Intermittent ADT

 No one likes Androgen Deprivation Therapy (ADT). Even in the short term, there are hot flashes to contend with, fatigue, and loss of libido. Longer term, there may be cardiovascular side effects, bone loss, fat gain, brain fog, low red blood cell count, blood sugar dysregulation, and mood swings. What are the potential risks and benefits of taking occassional vacations (called "intermittent androgen deprivation therapy"- iADT) from continuous androgen deprivation therapy - cADT?

For a discussion of all randomized trials of iADT vs. cADT, see this link. I will focus on a few of the most important trials that had homogeneous patient populations and had the longest follow-up. Patients must focus on the situation (called the "setting") they currently find themselves in - the advisability of using iADT differs with the setting.

I. Settings

1.  Active Surveillance

Active Surveillance for low- and some favorable intermediate-risk patients requires no interventions. There have been several trials of short-term use of hormonal therapies - see this link under the subheading "I. Systemic Hormonal Therapies." All trials suffer from "lead time bias," which means that progression is not detected until after the hormonal therapy wears off. Nothing is gained: one only buys time onactive surveillance with time on the hormonal therapy.

2. Localized High Risk, Pelvic Lymph Node-only (N1), or Salvage Radiation

ADT in these situations must be continuous. For localized high-risk prostate cancer (PCa), ADT must continue for 12 months if brachy-boost therapy is given, and 26 months if external beam therapy is given (see this link). If there are cancerous pelvic lymph nodes detected by conventional imaging, 3 years of ADT and 2 years of abiraterone is standard-of-care (see this link). If detected on PET scan only, there is less data. If it is adjuvant ADT given with salvage radiation, 4 months to 2 years may be used (see this link)

Stopping and restarting ADT is like stopping and restarting antibiotics - it selects for the most resistant strains. The resistant strains are killed by sustained use of ADT and possibly more intensive hormone therapy. If unleashed by a vacation, they are not easily killed by simply adding more ADT. One can cause an aggressive, resistant type of PCa to predominate by using iADT in this situation.

3. Recurrent PCa

It is controversial whether to use ADT at all when PCa detected only by rising PSA after attempted curative treatment. The PRESTO randomized clinical trial showed that in patients with rapid PSA doubling time, a year of intensive hormone therapy (with apalutamide) could delay progression for a long while. The EMBARK randomized clinical trial showed that in similar patients, treatment with enzalutamide slowed castration resistance and the incidence of metastases.

Crook et al. reported the results of a Canadian randomized clinical trial (NCIC- CTG PR.7) among 1,386 men with PSA recurrence after primary radiation therapy. They were randomized to iADT or cADT. The iADT protocol was:

• no one had detectable metastases on a bone scan/CT
• 8 months on, 8 months off
• Vacations continued unless PSA during the on cycle failed to fall below 4 ng/ml, or if the lowest PSA was 1 ng/ml above the nadir reached in the previous cycle, or if there was evidence of castration resistance (3 consecutive increases during an on cycle or clinical evidence).

After 7 years of follow-up:

• There were no significant differences in adverse events, except for hot flashes, libido, and urinary symptoms.
• Testosterone recovered to baseline in 35% in the iADT cohort. 
• Only 29% of men who were potent at baseline had a recovery of potency
• Median survival was 9.1 years for cADT vs 8.8 years for iADT (not statistically different)
• Median prostate cancer mortality was 18% for iADT and 15% for cADT (not statistically different)
• After adjustment to allow for time to get back on ADT and monitor PSA for 3 consecutive rises (Figure S5), eliminating ascertainment bias, there was no difference in time to castration resistance.
• Those who achieved lower nadir testosterone in the first year had lower PCa-specific mortality (see this link). Those with a higher nadir testosterone, developed castration resistance sooner and died sooner.

For recurrent men, iADT may give equal oncological results. Results may be improved, however, with more effective androgen deprivation.

4. Recurrent (Stage M0) or Locally Advanced (Stage N1) HSPC

Patients in these situations would rarely opt for treatment with ADT only, because they can potentially be cured with salvage radiation and adjuvant (limited term) ADT. 

In the ICELAND trial, 701 recurrent (no distant metastases) or locally advanced (metastases only in pelvic lymph nodes - Stage N1) patients from 20 European countries were randomized to receive iADT or cADT. The protocol was:

• All patients had ADT with Lupron for 6 months at the start
• The off-cycle was stopped when PSA increased to 2.5 ng/ml
• The on-cycle was stopped when PSA fell to 1.0 ng/ml
• Castration resistance was declared if there were 3 consecutive PSA increases above 4.0 ng/ml during the on-cycle.

The trial was stopped 36 months after randomization. In that time:

• Only 11% became castration-resistant
• There was no difference in castration resistance between iADT and cADT
• Testosterone only rose to about half of the baseline level during the off-cycle
• Overall survival was high (85%), and there was no significant difference between groups
• There were no differences in side effects or quality of life between iADT and cADT

While the trial didn't run long enough for meaningful differences to emerge, the lack of a quality-of-life benefit for iADT may dissuade men in this situation from attempting iADT. 

For newly detected patients with cancerous pelvic lymph nodes, a STAMPEDE trial has proved that continuous use of 3 years of ADT and 2 years of abiraterone improves survival and delays castration resistance over ADT alone. 

These patients can potentially be cured with whole pelvic radiation and intensive hormone therapy. Such potentially curative treatment has been suggested by retrospective studies. Prospective randomized clinical trials  (like this one and this one)will determine whether radiation with adjuvant hormonal therapy can provide a curative option to patients who are newly diagnosed with cancerous pelvic lymph nodes.

5. Metastatic Hormone Sensitive PCa (mHSPC)

Maha Hussain et al. reported the results of the SWOG-S9346 RCT. They randomized 1,535 men who were sensitive to hormone therapy.

