Thursday, May 16, 2024

Internet Myths about Red Meat

 "an odour assailed his nostrils, unlike any scent which he had before experienced." from "A Dissertation Upon Roast Pig" by Charles Lamb

Charles Lamb wrote that humorous fiction about the first time roast meat was accidentally tried. While the above quote describes the first accidentally roast pig, it could easily describe a grilled rib-eye steak. Grilled, bloody steaks are one of the great pleasures in life for many of us. 

There is enough evidence that saturated fat, and especially trans fats, are not heart-healthy. Cardiovascular disease is about 20 times the killer of elderly men compared to prostate cancer. Most of us take statins and exercise (I hope), so the occasional rib-eye won't clog our veins, as long as we eat it only occasionally. Of course, ask your cardiologist if you've already had evidence of obstruction.

There are many reasons to change diet, including cardiovascular health, and diabetes. Many men with prostate cancer use some form of androgen deprivation therapy (ADT) and are in danger of getting metabolic syndrome, especially if they are already overweight and sedentary. Men using ADT should monitor caloric intake and increase exercise, with their doctor's permission. Many patients like to change diets because it gives them a feeling of control in a situation where they have lost control of their own bodies. Others torture themselves (or are tortured by well-meaning loved ones) by depriving themselves (one more deprivation!) of their favorite foods. Eating and sharing meals with others is one of the pleasures of our lives, and is part of our social cohesion. But what is the evidence that diet plays a role in lengthening survival due to prostate cancer itself?

There are dietary fads. Current fads include plant-based/vegetarian/vegan diets, Mediterranean diet, ketogenic/low carb diet, alternate-day fasting, macrobiotic diets, microbiome diets, and so-called "cancer diets" that cut out sugars, animal fats, red meat, chicken, eggs, and dairy products, or that add foods with certain phytonutrients. It is extremely difficult to prove that diet has a causal effect in cancer progression. 

Associations between red meat intake and breast or colorectal cancers have been noted. Patients are highly motivated to seek out dietary changes they can do to regain control of their bodies.  Most patients search the Internet for clues but don't know enough about research methodology to distinguish gold from garbage. Many prostate cancer patients (and doctors, who should know better) have succumbed to the "conventional wisdom" that grilled red meat is bad for their cancer too. Is there any truth to that conventional wisdom? Here's the evidence.  

Only "Level 1" can prove that red meat consumption contributes to prostate cancer. (Follow these links to understand Levels of Evidence and GRADE). Higher levels of evidence, that are also high GRADE, replace lower levels of evidence. There is no Level 1 evidence (well-done randomized clinical trial), but there is some Level 2 evidence. A cohort study is Level 2 evidence only if it is prospective; i.e., the hypothesis to be investigated is formulated from the start. Longitudinal retrospective cohort studies are Level 3 evidence. See below for reasons why such studies almost always provide conflicting results.

Level 2 Evidence

The NutriNet Santé Cohort Study is a huge (61,476 adults over 35) prospective web-based cohort study in France. France has the highest rate of internet use of any large country, and it cuts across age and socio-economic classes. Participants fill out food questionnaires (3 random records of 24-hour food intake during a two-week period). They also provide information on physical activity, BMI, height, sex, age, lifestyle, health status, family history of cancer, and socio-economic conditions. They also may provide blood and urine samples and get a physical exam. Red meat can be beef, pork, veal, or lamb. Processed meat can be cured meats, sausage, bacon, ham, salami, spam, etc.

With a follow-up of 4 years, and 222 prostate cancers in the cohort, Diallo et al. reported:

  • Red meat intake was not associated with prostate cancer risk
  • Processed meat intake was not associated with prostate cancer risk
  • There was no association for any Gleason score.

Also, Level 2 evidence is provided by the UK Biobank Mendelian Randomization Study. They found the genomic mutations associated with red and processed meat intake and found the correlations with incidence of prostate cancer in over 140,000 people.

