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

Tuesday, June 21, 2022

Adjuvant Interventions for Active Surveillance

As of 2015, for men with low-risk prostate cancer (PCa), active surveillance (AS), is now the most popular "treatment" at 42%,  tripling since 2010. Its use was followed by radical prostatectomy (31%) and radiotherapy (37%). NCCN now lists AS as the preferred "therapy" for most men with low-risk PCa. They include these possible exceptions:

  • high PSA density
  • high number of positive cores
  • high genomic risk (e.g., on Decipher test, especially PTEN loss, TMPRSS2:ERG fusion, MYC activation,  or tp53 mutation)
  • known BRCA2 germline mutation

Other risk factors that are non-exclusionary but may suggest caution include family history, African-American ethnicity, and perineural invasion. Men with small amounts of Gleason pattern 4 are accepted in some AS programs now.

Memorial Sloan Kettering reported the following rates of AS patients who experienced grade progression:

  • 24% by 5 years
  • 36% by 10 years
  • 43% by 15 years
With the growing popularity of AS, and improved patient selection with mpMRI-targeted biopsies, there is interest in ways to extend time on AS. Several "adjuvant interventions" have been proposed to accomplish this. Adjuvant interventions can be categorized as systemic hormonal therapies, focal treatments, immunotherapies, and diet/supplements/lifestyle interventions.

It must always be recalled that the purpose of AS is to maintain quality of life (QOL) for as long as possible. Some interventions are minimal, do not harm the QOL, or may (like exercise) even enhance the QOL. Some interventions harm QOL but only for a limited period.

AS without intervention performs very well for most low-risk men, especially those with fewer risk factors. Interventions geared towards men on the less risky end of the AS spectrum must be less intrusive than interventions designed to prolong treatment-free survival among men who have greater risk.

In the end, the patient must weigh the risk and benefits of the intervention against the potential for AS prolongation.

I. Systemic Hormonal Therapies

5ARis (Proscar or Avodart)

Proscar (finasteride) and Avodart  (dutasteride) belong to a class of medications called 5-alpha-reductase inhibitors (5ARis) that are often prescribed to lessen symptoms of BPH. They prevent the metabolic conversion of testosterone to dihydrotestosterone (DHT), which is a much more powerful activator of the androgen receptor. It is the only known drug that can prevent prostate cancer. While there were initially some hints that it might cause high-risk PCa, many studies have now refuted that (e.g. this one or this one). When there is BPH, 5ARi use lowers PSA by about half and shrinks the prostate, which facilitates cancer detection. 

Fleshner et al. reported on a prospective clinical trial in which 289 men at 65 centers who chose to be on AS were randomly allocated to get dutasteride or a placebo. They were checked with a biopsy at 18 months and at 3 years. After 3 years of follow-up, they reported:
  • 38% of men using dutasteride and 48% using placebo  experienced progression, a statistically significant difference
  • 24% of men using dutasteride and 15% using placebo reported sexual adverse effects or gynecomastia
  • No prostate cancer-related deaths or metastases 

Finelli et al. retrospectively reported on 288 men on AS at Princess Margaret Hospital in Toronto. After median follow-up of 7 years, they found:

  • Pathologic progression (increased grade, increased # of cores>3, or any core involvement > 50%): 28% of men using 5ARis vs 56% of non-users.
  • Grade progression: 22% of men using 5ARIs vs. 40% of non-users
  • Volume progression: 18% of men using 5ARIs vs. 43% of non-users
  • Definitive treatment: 27% of men using 5ARIs vs. 51% of non-users
  • Frequency of progression to Gleason 8-10 was the same for both groups: 2% of men using 5ARIs vs. 4% of non-users

Kearns et al. retrospectively reported on 107 men who used a 5ARi and 902 men who didn't while on AS in the multicenter PASS trial.
  • There was no statistically significant difference in the percent of men reclassified
  • Men using 5ARis were less likely to undergo definitive treatment (19%) vs. non-users (24%)
  • There was no difference in adverse pathology among men opting for prostatectomy
Shelton et al. at Carolinas Medical Center reported that among 82 men who had very-low-risk PCa and BPH who were given a 5ARi for one year, over half had no cancer in a subsequent biopsy. This is especially encouraging because with prostate shrinking, we would expect the cancer to be easier to detect.