• Half were randomly assigned to cADT, half to iADT
• Half were recurrent after primary prostatectomy or radiation; half had not been treated previously
• All responded to 7 months of ADT with a PSA<4 ng/ml
• In the iADT cohort, vacation was ended when PSA hit 20 ng/ml (10 ng/ml at doctor's discretion), and was triggered when PSA fell to 4 ng/ml. They were taken off the study if PSA didn't fall to 4 ng/ml while on ADT, or if PSA rose again before the first 3 months of starting a vacation.
• Half had extensive metastases (ribs, long bones, viscera); half had minimal metastases (axial skeleton and lymph nodes).
• Median PSA at baseline was 41 ng/ml

After a median follow-up of 10 years:

• Overall survival was 5.8 years for cADT vs. 5.1 years for iADT
• Mortality increased 10% due to iADT (range 23% increase to a 1% decrease with 90% confidence). 
• Because the median increase did not reach the prespecified 20% hazard ratio for a clinically important difference, but the confidence interval included it, and a small percent (1%) lived longer with iADT, the study was considered statistically inconclusive. In other words, iADT may have been inferior, although they couldn't prove it definitively with the statistics obtained.
• The iADT cohort had better erectile function and better mental health at 3 months but not thereafter.
• There was no difference in adverse events.
• Castration-resistance started after the same amount of time in each group, after adjustment for allowing the iADT group to prove rising PSA while receiving treatment (Figure S5).

A secondary analysis of SWOG-S9346 trial combined with Medicare codes focused on the long-term side effects of iADT vs cADT. After 10 years:

• Thrombotic and ischemic events (e.g., heart, lung, or brain blockages and strokes) were significantly worse for iADT (33%) than for cADT (24%)
• There were no significant differences in bone, endocrine, or cognitive events.

6. Metastatic Castration-Resistant PCa (mCRPC)

One of the causes of castration resistance is that the androgen receptor (AR) amplifies (upregulates) in each cancer cell. Because there are now so many copies of the AR, it takes very little androgen to activate cell replication. Some patients suppose that once they are castration-resistant they can cease using ADT. The opposite is true. They are more sensitive than ever to even the slightest amount of testosterone.

While iADT cannot be used, some researchers at Johns Hopkins hypothesized that rapid alteration between high testosterone and very low testosterone, called Bipolar Androgen Therapy, or BAT, may be able to retard AR upregulation.  In clinical trials so far, BAT seems to slow enzalutamide resistance in some men (20%-30%) but accelerates progression in others (see this link). There has been some progress: those men with high AR activity seem to benefit. The test is so far only available at Johns Hopkins. There are already concerns about safety, so patients should not attempt BAT outside of a carefully monitored clinical trial.

II. No Difference in Time to Castration Resistance

The original hope of iADT was that it would slow progression to castration resistance. This was based on tests in mice conducted by Bruchovsky. In clinical trials, this early hope did not pan out. All of the randomized clinical trials with homogeneous patient populations: SWOG-S9346, NCIC-CTG PR.7, ICELAND, and EC507 confirmed that the time to castration resistance was not different for iADT and cADT. Any reduction of evolutionary selection pressure with iADT is balanced by the reduction in sheer numbers with sustained cADT. This is not surprising, given that intensive hormonal treatment with ADT and Zytiga, Xtandi, or Erleada has been proven to delay castration resistance in men who are mHSPC. 

III. Testosterone Recovery with iADT

The only reason to take a vacation from ADT is if testosterone recovers enough to provide relief from symptoms. Nabid et al. reported the testosterone recovery to normal testosterone based on how long they received ADT and whether their testosterone level was normal or below normal at baseline. Their data is from men curatively treated with ADT and radiation for intermediate and high-risk PCa. This table summarizes their findings:

		Percent who recover to normal
ADT Duration	Years to recover to normal T	among patients normal at baseline	among patients below normal at baseline
6 months	1.5 yrs	82%	53%
18 months	3.1 yrs	63%	28%
36 months	5.0 yrs	50%	21%

For 82% of men who have normal testosterone (T) at baseline and start with 6 months of ADT, it will take 1.5 years of vacation for their T to recover to normal levels. And almost half of men with below normal T at baseline will never obtain normal T levels. Older age and diabetes decrease the odds of T recovery.

A man who desires an ADT vacation should consider whether the vacation is likely to last long enough to give him a sufficient break from symptoms. Because men will be starting their vacation from castration at baseline, most men will never get the desired break.

Ong et al. similarly reported on testosterone recovery based on several clinical trials. A third of the men never enjoyed recovery to normal testosterone (>300 ng/dl or > 10.5 nmol/L). Older men (>65) were 20-33% less likely to recover normal testosterone.

		Time (median) to recovery to normal T (300 ng/dl)
ADT Duration	Percent who recover to normal T	among patients average at baseline	among patients normal at baseline
3 months	} 67%	6.2 months	5.5 months
6 months		15.2 months	12.7 months
18 months		36.0 months	30.8 months

Dai et al. reported the time it took to recover to normal level (>250 ng/dl) of T after one treatment with 9 months of ADT. T at baseline determined T recovery time.

T Recovery (> 250 ng/dl) Time	Percent who recover to normal
1 month	0%
3 months	37%
6 months	66%
9 months	86%
12 months	93%

Tunn et al. reported specifically on men on iADT. They found that after 6 months of ADT, T recovery to baseline occurred in 79% in the first vacation, taking a median of 100 days. Recovery diminished in the second vacation - 65% recovered in 115 days. They also found no difference in time to castration resistance between iADT and cADT.

Relogulix (Orgovyx) is a fast-acting oral medication that provides ADT. It is a better choice for iADT. After taking it or Lupron for almost a year, T rose to normal levels within 3 months with Orgovyx but barely above castration level with Lupron (see this link).

IV. Earlier Use of iADT

It has been hypothesized that iADT is more beneficial if used earlier. PET scans may be able to identify occult metastases while they are still small enough for occasional hormone therapy to keep them in check. PRESTO and similar trials of short-term intensive use of second-line hormone therapies may be able to provide a longer and safer break from side effects.

V. iADT Protocols

There are no established iADT protocols. It is always based on judgment, and should be arrived at after discussion with one's oncologist. Here are a few factors to consider.