  • Red meat intake was not associated with prostate cancer risk
  • Processed meat intake was not associated with prostate cancer risk

Allen et al. reported the results of The European Prospective Investigation into Cancer and Nutrition (EPIC). It was a very large cohort study with 142,251 men and 2,727 cases of prostate cancer (none at enrollment) and 8.7 years median follow-up. It randomly sampled the cohort to ask for 24-hour dietary intake. They found that:

  • Red meat and processed meat intake was not associated with prostate cancer risk
  • There was no association for advanced or localized PCa or by Gleason score
Level 3 Evidence

Cross et al. prospectively reported on red meat associations with prostate cancer in the PLCO screening trial. They found no association with any meat products, but a small positive association with very well-done meat.

Contradictory findings were reported in several observational cohort studies.

The MEAL Randomized Clinical Trial (RCT) - Level 1 Evidence

The MEAL RCT is the only Level 1 evidence we have on dietary causes of prostate cancer.

Parsons et al. randomized 478 low-risk men who were using active surveillance at 91 cancer centers to one of two groups:

  • The intervention group received telephone prompts to eat 7 or more servings of vegetables per day, including 2 servings of each of cruciferous vegetables and tomato products.
  • The control group only received written information

They all kept detailed food diaries, and plasma carotenoid assessment was used to prove compliance. After 2 years, the intervention group increased their consumption of vegetables and reduced consumption of red meat and animal fats. However, there was no difference in time to progression.

This trial proves that increasing vegetable intake has no effect on even the "lightest" prostate cancer. It also shows there is no "dose response" due to meat consumption. A "dose response" means that the more one uses some intervention, the greater the effect will be. We see this frequently with drugs - the higher the dose, the greater the response, up to a certain point; and the lower the dose, above some minimum, the lower the response. Some argue that meat-eating has no dose response but is binary -- eliminating all non-vegetable protein sources can make a difference. 

A typical dose-response curve:

Other Vegetarian Trials

It is worth mentioning Dean Ornish's  Prostate Cancer Lifestyle Trial (PCLT)  randomized 93 men on active surveillance to either:

  • A vegan diet with complex carbs and very low fat. They also exercised, took a variety of vitamins and food supplements, managed stress, and met in groups.
  • The other group just had usual care.

After 2 years of follow-up, fewer men in the treatment group had prostate cancer treatment. There was no difference in PSA. How much of the difference is due to exercise, may be speculated upon, and is the argument against unwarranted claims, such as this one. Early results of the ERASE trial suggest that exercise can make a difference. Cardiovascular parameters improved more in the intervention group.

A pilot trial among 36 recurrent men randomized them to either:

  • 11 weeks of mostly plant-based foods and oily fish, with no or less animal proteins. They also practiced mindfulness.
  • usual care

After 3 months, there was no difference in the rate of PSA change. 

There have been no other randomized studies in men with prostate cancer. There have been a couple of prospective trials without a control group to compare results.

Why Only Level 1 Evidence is Important to Patients

Level 2 or 3 studies are only hypothesis-generating for other researchers to conduct Level 1 trials. They should never be used by patients to make life-changing decisions. Observational studies suffer from "selection bias." This means that the patients who got the treatment (here, red meat) were in some ways different from the patients used as the control group (here, vegetarians). Researchers use statistical techniques like "propensity score matching" in the hope of correcting for this bias. But a new data analysis proves why they don't work. 

Wang et al. looked at 15 published studies on the topic of red meat and mortality, and at a huge dataset, The National Health and Nutrition Examination Survey 2007-2014 (NHANES), a longitudinal observational study (level 3 evidence) of over 10,000 persons. 

Their review of 15 published studies analyzed in 70 unique ways found:

  • Red meat intake was associated as originally analyzed with anywhere from a 37% reduced risk of death to a 131% increased risk of death.
  • They were able to re-analyze that data 10 quadrillion different ways (each way used a different set of variables like age, health status, etc.).

They randomly chose 1200 different ways that all seemed appropriate and applied them to the NHANES dataset.