It is also worthwhile to note that 5ARis improve the sensitivity of PSA to detect prostate cancer; rises while taking the drug are more likely to be due to prostate cancer progression than to BPH (see this link). Chiang et al. proposed that 5ARis can be used to render PSA doubling time a good indicator of progression for men on AS.

Tan et al. at UCLA reported that 5ARis, because they reduce urinary symptoms, may reduce the anxiety associated with AS. This may encourage men to stick with AS longer. In 2011, the FDA approved daily Cialis for LUTS and BPH. Cialis (tadalafil) is now available as a low-cost generic. Taking it with a 5ari may mitigate some of the sexual side effects too.

Androgen Deprivation Therapy (ADT)

Cussenot et al. reported on a French Phase 3 clinical trial among 115 men on AS randomized to get one 3-month shot of  Lupron or not. After a year, they were biopsied:

  • 53% had negative biopsies, if they'd had the Lupron vs. 32%, if not
  • Prostate symptoms improved at 3-9 months among those who took the Lupron
  • Sexual function was similar in both groups after a year
  • Other endpoints were no different: % with grade progression, progression on MRI, PSA progression, anxiety

The problem with such clinical trials is "lead-time bias." That means that the Lupron may have shrunk the cancer while it was effective, but after testosterone returned to normal, the cancer may have resumed growth at the same pace. To control for lead-time bias, the biopsy in the Lupron-using group should have occurred 12 months after their testosterone returned to its baseline level. If all the Lupron did was defer progression for 3 months, there was no benefit and probably some quality-of-life harm while taking it.

Apalutamide (Erleada)

Erleada is a powerful 2nd generation anti-androgen. It is useful in newly-diagnosed men with metastases and castration-resistant men without metastases. The major toxicities are fatigue, hypertension, rash, diarrhea, nausea, weight decrease, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

Barrett et al. reported on a single-arm pilot trial called TAPS-01. Nine men on AS were given 3 months of apalutamide.

  • At the end of treatment, prostate volume shrank by 38%, tumor volume shrank by 54%, and the ratio of tumor volume to prostate volume shrank by 27%
  • 3 months after treatment, prostate volume returned to baseline, while tumor volume and the ratio were 32% and 29%, respectively, less than at baseline
  • 15 months after treatment,  tumor volume and the ratio were 18% and 24%, respectively, less than at baseline
  • QOL scores decreased during treatment but returned to baseline 6 weeks after treatment

They are planning to recruit 335 patients for a Phase III randomized trial.

Michael Schweizer presented the results of another small  (n=22) trial at the 2020 SUO meeting. Patients were mostly low risk (64%), but a few were very favorable intermediate risk (36%). They were given 3 months of apalutamide.

  • At the end of treatment, 59% had negative biopsies.
    • 35% had negative biopsies 9 months later
  • All 4 patients who were biopsied at 2 years had positive biopsies
  • PSA returned to baseline level 9 months after treatment

There is a randomized Phase 2 trial in France (see this link).

Enzalutamide (Xtandi)

Shore et al. reported the results of the ENACT clinical trial in which 227 men at 66 sites were randomized to get 1 year of enzalutamide monotherapy+AS (enza) or AS-alone. None had very low-risk PCa, 53% had low-risk PCa, and 47% had favorable intermediate-risk PCa.