1. PSA after first ADT cycle

An undetectable (<0.2 ng/ml) PSA nadir, whether achieved rapidly or slowly, on the first cycle of ADT is prognostic for successful cycles with iADT. If the lowest PSA is still detectable after several months of ADT, especially if a high nadir is achieved rapidly, cADT may be a better strategy (see this link).

2. Time on On-Cycle and Off-Cycle

• The Pr.7 trial used an arbitrary protocol of 8 months both on- and off-cycle.
•  Others continue the on-cycle for at least a year. 
• The time off-cycle may be different from the duration of the on-cycle. 
• One can use an arbitrary time for the on-cycle and use a different factor, say PSA doubling time, for the off-cycle. 
• One can let the on-cycle duration be variable: say, 8 months for the first on-cycle, 12 months for the second, 18 months for the third.
• The on-cycle duration variability can be based on the previous on-cycle PSA history (e.g., increasing nadirs), or off-cycle factors (e.g., higher PSA in last off-cycle).

3. Testosterone level achieved on the Off-Cycle

Since there is no other known purpose of iADT than to maintain quality of life, it may make sense to continue the off-cycle until normal testosterone (T) is maintained for some length of time. Some men will never achieve normal T levels (see above), so there is no point in risking iADT. It is important to measure T at baseline and during the off-cycle.

4. Maximum PSA target on Off-Cycle

The SWOG trial of men with metastases visible on a bone scan/CT used a maximum PSA of 20 ng/ml (10 ng/ml at doctor's discretion) as the signal that it was time to end the vacation. Trials that look at non-metastatic patient groups usually use a much lower PSA threshold for ending the vacation (typically 4 ng/ml). PET scans can detect metastases at lower PSAs (see this link), so the threshold may be set somewhere in between. The patient can decide what threshold he is comfortable with.

5. PSA Doubling Time (PSADT)

It is reasonable to use rapid PSA doubling time (PSADT) as the signal that it is time to end the ADT vacation. Typical threshold PSADTs may be 3, 6, or 9 months, depending on the patient's degree of comfort. Here is a PSADT calculator.

6. Symptoms/Radiographic Progression

PSA will usually provide an early signal of progression. However, the appearance of new metastases, enlarged metastases, bone pain may provide evidence of progression even before PSA has picked it up. The Bone Scan Index may be a useful metric. 

7. Finasteride on Off-Cycle

Retrospective analysis suggested that finasteride might be helpful in extending the vacation time (see this link). However, when it was tried in the prospective clinical AVIAS trial, there was no benefit in extending the off cycle by adding dutasteride.

8. Biology/Genomics

We are learning how to use genomic tools as an aid to decision-making. Recurrent, non-metastatic men with a high risk of developing metastases (Decipher high-risk) may wish to think twice about iADT, while those with low-risk Decipher scores may feel more comfortable opting for iADT. A recent new test developed by Veracyte (the company that makes Decipher) may one day be able to identify patients who are very responsive to hormone therapy and may be able to try iADT. Johns Hopkins has developed a test of Androgen Receptor activity that may prove useful in determining whether iADT with BAT makes sense.

9. Metastasis Directed Therapy (MDT) using SBRT

Men who play "whack-a-mole" with metastases as they crop up usually see their PSA drop. This is because serum PSA comes mostly from larger, detectable metastases that have developed their own blood supply. It is tempting to use iADT when serum PSA is negligible; however it may be risky to take long ADT vacations when PSA has been artificially tampered with. See "The Perils and Pitfalls of Treating PSA."

Tang et al. conducted the EXTEND trial at MD Anderson to see if SBRT to oligometastases could extend the ADT vacation without risk. 87 oligometastatic men were randomized to get ADT with or without SBRT. After 6 months, all were given a vacation from ADT. The vacation ended when PSA reached 20 or new metastases appeared. Those who got SBRT were able to take a significantly longer vacation before progression.

10. Adaptive iADT

Several schemes have been proposed for determining the optimal way of using iADT. The goal of these mathematical models is to delay castration resistance. They make adjustments to ADT use based on each person's response, and change as his tumors evolve. They can be thought of as tailoring ADT to suit the individual. So far, they have only been used clinically in small pilot trials or proposed pre-clinically. Here are a few examples:

A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer

Evolution-based mathematical models significantly prolong response to abiraterone in metastatic castrate-resistant prostate cancer and identify strategies to further improve outcomes

Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer

Practically scheduling hormone therapy for prostate cancer using a mathematical model

Intermittent Androgen Suppression: Estimating Parameters for Individual Patients Based on Initial PSA Data in Response to Androgen Deprivation Therapy

VI. Cardiovascular (CV) Adverse Events (MACE)

The most life-threatening adverse events that can be attributed to ADT are cardiovascular: MACE=Major Cardiovascular Event (myocardial infarction or stroke).

In the SWOG-S9346 trial by Hussain et al., thrombotic and ischemic events (e.g., heart, lung, or brain blockages and strokes) were significantly worse for iADT (33%) than for cADT (24%). CV events are highest during the first 6 months of initiating ADT. It may be that the fluctuating T and estrogen levels inherent in iADT causes coagulation. Oral estrogen, which results in peaks and valleys in serum concentration, was known to cause blood clots and was eliminated as a therapy for that reason.

However, a meta-analysis of iADT trials found no difference in CV events compared to cADT, but there was a difference in deaths due to CV events. Those who used iADT were 15% more likely to die of MACE.

Orgovyx has been found to have a better CV risk profile than Lupron, although MACE incidence is not high for either drug. Incidence of MACE was 2.9% for Orgovyx vs. 6.2% for Lupron (see this link). If MACE occurred, it usually occurred within 6 months of starting ADT, and was significantly higher in men with a history of it (3.6% for Orgovyx vs. 17.8% for Lupron). GnRH antagonists (like Orgovyx or Firmagon) may release proteins that prevent plaques from forming in cardiac blood vessels (see this link), while GnRH agonists (like Lupron) may increase plaque instability (see this link and this link). The PRONOUNCE trial, which would have been definitive, failed to adequately recruit, and was ended early with no difference in MACE at 1 year between Firmagon and Lupron. A retrospective study suggested that Firmagon had lower MACE than Lupron.

