restored fully. Loss of libido and psychologically induced loss of erectile function and depression are common results of all the aforementioned. Even when erectile function can be induced chemically, there is significant cost attached to 34 years of ED medicines or injections.

Radiation

The choice is not nearly as clear when the decision is between AS and radiation therapy (either external beam or brachytherapy) for young low-risk patients. Incontinence is a very low probability side effect of radiation, and potency preservation is much better within every age group, chronic side effects of any kind are rare with modern technology. It is often argued that we don’t know how cancer control will change with 25+ years of follow-up after dose-escalated radiation. As we have seen (see this link), recurrence rates did not reach a plateau for RP or IMRT; however, if we were to examine low-risk patients only, it is likely that long-term results would be more stable for both surgery and radiation.

It is worth mentioning that there is another bit of “conventional wisdom” that does not hold up under scrutiny of the medical evidence. Many urologists incorrectly state or imply that the side effects of radiation are progressive and won’t show up for many years. Under that scenario, a 45 year-old man treated with radical radiation would eventually wind up with impotence 10 years later, as well as urinary and rectal problems. The PROSTQA study (see this link) of men treated in 1999 showed that most of the radiation-induced toxicity showed up early, and that much of the “late-term toxicity” observed may actually have been attributable to age, diabetes, and comorbidities (see this link).

The percent experiencing grade 2 or higher urinary toxicities (excluding incontinence) by 5 years, 8 years, and 10 years after treatment was:
  • ·      IMRT: 8.6% at 5 years, 11.2% at 8 years, and 10 years (76% of 10-year total by 5 years)
  • ·      BT: 4.3% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
  • ·      RP: 3.1% at 5 years, 3.7% at 8 years, and 5.5% at 10 years (56% of 10-year total by 5 years)
Ironically, we would conclude  (erroneously) from the above that it is prostatectomy, rather than radiation, that has cumulative urinary side effects that progress most over time.

The percent experiencing grade 2 or higher rectal toxicities by 5 years, 8 years, and 10 years after treatment was:
  • ·      IMRT: 7.8% at 5 years, 8 and 10 years (100% of 10-year total by 5 years)
  • ·      BT: 1.7% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
  • ·      RP: 0% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
We have seen in a previous commentary that erectile dysfunction due to radiation was lower than for RP within every age group, that it occurred within the first 9 months following treatment, and that half of the observed deterioration over time was due to the normal aging process.

The case for active surveillance and against radical treatment at a younger age is less convincing if radiation is the treatment of choice. It is for currently mostly a moot point because younger low-risk patients are seldom offered radiation therapy.

Conclusions

I have been personally influenced by the testimony of a 45 year-old man in my prostate cancer support group who was inconsolable and under treatment for suicidal ideation after the loss of continence and potency. Younger men who are single and suddenly find themselves to be impotent and incontinent often despair of finding a mate, and younger men who are married sometimes find their marriages on shaky ground.

It is also important to remember that the longer one is able to stay on AS, the higher the probability a cure will emerge from all the research now in the field. Already it seems that 5ARis (Proscar or Avodart) may delay or even reverse progression in low risk PC. There are a number of hormonal medicines and immunotherapies already being tested that might prove to be even more potent.

AS protocols are already improving, and will continue to be safer. Many institutional protocols now dictate that the first follow-up biopsy should be multiparametric MRI-targeted and/or targeted using a transperineal mapping biopsy. To avoid the danger of excessive biopsies in younger men, many institutions have moved off of the original protocol of annual biopsies. After the first follow-up biopsy, what happens next depends on what happened before. If there were no signs of any progression, the next biopsy can be two years later; after that, maybe 4 years with just an imaging study in between, etc. I know that even Johns Hopkins, which had the strictest AS protocol, relaxed their position on annual biopsies.

We have now seen that starting with AS is a more rational decision than starting with RP for all low risk men. However, the decision is often not a rational one, but is based on fear, traditional “baggage” carried over from other cancers, and the influence of loved ones, relatives and friends. In the end, the young patient must decide what he is most comfortable doing. Maybe it will be AS, maybe SBRT or brachytherapy, maybe surgery. What I am uncomfortable with is his doctor making those life-changing decisions for the patient, and ruling out any options without evidence. The low-risk patient certainly has plenty of time to investigate all options thoroughly for himself before coming to a decision. Taking one’s time often allows one to put emotions in perspective. Leaving all options open until one is ready to decide is the best stance to take. I have only seen treatment regret in men who didn't take the time to do that.