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.

Provenge

ProstATak

Proscavax

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.

Metformin

The MAST RCT proved that metformin made no difference in whether their grade increased or if they received treatment.

Curcumin

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.

Diet

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

Exercise

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.