VII. Managing Other ADT Side Effects

It may be possible to at least manage some of the most annoying ADT side effects without resorting to iADT. Here are interventions that can be used now or on the horizon for some of the common side effects of ADT. Each patient must determine for himself the balance between interventions and risk of the side effects.

1. Fatigue

The small randomized EXTEND trial at Duke last year reported that men who undertook a supervised program of aerobics and weight training before and during hormone therapy were able to significantly improve their fatigue scores and quality of life relative to men who did not take the program. Similar programs have been found to combat fatigue in small randomized trials in Australia (see this link and this one), and the UK, 

There is a Phase 3 trial of Exercise and Methylphenidate (Ritalin) at MD Anderson with results expected by Nov. 2023.

Stopping smoking and restricting alcohol use may be beneficial.

Weight-bearing exercise may be contraindicated in men with multiple bone metastases due to risk of fracture. Cardiovascular morbidity may preclude aerobic exercise in some men. One should always check with one's doctors before beginning an exercise regime.

2. Libido

It should be understood the loss of desire for sex (libido) is not necessarily accompanied by a loss of erectile function, Men are often still able to have functional erections while on ADT if they use Trimix. Many men and their partners learn to value intimacy without intercourse. In some men, the loss of libido leads to a deterioration of relationships and a loss of one's masculine self-concept causing psycho-social problems.

3. Bone Loss

Long-term use of ADT leads to loss of bone mineral density (BMD). Resistance exercise and estrogen patches (see this link) can help maintain BMD.  Unless there is fracture risk from multiple metastases, bone restorative agents (Zometa or Xgeva) should not be used before castration resistance because their most serious side effects are cumulative. 

Excess calcium intake should be avoided due to risk of hastening progression (see this link and this one), cardiovascular side effects and kidney stones. There is no evidence that Vitamin D has any benefit unless one has a deficiency (see this link); in fact, high exogenous doses can pull calcium out of bones. Bloodwork at baseline and annually can determine if there is a deficiency.

Men using ADT should have a DXA scan at baseline, and annually thereafter. Here is a link for calculating FRAX score.

4. Lean Body Mass/ Muscle strength

Exercise has been found to help maintain lean body mass and avoid fat accumulation in a large number of small randomized trials (see this link), including this one. Transdermal estrogen is also known to preserve lean body mass. Amgen was developing a drug that may one day be used to inhibit myostatin in men on ADT (see this link and this one).

5. Metabolic Syndrome/Hyperlipidemia

Body Mass Index (BMI) and metabolic syndrome increases are well-known effects of ADT. They have been found to worsen prognosis. Again, exercise can help ameliorate it.

6. Hyperglycemia/ Insulin Resistance

Pioglitazone (Actos) an FDA-approved insulin sensitizer is being investigated as an adjunct to ADT in this clinical trial.

7. Hot Flashes

The following are good, albeit imperfect, solutions for hot flashes: aural acupuncture, estrogen patches, Progesterones (Megace or Provera), venlafaxine (Effexor), and oxybutynin.

8. Mental Effects/Mood Swings/Depression

Mindfulness, psychotherapy and antidepressants may help. Vortioxetine (Brintellix), an antidepressant, has been used in a pre-clinical study to reverse the ADT-induced cognitive impairment in rats.

9. Anemia

ADT may cause anemia in some men due to the lack of erythrocyte stimulation that testosterone would normally accomplish (see this link).  Erythropoietin (Procrit) may be able to reverse it if red blood cell levels get seriously low.

VIII. Shared Decision-Making

If you are feeling lost and confused after reading all of the above considerations about iADT, you are not alone. This is a consequential decision that should not be made lightly. It is a good idea to have a detailed conversation with your oncologist and significant support network.

Duration of ADT needed with salvage radiation

No one wants androgen deprivation therapy (ADT) along with ("adjuvant to") salvage radiation therapy (SRT). We are accumulating evidence about how long one needs to stay on it to prevent the cancer from coming back, but judgment is still necessary.

There are some situations where it is unclear that SRT is needed at all (discussed in this link). This includes: a very long time (>18 months) before biochemical recurrence (BCR), slow doubling time, low Gleason score, elderly, significant comorbidities, no metastases with PSMA PET, and low Decipher score.

6 months ADT somewhat better than none

GETUG-16 (article here) found that 6 months of ADT is better than no ADT. Incidence of metastases was improved by 27% among 743 patients. Whole pelvic radiation was at the doctor's discretion.

SPPORT (RTOG 0534) found that 4-6 months was beneficial for everyone and that there was no difference between 4 and 6 months.  It was a very large trial (n=1,762) and used 8-year Freedom from Progression (mostly PSA) as its primary endpoint. A third of patients received whole pelvic radiation.

RADICALS-HD found that 6 months was no more beneficial than none! This was a large trial (n=1,500) that ran for 15 years. It used Metastasis Free Survival (MFS) as its primary endpoint. There was an 11% improvement in incidence of metastases which was not statistically significant. Only 15% received whole pelvic radiation.

DADSPORT meta-analysis sought to resolve the conflicting findings by combining the results of all 3 trials. It found an 18% improvement in incidence of metastases.

The endpoint and the follow-up are important. For men who are aged 60-70 at the time of prostatectomy, none of the trials had long enough follow-up to detect a difference in overall survival. MFS improvement may be small in the short-run, but metastases may appear later and adversely affect quality of life. Those who want to be definitively cured (i.e., no evidence of disease as evinced by PSA) should have at least short-term ADT.

24 months of ADT slightly better than 6 months

RTOG 9601 showed that 24 months of adjuvant ADT did not improve survival when postprostatectomy PSA was below 0.7 ng/ml. A recent analysis by Spratt et al. suggested that adjuvant ADT is always necessary when PSA ≥ 1.5 ng/ml, but that risks may outweigh benefits when PSA is lower than 0.6 ng/ml. There were 760 patients with 13 years of follow-up. The primary endpoint was overall survival.