  • Disease progression: 28% on enza vs 37% on AS
  • Pathologic or therapeutic progression was lower with enza at the end of therapy (8% vs 23%), but there was no difference a year later (16% in both arms)
  • By 2 yrs after randomization, there was no significant difference in the % with positive biopsies, % of positive cores, or the % with a secondary rise in PSA.
  • Among intermediate-risk patients, therapeutic progression was 25% for enza vs 39% for AS-only
  • Adverse events (AEs) were experienced by 92% for enza vs. 55% for AS-only
  • Drug-related AEs were fatigue, breast effects, ED, baldness, libido loss, hot flashes, and GI disturbances

This trial exhibited significant lead-time bias. PSA progression occurred precipitously at 15 months when the enzalutamide wore off (Fig 2B). If the enza patients were monitored starting when the enza wore off and they were compared to the AS-only patients from the date of randomization, there would be no effect ever seen for enza therapy. Patients suffered the side effects of enza for nothing. There may be some opportunity for its use in favorable intermediate-risk patients on AS, but that requires further trials.

II. Focal therapies

We looked at photodynamic therapy (PDT) using sensitization with TOOKAD previously (see this link). After 4 years of follow-up, 24% of TOOKAD users and 53% of AS-only users converted to radical therapy (RP or RT). But 5-yr conversion rates were similar at MSK (24%) and Klotz (28%). There are several apparent reasons for this discrepancy:

  • Very low-risk patients were excluded in the TOOKAD trial
  • TOOKAD retreatment was given if a 1-yr biopsy indicated progression.
  • All of the TOOKAD group had mpMRI, while none of the AS-only group did. Many in the AS-only group would have been excluded from AS if mpMRI had been used to confirm their low-risk cancer.

The other major finding was that 49% had a negative biopsy after TOOKAD treatment and retreatment vs 14% with AS-only. In another study, 52% had no evidence of disease on a confirmatory biopsy with AS-only. In a UCLA study using mpMRI to find suspicious sites, the apparent remission rate was 40%. The reason for the discrepancy is that the AS-only group in this trial included many men who should never have been on AS if mpMRIs had been used initially to find their cancer.

As we've seen (above), an apparent remission rate of 54% can be achieved by simply taking a Proscar or Avodart pill (see this link).

For a discussion of treatment toxicity, see the previous article. Also, see the comparison with SBRT at 2 years post-treatment. It shows the patients would have been better off had they been given definitive treatment with SBRT.

The FDA has rejected TOOKAD as a treatment for low-risk prostate cancer, but a longer follow-up study is expected in 2025.

Ehdaie et al. conducted a clinical trial of an MRI-based HIFU technique (see this link for analysis of a whole-gland TULSA-PRO trial). They only treated intermediate-risk patients (78% Grade Group 2, 22% Grade Group 3). The goal was to see if HIFU could maintain such patients on active surveillance and forestall radical treatment. There were 101 patients treated at 8 institutions. At 2 year follow-up:

  • 20% still had cancer in the ablation zone, 12% Grade Group 2 or higher
  • 60% still had cancer in the prostate, 40% Grade Group 2 or higher
  • PSA reduced from 5.7 to about 3.1
  • Among men with good erectile function at baseline, erectile function dropped by 40%, but only by 10% with ED meds.
  • Urinary function was maintained.
  • Transient hematuria (24%) and urinary retention (15%) were common immediately following treatment

We see results similar to TOOKAD above. There, about half still had cancer 4 years after treatment; Here, 60% 2 years after treatment. With 40% still having Grade Group 2 or higher, this treatment failed for many at keeping them on active surveillance and forestalling treatment. It doesn't matter how low the toxicity is, if the treatment doesn't do job #1. With significant PSA remaining after HIFU, patient anxiety and regret (not measured) may still be high. It's hard to see what was gained by putting patients through this operation.

It would be nice to see a comparative trial in intermediate-risk patients randomized to either HIFU or SBRT.

There is a clinical trial in Norway among intermediate-risk men with MRI-detected lesions on AS to be focally treated with HIFU (see this link).

III. Injections

Several one-time injections have been tried or proposed that could possibly extend time on AS.

Fexapotide Triflutate (FT)

FT was previously reviewed (see this link). It is injected only once into any quadrant of the prostate where Gleason 6 has been detected. It causes apoptosis of all prostate cells, benign and cancerous, but has no effect on other tissues. It was only used in men who had only one core that had <50% GS6 cancer. To recap:

After 4 years of follow-up:

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

Again, the treatment rate for AS progression is very high, especially in this very low risk population. The FDA has delayed approval pending 2 years more follow-up data.