  • Analysis of the 1200 methods for analyzing the data found:
  • There was no statistically significant association between red meat intake and death. With 95% confidence, it ranged from a 49% reduced risk of death to a 75% increased risk of death.
  • In total, 64% of analyses showed a reduced risk of death, while 36% showed an increased risk. Only 4% of analyses had statistically significant results. Of those, 83% showed reduced risk of death, and 17% showed increased risk of death.
  • Most analyses resulted in very little association (±10%)

Conclusion: with studies that are low-level evidence, the method chosen for the analysis changes the conclusion. Similar studies of analytic choice have similar results (see this link and this one).

Other Protein Sources

There is no Level 1 evidence for any protein source. Lower level evidence yields conflicting associations for every protein source. Below is just one example of each (note: negative associatiation means consuming more was beneficial, positive association means consuming more was deleterious).

Dairy: There are observational studies that have shown positive, negative, and no correlation with prostate cancer outcomes.

Chicken: Observational studies show no association, a positive association, or a negative association with prostate cancer progression.

Eggs: Observational studies show no association, or a positive association, with prostate cancer progression.

Fish: Observational studies show no association, a negative association, or a positive association with prostate cancer outcomes.

Vegan/Vegetarian: The complete protein source for vegans is high in carbohydrates (e.g., soy, beans and pasta). Observational studies with diets high in soy show no association, negative association, or a positive association. A small randomized trial designed to see if there was any effect of a diet low in carbs on PSADT. It was stopped early because of no effect.

Humans evolved to be omnivores. Our gut bacteria co-evolved and thrive on a varied diet. Plants are necessary for good gut motility.


There is no usable evidence that cutting back on red meat is beneficial. Given the lack of convincing evidence, it is a good idea to:

  • Vary one's protein sources (unless cardiologist dictates otherwise)
  • Don't deprive yourself! You have cancer -- treat yourself well, at least occasionally.
  • If you are on ADT, your metabolism is slower, so consume fewer calories and exercise more.
  • Eat plenty of vegetables, especially cruciferous and highly-colored vegetables.
  • Avoid vitamins, minerals and supplements unless you are deficient. Get your micronutrients from food. Your body will take what it needs and discard the rest. Don't try to outsmart your body -- you will lose. It has millions of years of evolution on its side.

Saturday, April 13, 2024

Pluvicto+Xtandi Delays Progression Better than Xtandi-alone in mCRPC

Both Pluvicto (177LuPSMA-617) and Xtandi (enzalutamide) have been separately shown to delay progression and extend survival among metastatic and castration-resistant men with prostate cancer (mCRPC). Because they inhibit prostate cancer in different ways, it was hoped that combining them would have an additive benefit. In a clinical trial, enzalutamide temporarily increased expression of PSMA, so a synergistic effect is possible.

Emmett et al. reported the first results of the ENZA-p trial. 162 mCRPC patients with 2 or more risk factors were treated at 15 hospitals in Australia. Unlike the VISION trial, they did not previously receive docetaxel or 2nd line hormonal treatment for mCRPC. The risk factors were:

  1. metastatic at original diagnosis
  2. elevated LDH, ALP, albumin (PSA> 5 ng/ml)
  3. PSADT< 84 days
  4. < 3 years since diagnosis
  5. ≥5 bone or visceral metastases 
  6. pain requiring opiates
  7. received abiraterone for mHSPC (docetaxel for mHSPC was allowed)

After 20 months of follow-up, the outcomes were:

  • Median PSA Progression-Free Survival was 13.0 months for the combo vs 7.8 months for enza-only
  • Median Radiographic Progression-Free Survival was 16 months for the combo vs 12 months for enza-only
  • Percent with >50% PSA reduction was 93% for the combo vs 68% for enza-only
  • Percent with >90% PSA reduction was 78% for the combo vs 37% for enza-only
  • Too early for overall survival
  • Improvement in pain scores were 61% for the combo vs 27% for enza-only
  • Side effects for the combo vs enza-only were fatigue (75% vs 70%), nausea (47% vs 27%), and dry mouth (40% vs 10%).
  • 81% received all 4 doses of Pluvicto.