RADICALS-HD showed that 24 months of ADT improved survival over none or 6 months. 10-year MFS improved from 72% to 78%, while incidence of metastases declined by 23%. In the subgroup that had a PSA>0.5, incidence of metastases declined by 33%.

So 24 months of ADT is better than 6 months or none if one's goal is to avoid metastases.

8 months (36 weeks) of ADT with enzalutamide

The EMBARK trial found that by intensifying ADT with enzalutamide (Xtandi) compared to ADT alone, the MFS improved by 58%, and PSA-free survival improved by 97% with 61 months of follow-up. 

12 months of ADT with apalutamide

The PRESTO trial found that by intensifying ADT with apalutamide (Erleada) compared to ADT alone, biochemical (PSA) recurrence-free survival (bRFS) improved by 48% with 21 months of follow-up.

6 months of ADT with apalutamide and abiraterone

The Formula 509 trial found that by intensifying ADT with both apalutamide (Erleada) and abiraterone (Zytiga) compared to bicalutamide 50 mg/day, MFS improved by 43%, and PSA-free survival improved by 29% with 34 months of follow-up. Among post-op patients with PSA>0.5, MFS improved by 68%.

Positive lymph nodes

When cancerous lymph nodes are detected via pelvic lymph node dissection (PLND) at the time of prostatectomy, there is little doubt that 2-3 years of ADT are needed along with whole pelvic SRT (see this link). A PSMA PET scan may also identify cancerous pelvic nodes. One of the STAMPEDE trials lends credence to this strategy. They found that in men who were newly diagnosed with positive lymph nodes on a CT scan, 3 years of ADT with 2 years of abiraterone, decreased incidence of distant metastases by 47%. While this wasn't post-prostatectomy, it is hard to see why that fact would make a difference.

An NRG Oncology clinical trial is randomizing node-positive recurrent patients who will be getting SRT to 2 years of ADT with or without apalutamide.

AI and Genomics

Artificial intelligence (AI) is proving useful in determining the optimal duration of ADT. AI depends on feeding a lot of data about patients and their outcomes, so it will improve as a tool over the years.

Decipher scores based on the genomics of prostatectomy tissue can help discriminate between those that need more hormone therapy and those that need none.

Similarity to Adjuvant ADT with Primary Radiation

There is no reason why the decision about duration of adjuvant ADT post-prostatectomy should be different from the duration with primary external beam therapy. In general, the higher the risk, the longer the optimal duration. There are no precise cut-offs, so judgment and discussion with your radiation oncology is necessary.

Is there any benefit to early spinal radiation of metastases?

Is there any benefit to early treatment of asymptomatic men with many bone metastases? We saw that, at least in a retrospective study, there was no oncological benefit to treatment of oligo (1-5) bone metastases. But even if there is no benefit in delaying cancer progression, perhaps spinal radiation can prevent pain and crippling spinal compression?

Dearnaly et al. reported the results of a large multicenter randomized trial in the UK among 420 men with castration-resistant prostate cancer with asymptomatic spinal metastases on a bone scan. The goal was to determine whether early detection with MRI and treatment (SBRT radiation) could prevent clinical spinal cord compression (cSCC).

• The MRI detected early signs of spinal cord compression in 31% (61 patients), and they were treated with SBRT radiation using 20 Gy in 5 treatments.

The 1-yr and 2-yr results for all 210 men given MRIs (the "intervention group"), whether SCC was detected radiographically or not:

• At 12 months after randomization, the incidence of cSCC was 4.3% for the intervention group and 6.7% for the control group (no statistically significant difference)
• At 24 months after randomization, the incidence of cSCC was 9.2% for the intervention group and 12.6% for the control group (no statistically significant difference)
• Pain scores and severity of SCC were similar in both groups.
• Chemotherapy was more often used in the control group.
• Prostate cancer-specific mortality was similar in both groups.
• Overall survival was the same (22 months) in both groups. Note: this was a very progressed population of patients

The 1-yr and 2-yr results for only those 61 men who showed early signs of MRI detected (MRI+) SCC vs the remaining 139 patients who were MRI-:

• At 12 months after randomization, the incidence of cSCC was 11.5% for the MRI+ group and 1.3% for the MRI- group (note: statistically significant difference even after treatment)
• At 24 months after randomization, the incidence of cSCC was 13.2% for the MRI+ group and 7.6% for the MRI- group (note: statistically significant difference even after treatment)
• MRI+ patients had more clinical SCC, regardless of early detection and therapy.

So, there was no benefit to early detection and treatment. Perhaps there is a sub-group that could benefit?

Gillespie et al. reported the results of a small multicenter randomized trial among 78 men and women (22% had prostate cancer) who had more than 5 metastatic lesions identified on a bone scan, where none were yet painful ("asymptomatic"), but at least one of the bone metastases was "high risk." High risk was defined as any of:

• 2 cm or more in diameter
• at a junction in the spine between the cervix, thorax, lumbar, and sacral vertebrae
• in the hip or sacroiliac joint
• in a long bone (arms or legs) (note: this is rare for prostate cancer)

Patients were randomly treated with non-ablative radiation. After at least 1 year of follow-up, they observed the rate of skeletal-related events (SREs) and mortality. SREs could be pain, spinal compression, or fractures:

• SREs occurred in 1.4% of those receiving radiation vs 29% of those receiving standard care
• After 3 months, but not afterward, there was less pain reported by those who received radiation.
• There were no quality of life differences at any point in time.

After a median of 2.4 years of follow-up:

• Survival was 1.5 years for those with no SRE vs 1.1 year for those with an SRE

The discrepancy with the larger Dearnaly trial may be due to the identification of high-risk spinal mets; or the lower incidence of prostate cancer, the small sample size, and limited follow-up.

Dosimetry

A single ablative dose for painful non-spinal metastases has been found to be superior in this study. Fewer higher doses (24 Gy in 2 treatments) were more effective than 20 Gy in 5 treatments for relieving pain from spinal metastases in this study.  Sahgal et al. in a Canadian/Australian multi-institutional trial, found there was a better pain response with SBRT (24 Gy in 2 fractions) compared to IMRT (20 Gy in 5 fractions). After 3 months, significant pain improvement was 35% for SBRT vs 14% for IMRT. 