Liproca (2-hydroxyflutamide)

Liproca is an intra-prostate injection for men on the riskier end of the AS spectrum. Klotz et al. reported on a dose-finding clinical trial of the one-time injection of a large volume (doses were varied) of the anti-androgen into the prostates of 61 men on AS who had the following characteristics:

  • GS 3+3 or 3+4, and
  • PSA > 6 ng/ml and PSA density > 0.15, or
  • PSA between 10-20 ng/ml, or
  • Any core >50% cancer, or
  • PIRADS 4 or 5, or
  • Men of African descent

After 6 months of follow-up:

  • After a transient PSA increase due to the large volume of liquid,  about half had a PSA reduction >15% by 6 months post-injection
  • Testosterone was at baseline by month 6
  • About ¾ of patients had a decreased prostate volume
  • No worsening of PIRADS scores were seen
  • Systemic leakage of the anti-androgen was low and transient
  • No adverse events were attributable to the anti-androgen

If they expand the trial, the 16 ml dose will be used, and biopsies will be given to determine efficacy.

Prostatic Artery Embolization

Frandon et al. reported on a pilot trial of 10 patients with a single positive GS6 biopsy core. The artery leading to that prostate lobe was embolized.

  • 4 of 10 patients had negative biopsies
  • No MRI-visible lesions in 3 of 10
  • Prostate symptoms and erectile function were unchanged from baseline
  • 9 of 10 patients were still on AS after a year. The 1 who progressed had his positive core outside the target lesion

With the majority still having positive biopsies, it is a doubtful treatment.

IV. Immunotherapy

Prostvac was given to half the men, an placebo (empty cowpox vector) to half. After 6 months, there was no difference in grade progression or in T-cell responses.

There are three other clinical trials of immunotherapies to extend active surveillance.




V. Supplements, Diet, & Exercise

Vitamin D

Marshall et al. reported on 46 patients on AS given 4000iu/day Vitamin D. After a year:

  • There were no significant changes in PSA
  • In terms of Gleason scores or positive cores: 55% decreased, 11% stayed the same, and 34% increased

Although there was no control group, these results were unspectacular.

There are 2 clinical trials. One in Australia, and one among US Veterans.


There are two clinical trials for curcumin. One at the University of Rochester; one at UTSW. Curcumin has been found to interfere with PSA assays (see this link), which makes its use on an AS program problematic.

Green Tea

There is a large, randomized, multi-institutional trial of green tea catechins for active surveillance.


The MEAL RCT proved that adding more vegetables to the diet did not extend time on active surveillance.


The ERASE RCT randomized 52 Canadian men on AS to either 12 weeks of high-intensity interval-training exercise or usual care. At the end of the intervention:

  • Peak blood oxygenation increased significantly in the exercise group and decreased in the usual care group
  • Compared to usual care, PSA decreased significantly and PSA velocity slowed
  • Histology demonstrated that in the exercise group, cancer cells shrank by at least 5% in 15 of 23 men (65%) vs. in only 7 of 23 men (30%) in the usual care group. 
  • In the exercise group, growth by 5% or more only occurred in 2 of 23 men (9%) vs 5 of 23 men (22%) in the usual care group.

Early results seem to favor staying on AS. Even if these early effects do not eventually translate into less conversion from AS, there was a health benefit. There may also be a benefit in terms of decreased tumor hypoxia if radiation therapy is eventually chosen.

Guy et al. reported on a retrospective study among men on AS at Sunnybrook Hospital in Toronto and Royal Marsden Hospital in London. They found that men who participated in weekly vigorous physical activity were 58% less likely to reclassify vs. those who did not.

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?


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.

Odds of missing higher grade in ALL the biopsies

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
Metastasis-free survival
Epstein protocol
Johns Hopkins
15 years
Less strict:
favorable risk only
Confirmatory and periodic thereafter
20 years
Any localized regardless of PSA or grade



10 years


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).