Based on these results, and pending later follow-up on overall survival, Pluvicto should be combined with enza.

Friday, March 15, 2024

The importance of Peer-Review

When I was new to prostate cancer research in 2011, I attended my first PCRI Conference. One of the presenters was Eugene Kwon. He presented some early data on an experimental new tyrosine kinase inhibitor called cabozantinib. Tyrosine kinase is an enzyme that stimulates metastatic growth. Kwon showed the following "gee whiz" images that had the whole room abuzz. It seems to show the complete resolution of numerous bone metastases on a bone scan in 3 patients in 6 or 12 weeks:

Kwon presented "Cabo" as a game-changer in PCa treatment to an auditorium full of patients and on YouTube. Was it too good to be true?

Several Phase 3 trials found that Cabo only disguised bone metastases so that they no longer showed up on a bone scan. Smith et al. (in the COMET-1 trial) showed that Cabo did not improve PSA or survival, and it had unacceptable toxicity. Basch et al. (in the COMET-2 trial) found that pain palliation was no better than mitoxantrone (an early kind of chemo.)

In spite of these negative findings, research went ahead into using Cabo with a variety of combinations. Neeraj Agarwal presented the results of the combination of Cabo+atelolizumab in the CONTACT 2 trial at an ASCO presentation. In theory, cabo makes bone metastases more permeable to immunotherapies like atelolizumab (A). And in an early Phase 1 trial it seemed to help progressed patients. 507 patients with soft-tissue mets were randomized to receive either Cabo+A or the control drug Xtandi/Zytiga (whichever one they hadn't had already). After 12 months, the results were as follows:

  • Radiographic progression-free survival (rPFS) was 6.3 months for Cabo+A vs 4.2 months for the control (statistically significant)
    • rPFS among men with liver metastases was 6.0 months for Cabo+A vs 2.0 months for the control (statistically significant)
    • rPFS among men who had had docetaxel while hormone sensitive was 8.8 months for Cabo+A vs 4.1 months for the control (statistically significant)
    • rPFS among men who had bone metastases  was 6.3 months for Cabo+A vs 4.1 months for the control (statistically significant)
  • Objective Response Rate was 13.6% for Cabo+A vs 4.2% for the control (statistically significant)
  • Overall survival was 16.7 months for Cabo+A vs 14.6 months for the control (not statistically significant, but data immature)
  • Treatment-related adverse events (serious or life-threatening) were 33% for Cabo+A vs 8% for the control.

Agarwal concluded that Cabo+A showed a clinically meaningful improvement in PFS vs second advanced hormonal therapy. This supports Cabo+A as a potential new treatment option for mCRPC patients who have progressed on one second-line hormonal therapy.


Kim Chi provided the peer review. He pointed out that:

  • The differences in PFS are modest and not clinically meaningful.
  • There was no difference in time to pain progression and the same deterioration in QOL.
  • As in the trials of Cabo alone, there is so far no difference in survival. In the COMET 1 trial (above) there was never any difference in survival. Cabo masked the deterioration, such that it only appeared that there was an improvement in rPFS.
  • The difference in rPFS is the same as with Cabo alone (about 6 months). The immunotherapy didn't seem to improve outcomes.
  • The control group (switch to the untried second-line hormonal) is not what most patients would try next. They would try docetaxel (rPFS= 8-9 months), cabazitaxel (rPFS= 8 months), or Pluvicto (rPFS= 8.7 months). All provide better rPFS than Cabo+A.
  • Due to toxicity, there were dose delays/holds/reductions in 40-60% of patients
  • Patients would experience less toxicity and greater benefit with taxane chemotherapy.
  • Low rate of subsequent therapy (25%), suggests that these patients lost an opportunity to get another life-prolonging therapy.