There is similar data from Heidelberg. Sprave et al.  reported better pain response at 6 months (but not at 3 months) with SBRT (24 Gy in 1 fraction) vs 3DCRT (30 Gy in 10 fractions). 

Conflictingly, Ryu et al. reported the results of the NRG Oncology/RTOG 0631 randomized clinical trial. They tried to obtain proof that SBRT (16-18 Gy in one dose) was superior to IMRT in one dose (8 Gy) in terms of pain response. After 3 months, 61% of those treated with IMRT had a significant pain improvement vs 41% of those treated with SBRT. After 1 year, there was no difference in pain scores. After 2 years, there was no difference in spinal fractures or compression. 

Spinal dosimetry depends on extent and soft-tissue involvement, and may require a neurological consult.

Docetaxel Extends Enzalutamide Effectiveness

 Enzalutamide (Xtandi) is one of the two second-generation hormonal medications that has been proven to extend survival in men with metastatic castration-resistant prostate cancer (mCRPC). The other is abiraterone (Zytiga). A pilot study suggested that docetaxel can sometimes reverse enzalutamide resistance.

The PRESIDE randomized clinical trial (RCT) treated 687 mCRPC patients in 123 sites throughout Europe. All of them were given enzalutamide along with ADT. 271 started to fail (PSA increase or tumor increase on scans) after 13 weeks. Then they were randomized to receive either:

1. Triplet therapy: Enzalutamide and docetaxel and ADT concurrently, or
2. Docetaxel and ADT and placebo

The triplet therapy extended progression-free survival over docetaxel+ADT, indicating that enzalutamide remained effective. The increase was small, but statistically significant.

Treatment-related adverse events were similar in the two groups, which were mostly attributable to docetaxel.

The triplet group had more serious events - 49% vs 39%

This confirms the earlier Phase II CHEIRON RCT. CHEIRON proved that the combination could delay progression, but it did not improve overall survival.

In a similar RCT, called "ABIDO," a triplet with abiraterone and docetaxel was tried. In early results, toxicity, particularly neutropenia, was significantly worse for the triplet. There was no benefit to this triplet.

This is our first proof that resistance to enzalutamide can be reduced with docetaxel. It also shows that triplet therapy may be beneficial in patients who have already progressed to castration resistance. We would expect a larger effect if used at the first sign of castration resistance.

(Update 8/23) An RCT randomized 81 mCRPC patients to either abiraterone (abi) or abiraterone+cabazitaxel. The combination had superior results:

• Radiographic progression-free survival was 14.8 months for the combination vs 6.4 months for abi alone.
• Overall survival was 24.5 months for the combination vs 18.3 months for abi alone.
• PSA declined more than 50% in 92%  of men using the combination vs 56% using abi alone.

Other combinations with abiraterone that have proved to be useful for patients with mCRPC include apalutamide+abiraterone (ACIS RCT), ipatisertib+abiraterone (IPATential150 RCT), and olaparib+abiraterone (PROpel RCT)-- Results for a PARP inhibitor+abiraterone were not as universally favorable in the MAGNITUDE RCT. Triplet therapy is already standard-of-care in newly diagnosed mHSPC (see this link).

Short-term androgen annihilation in non-metastatic recurrent men after SRT delays progression

 A difficult question for patients who still having rising PSA after prostatectomy and salvage radiation is: Is there any advantage to starting advanced hormone therapy before metastases are visible?

Rahul Aggarwal presented the early results of the PRESTO trial. Patients (n=504) were chosen who had the following characteristics:

• Failed prostatectomy and salvage radiation (85%). Half of those who had salvage radiation, had adjuvant ADT at the time
• PSA>0.5 ng/ml
• PSA doubling time (PSADT) ≤ 9 month
• no metastases on conventional imaging (bone scan/CT/MRI)

Patients were randomly assigned to one year of any of the following treatments:

1. ADT only
2. ADT+apalutamide
3. ADT+abiraterone+apalutamide

With follow-up of 21 months, biochemical progression-free survival (bPFS, PSA stayed under 0.2 ng/ml) was:

• 20 mos. in Group A
• 25 mos. in Group B (48% improvement vs Group A)
• 26 mos. in Group C  (52% improvement vs Group A)
• No significant differences attributable to PSADT
• Group C wasn't significantly different from Group B (Zytiga added little)

Other findings:

• Testosterone recovered in 4-5 months in all groups
• More hypertension with abiraterone

Other trials have looked at adding a limited term of 2nd line hormonal medicines when there is rapid PSADT but before metastases have been discovered on conventional imaging.

• Spetsieris et al. added abiraterone for 8 months. Afterwards, bPFS was 27 mos vs 20 mos. for ADT-only.
• Madan et al. reported substantial PSA control with intermittent use (two 3-month cycles) of enzalutamide alone without ADT. PSA didn't rise for 6-7 months after the first and second cycles.
• Neal Shore reported a similar benefit to apalutamide in the EMBARK trial.

With detection of metastases with PSMA PET scans, the advantage of early intervention will become clearer. There is also a clearer advantage for men with a higher Decipher score.  Recurrent men with rapid PSADT after salvage radiation should consider a short-term intervention with one of the advanced hormonals.

The Constitution of Medical Knowledge

Patients are often confused by seemingly conflicting findings of studies, or equally good doctors recommending different treatment plans. How are we to decide? Medical science is a process created by a “reality-based community” to help decide such questions. Science isn’t just hypothesis-testing with empirical observation, although that is a big part of it. It is also the consensus of a community of experts. In 1660, scientists led by Isaac Newton formed The Royal Society as the first institution designed to collect, encourage, and evaluate scientific knowledge. They published the first scientific journal in 1665 (which is still in publication). Were they ever wrong? Often! For example, for 250 years everyone wrongly believed Newton’s theory that gravity was a fundamental force of nature. And that is the point – knowledge is fallible and not subject to the personal authority of any one person. But over time, the arc of the universe of scientific knowledge bends towards truth.

There have been many improvements to the system of medical science since the Scientific Revolution. The first peer-reviewed journal was published in 1731. But peer-review as we now know it didn’t begin until the 1970s. The first randomized clinical trial occurred in 1747 (citrus for scurvy), but the rules for running double-blinded randomized clinical trials, and progressive Phase 1-3 trials weren’t systematized until Austin Bradford Hill and Harry Gold in the post-WWII era. Statistics entered medicine in the 1970s. Systematic reviews began in the late 1970s. Evidence-based medicine, as we know it today, was taught in medical schools since the 1980s.

Jonathan Rauch in “The Constitution of Knowledge: A Defense of Truth” describes knowledge as a funnel. At the top are all the guesses, the hypotheses, that drive scientific investigation. This would include (in order of increasing reliability):

5. Much of what is posted on any patient health forum every day: anecdotal “evidence” from patients; YouTube videos posted by Snuffy Myers, Mark Scholz, etc.; lab studies (mouse or test-tube); 

4. observational/epidemiological studies of patients; 

3. retrospective case-controlled studies, and systematic reviews/meta-analyses of them; cohort studies with retrospectively specified variables.

2. cohort studies (people followed from before disease occurrence) with prospectively specified variables; e.g., Mendelian Randomization Study). 

All of them are just hypothesis-generating. Most hypotheses are, and should be, wrong. Science depends on evaluating lots of hypotheses. There is no shame in guessing wrong; the only problems are when guessing stops and when one confuses a guess for a fact.

1. Large, well-done, and confirmed randomized clinical trials are at the bottom of the funnel; they are not just hypothesis-generating, they constitute truth in medical science. These categories were universally agreed upon after looking at which kinds of studies are likely to have conflicting results, and which almost never have conflicting results. All scientists believe in these categories; “pseudoscience” occurs when people claim to be doing science but ignore these categories. 

Here’s a fuller description:

Levels of Evidence 

 GRADE 

Pseudoscience

Some institutions regularly GRADE prostate cancer research (NCCN, AUA, ASTRO, ASCO, SUO, EAU, CUA, PCF, and others). The institutional opinions (and not anyone’s personal opinion) are the standard-of-care. Until disproved, they constitute current medical truth. While even the best research doesn’t predict for the individual, one is foolish to ignore our best estimate.

There is no science without consensus by experts - science is a social construct. One can argue that there are and always have been objective truths, but we can only know what is in some way perceivable by humans. Did the Earth always revolve around the sun? Of course. But it did not enter the realm of science until Copernicus hypothesized it (1543), and Galileo (1609), Tycho Brahe (1573), Johannes Kepler (1609), and Isaac Newton (1687) proved it and showed how. That’s when astronomy became a science. There is no science without hypothesis-testing and empirical observers. 

 Loss of Respect for Expertise 

How do we know what is true? None of us has the time or the inclination to test everything for ourselves. We rely on trusted experts to tell us. Few doubt that the heart pumps blood to our lungs and other tissues, although few have seen our hearts do that. We know that William Harvey discovered that fact in 1628, and it is now universally accepted as true and foundational to all cardiology. Even fewer know how the cardiac tissues cause the heart to beat, how arrhythmias are diagnosed, or how plaques can cause heart attacks. We rely on cardiologists to know all that, and within cardiology are sub-specialties (e.g., heart transplant specialists, sports cardiology, electrophysiology, etc.). There are dozens of medical specialties, each with several sub-specialties. There are even specialists in cutting across categories, and assuring that the latest innovations become available to patients; this is called “translational medicine.” In this era of specialization, few know much outside of their specialty, and as patients, we must, at some point, rely on the experts for our knowledge about disease, diagnosis, and treatment. 

Medical science became probabilistic in the 20th Century. All medical institutions agreed that statistics are the only way to reject hypotheses, judge superiority or inferiority, infer causality, and to analyze and reduce errors. Statistics are difficult to understand and are non-intuitive, even for many doctors. As sophisticated statistical techniques were adopted by the medical institutions and their publications, lay people, who did not have their arcane knowledge, were increasingly left out of the truth community. 

The Dunning-Kruger Effect is a cognitive bias on the part of incompetent people overestimating how much they know. In medicine, a little knowledge is a dangerous thing. When I started writing my novel, Thaw’s Hammer, about a killer virus, I thought I knew enough about the subject to write a credible novel. Four years later, I knew how much I didn’t know. I grew to admire the experts who had to understand the biochemistry of the replicative apparatus, the interactions with host cells, and the immune system. Viruses are the most numerous and diverse forms of life on Earth. Anyone who thinks they fully understand them is wrong. The experts differ from lay people in knowing they don’t completely understand them. Still, an expert understands a lot more than any lay person who thinks he knows more. I know enough to reject any advice from a Jenny McCarthy or a Joe Rogan in favor of advice from the CDC. 

Overconfidence in subjective assessments, when contrary to scientific consensus, is also influenced by alignment with political and religious social groups. The Dunning-Kruger Effect is particularly strong on the issues of vaccination (particularly Covid-19 vaccination), genetically modified foods, and homeopathic medicines (see this link).

Fundamentalism in Medicine

Knowledge is progressive and cumulative. Newton said, “If I have seen farther, it is because I have stood on the shoulders of giants.” Opposing this kind of humility, are people who think, based on a few facts or “alternate facts,” that they have arrived at the truth hidden from the rest of us. What they are really doing is inhabiting what Rauch calls an “epistemic (knowledge) bubble.” They are only allowing into their knowledge bubble those data, and persons, that confirm their biases. They take studies out of context and fail to rigorously analyze studies they agree with while finding reasons to disqualify studies that don’t agree with their preconceived notions. They reject the methods of analysis developed by the institutions they reject. They are usually smart and think that they are fully capable of judging the data for themselves. This takes a certain kind of narcissism – as if the whole world is full of “sheeple” and only they know the real truth. They are also lazy – it would be too much work to learn and evaluate the whole body of knowledge. 