Patients are sometimes tempted to learn about therapies from YouTube videos and other social media. Patients should be alerted that without good peer-review they may be dangerously misled. 

Friday, January 26, 2024

Higher dose improves results in high-risk patients

GETUG-AFU-18 is another trial where the findings are obvious, and irrelevant, because radiation and hormone medication technology have improved far beyond what was available when this trial began 15 years ago, and long follow-ups are necessary to detect outcome differences in men with localized prostate cancer. A similar trial (RTOG 0126) in intermediate-risk patients found a curative benefit for the higher dose, although no increase in overall survival within 8 yearsd.

The trial randomized 505 high-risk patients in 25 French centers to receive a radiation dose of either 70 Gy or 80 Gy

  • All patients received 3 years of ADT. (If started today, it may have been 2 years of ADT (see this link) with external beam radiation.) 
  • All patients had no detectable cancer in pelvic lymph nodes (N0), but 83% received whole pelvic radiation.
  • High-dose patients received IMRT, but many (41%) lower dose patients received 3D-CRT (which is seldom used anymore).

After 10 years of follow-up, only 92 men progressed, which was less than expected. The results were:

  • 84% were progression-free in the 80 Gy arm, 72% in the 70 Gy arm. 
  • 44% reduction in the biochemical failure rate
  • 52% reduction in prostate cancer-specific mortality
  • 39% reduction in overal mortality rate
  • No difference in late-term urinary or rectal toxicity. Serious (grade 3) toxicity was rare (2-3%)
  • No difference in patient-reported quality of life

It comes as no surprise that higher dose radiation to the prostate is more curative. Since there is no toxicity cost to giving the higher dose, it is the clear standard of care.

Several randomized clinical trials (ASCENDE-RT and TROG RADAR) have now proven that increasing the prostate dose with brachytherapy improves outcomes. Clinical trials using SBRT for high-risk patients are underway, and moderate hypofractionation is already standard of care. The FLAME trial showed results can be improved by targeting MRI-detected intraprostatic lesions with a radiation boost. POP-RT showed the importance of whole-pelvic treatment. The whole-pelvic treatment area was expanded (see this link).

STAMPEDE showed that 3 years of abiraterone+ 2 years of ADT improved results over ADT alone. Hormone treatment has been intensified and shortened in the AASUR trial. The PREDICT-RT trial investigates Decipher genomic scores to determine intensity and duration of hormone treatment with apalutamide. DASL-HiCAP tests darolutamide. 

The FDA approval of PSMA PET/CT for high-risk patients improves patient selection. Those found to have distant metastases might be better treated with hormone therapy alone. Those found to have only pelvic lymph node metastases might still be curatively treated with radiation and hormone therapy.

Thursday, September 21, 2023

Pluvicto does not work better if used before docetaxel in mCRPC

We have seen (see this link) that Pluvicto works about the same as Jevtana in men who are metastatic and castration-resistant (mCRPC) and who have already used docetaxel and failed one advanced hormonal therapy (abiraterone or enzalutamide). But would there be any advantage in mCRPC men who have not yet had any chemo?

Satapathy et al. sought to answer this question. They randomized 40 men to either docetaxel or Pluvicto who were chemo-naive, and mCRPC.

After a follow-up of 33 months they found that both groups survived for 15 months, based on the therapy they were intended to get. When they looked at the therapy they actually got, there was still no statistically significant difference (19 months for Pluvicto vs 15 months for docetaxel).

This was a very small Phase II trial, so it is possible that there would have been a significant difference in a larger trial. However, while there are trials that randomize mCRPC patients to 177LuPSMA or 2nd line hormonal (see this link), I am not aware of any other trials exploring the sequencing of docetaxel or Pluvicto in chemo-naive mCRPC patients.