Fundamentalism has been around in religion at least since the Protestant Reformation. But it emerges in all other areas of human knowledge – politics (as populism), law (as originalism/ anti-stare decisis), and folk/Internet medicine. It is usually short-lived: the fundamentalists of one generation eventually give way to the acceptance of an orthodoxy and hermeneutics for interpretation of texts. Fundamentalism substitutes personal authority for institutional authority. Personal knowledge is acquired rapidly and doesn’t require input from others. Because personal ego is at stake, it excludes all information that doesn’t confirm. Institutional knowledge, on the other hand, builds on a foundation of knowledge of the “truth community,” and includes conflicting data. The conflicting data create new hypotheses and the opportunity for knowledge to expand. If enough conflicting data accumulate, they may cause what Thomas Kuhn called a “paradigm shift.” 

Google is a wonderful thing. Knowledge is potentially at our fingertips, but information out of context can mislead. Instead of knowledge, we can be left with information that only confirms what we think we know. Social media ideally expose us to all sides of any issue. But if we are not open to all sides, social media can only reinforce the knowledge bubble we have built around our pre-determined beliefs. Without challenges to what we think we know, there is no progress. 

Distrust of Institutions 

There has been growing distrust of institutions among lay people, sometimes with good reasons. There were abuses like “p-hacking” that fostered distrust. Until recently, publications did not require authors to be transparent about potential conflicts of interest. Often, negative findings were not published (the US government now requires all registered clinical trials to publish their findings). Budget cutbacks at the NIH decreased funding for medicines and technologies that did not have profit potential. Mistakes and abuses were publicized in the media and over the Internet. Institutions are valuable not because they don’t make mistakes, but because they correct mistakes and abuses. Retractions and corrections are published. Researchers who lie are found out and excluded from future publication. 

The other threat to truth came from an unlikely source – conspiracy theorists. Before the Internet, they were just isolated “nut jobs.” But social media provided the means for them to find others with enough common beliefs to form a “non-truth” community. On the patient forum, HealthUnlocked, I’ve seen several who point to a supposed Big Pharma/FDA conspiracy. Although they are still a minority, they can have outsize influence by dominating conversations, mixing truth and lies, purveying lies so outrageous that some believe there must be some truth to them, and by blinding the conversation with so much bullshit that reasonable people despair of ever discerning the truth. On Facebook, Twitter and YouTube, bad actors can stage a concerted campaign to “like” and “share” content they want to use as propaganda. They can “troll” serious posts to render the conversation harder to follow. 

Because institutional knowledge was not readily comprehensible to laymen, and because distrust mounted as abuses were well-publicized, the Internet (Dr. Google) became a substitute for expertise. Laymen believed they understood the subjects as well as experts and their institutions, and they were able to find others on social media willing to tell them so. When biases are confirmed by media personalities they become particularly pernicious. We always believe relatable people we know and like (from TV, videos, and podcasts) versus strangers who author incomprehensible studies full of numbers and jargon we don’t understand. This cognitive error is called “the availability heuristic” – it’s why you may believe the claims of someone you know on an Internet forum over high-level statistical evidence. The danger of substituting personal knowledge for institutional knowledge in medicine became apparent with the anti-vaxxer movement. It had always been a fringe group, but in the US, a third of the population did not get vaccinated against Covid-19.

What can be done?

What can be done to restore faith in institutional truth? Rauch sees hope in the measures Facebook took after it came to light that bad actors from Russia manipulated Facebook’s algorithms to change what was seen by Facebook members. Facebook changed its algorithms and created software to eliminate bots. They also labeled and demoted content of dubious veracity. They established an independent oversight board with transparent rules. It reports to and is financed by independent trustees, who can remove its members if they act in bad faith. The board’s decisions are binding on Facebook and anyone who uses Facebook. Its decisions are published. It acts much like an independent court. The problem for a patient health forum like HealthUnlocked is that unless the oversight body is a panel of doctors, they cannot privilege the content of one post over another without risking lawsuits.

The most any patient forum can do is establish rules for civil discourse. I would suggest the following rules and guidelines for anyone posting in a patient forum:

(1) No ad hominem remarks. Ad hominems are remarks that insult the person. “You’re wrong about that and here’s why…” is entirely appropriate. “Jane, you ignorant slut!” is entirely inappropriate. Responses must speak to content, not the supposed intentions of the poster. If you don’t have anything good to say about a person, say nothing. This should eliminate trolling. Trolls thrive on attention and virtue-signaling, so don’t feed the trolls by responding in kind. Alert a moderator immediately. If you feel you have to make personal remarks, do it in private mail.

(2) Members cannot post dangerous or illegal content (e.g., a recipe for a known toxic substance or instructions on how to obtain it). They may post unproven or experimental therapies, and especially their own experience with them. Members are encouraged to identify experimental therapies as experimental. Hypotheses are entirely appropriate and encouraged.

(3) Avoid strawman arguments. Strawman arguments are ones that replace what the poster is actually saying with a false one which is then refuted. If you are starting a reply with the words “"So what you're saying is ... ?" or “Then you must also believe that…” you are probably setting up a strawman. The opposite is a steelman argument, where you restate what the poster said in the strongest form. It shows you are listening and want to resolve the issue.

(4) Avoid sarcasm. Sarcasm doesn’t work on the Internet. It usually only works if one can see your facial expressions and hear it in your voice. There are no sarcasm emojis, and the original poster will probably believe you meant it seriously. Making fun of a person is just a form of ad hominem. Humor is fine, but not as a rhetorical technique.

(5) Be aware that consensus is rare. Patients may get a lot of conflicting advice or anecdotes, and that’s okay. Discuss with a doctor you trust.

(6) Don’t take it personally if someone disagrees with you. Consider the issue as dispassionately as you can. It’s not necessary to reach agreement, just to flesh out the issue from all sides.

(7) Caveat emptor! No one on a patient forum is a doctor, and no one’s advice or personal experience should be taken as definitive. Anecdotes are not evidence. Check everything with your doctor. It is entirely appropriate to ask for source material for advice that goes beyond the standard-of-care, and to discuss those sources with your doctor. But remember that doctors may have little patience for sources that do not come from peer-reviewed journals or are low-level or low-quality evidence (see above).