Saturday, May 6, 2023

Xtandi (enzalutamide) +ADT slows metastases in recurrent men

It is always difficult for a recurrent patient (rising PSA after prostatectomy, radiation, or both) with no metastases to decide when to start salvage hormone therapy and, if so, which hormone therapy. That is the question that the EMBARK randomized clinical trial (RCT) sought to answer. We have recently seen that the PRESTO trial proved that a one-year course of ADT+ apalutamide (Erleada) significantly delayed biochemical progression compared to ADT alone.

EMBARK Protocol

This was a huge trial with 1,068 patients treated at  256 centers around the world. To qualify, patients had to have:
  • Biochemical progression after attempted curative treatment with prostatectomy (RP), radiation (RT), or both (SRT).
  • PSA≥ 1 ng/ml if RP; ≥ 2 ng/ml above nadir if RT
  • PSA doubling time (PSADT) ≤ 9 months
  • No metastases on conventional imaging
Patients were randomized to one of three groups:
  1. enzalutamide + ADT with leuprolide (combination)
  2. ADT (leuprolide)-only (the control group)
  3. enzalutamide-only (enza monotherapy)
The control group received a placebo (blinded). The third group was not blinded. There were periodic PSA tests, but neither patients nor their physicians were privy to the PSA results.

One of the goals of the trial was to see which treatment strategy allowed for the longest hormone-therapy vacation (see this article about intermittent ADT- Setting 3). Patients in all 3 groups were given a hormone therapy vacation as long as their PSA became undetectable (< 0.2) by week 36. The vacation ended when PSA rose to ≥ 2.0 (if previous RP) or ≥ 5.0 (if no previous RP).

Oncological Results

After 5 years of follow-up, the early results were reported by Neal Shore at an ASCO meeting: 
  • Relative to the control group, the incidence of distant metastases was reduced by 58% by combination therapy, and by 47% by enza monotherapy.
  • Overall survival results are not yet mature, but so far mortality has been reduced by 41% by combination therapy, and by 23% by enza monotherapy
  • Time to PSA progression (castration resistance) was increased by 93% by combination therapy, and by 67% by enza monotherapy.
  • Time to chemotherapy was increased by 64% by combination therapy, and by 46% by enza monotherapy.

Vacation (iADT) Results
  • The percentage of patients that achieved undetectable PSA (< 0.2) by week 36 of therapy and were able to take a vacation was 91% for the combo, 68% for the control, and 86% for enza-monotherapy.
  • The vacation lasted for 20 months for the combo, 17 months for the control, and 11 months for enza-monotherapy
  • Testosterone only reached about half of baseline during the vacation in the combination and control groups. Testosterone rose to well above baseline in the enza-monotherapy group.

Toxicity Results
  • Serious or worse adverse events attributable to medications occurred more often in the groups given enzalutamide (18% of the combo and 16% of the enza monotherapy groups compared to 9% in the leuprolide-only group).
  • Fatigue was the most common side effect and occurred more often with enzalutamide (47% for the monotherapy, 43% for the combination) than with leuprolide alone (33%)
  • Hot flashes much less often occurred in the enza-monotherapy group (22%) than in the combination group (69%) or the leuprolide-only group (57%).
  • Gynecomastia/nipple pain was prevalent in the enza-monotherapy group (45%/15%)
  • All other side effects were experienced about equally.

  • If one is recurrent with PSADT≤ 9 months, treatment with a combination of Lupron and Xtandi improves oncological outcomes
  • If the trial were started now, everyone would get a PSMA PET/CT. It is likely that most would detect distant metastases.
  • Intermittent hormone therapy is likely to provide the longest vacation if one is getting the combination, but the quality of the (half as long) vacation may be better with enza-monotherapy because of greater testosterone recovery.
  • Enzalutamide increases many side effects, including fatigue.
  • Enza-monotherapy is less likely to cause hot flashes, but more likely to cause gynecomastia.

Thursday, April 27, 2023

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-S9346NCIC-CTG PR.7ICELAND, 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



18 months

3.1 yrs



36 months

5.0 yrs



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


3 months


6 months


9 months


12 months


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.