ADT, Apalutamide and Exercise in the Treatment of Prostate Cancer

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Hormone Deprivation therapy, also known as Androgen Deprivation Therapy (ADT) is a common long-term treatment for men with more serious prostate cancer or short-term therapy before undergoing radiation therapy. Either way, when a man’s testosterone levels go down to nearly zero, life is experienced differently.

My partner, David at XY Wellness recalls when he was on short-term ADT  before radiation nearly fifteen years ago;

“ ADT materially alters how you interpret and engage with the world around you. It taught me that there is far more than a mind-body connection by suggesting that they are one in the same.”

He continues;

“While undergoing ADT, it is not so much that the man is disinterested in sex but that it simply does not cross his mind.”

Recently, Apalutamide, trade name Erleada was approved for treating men with rising PSA (recurrence) after treatment for prostate cancer without metastasis. Currently, this is the first standard treatment for a scenario for a rapidly rising PSA without metastasis after a study was published in the New England Journal of Medicine.

Study Details

  • A total of 1207 patients underwent randomization: 806 were assigned to the Apalutamide group(240 mg per day) and 401 to the placebo group in the phase 3 SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) trial

NOTE: It is common for there to be funky names to large trials like this and other ADT studies, i.e, LATITUDE, CHAARTED, etc. It helps physicians (especially when lecturing) and lay people alike mention the studies with ease. Of course, SPARTAN has a warrior kind of implication… as in, are you ready to fight? Clever.

  • Follow up was for close to two years.

 

  • Study participants had confirmed prostate cancer that was castration-resistant and was at high risk for the development of metastasis, which was defined as a PSA doubling time of 10 months or less during continuous androgen-deprivation therapy.

 

  • Patients with evident bone metastasis were excluded from the study.

 

  • RESULTS: Time to metastasis, progression-free survival, and time to symptomatic progression were significantly longer (70% better) with Apalutamide than with placebo

 

  • Apalutamide was associated with higher rates of rash, fatigue, joint pain, weight loss, falls, and fracture than placebo.

(Study Link)

 

My Take on the Use of Apalutamide (Erleada is the trade name) non-metastatic Castrate Resistant Prostate Cancer

Apalutamide is an anti-androgen agent, meaning it lowers testosterone and Dihydrotestosterone (DHT) to almost zero, similar to other forms of Androgen Deprivation Therapy (ADT) except this new drug blocks the genetic formation of androgen receptors.

The study was paid for by Janssen Pharmaceutical, the developer of the drug. I say this because when studies funded by the company that makes the drug questioned, the results are often favorable to the company sponsoring the product. Thus, there seems to be some bias playing a role in such scenario.

That said, the design of the study was good, and it was published on one of the most respectable journals, New England Journal of Medicine (NEJM), so I will proceed with a small air of caution.

Seventy percent improvement from cancer worsening in two years compared to placebo is darn good. Of course, no drug that works well comes without downside (excuse the pun).

Men on Apalutamide showed higher rates of rash, fatigue, joint pain, weight loss, falls, and fracture than placebo.

Long-term treatment of ADT is associated with side effects, such as fatigue, reduced bone mineral density, increased fracture risk, decrease in skeletal muscle mass (muscle wasting), associated with the development of metabolic syndrome/insulin resistance, increase in adverse cardiovascular events effects and increases the risk of anemia, hot flashes, gastrointestinal tract disturbances, loss of libido, impotence, osteoporosis, gynecomastia, deep vein thrombosis, congestive heart failure, myocardial infarction, pulmonary edema, cognitive decline and psychological changes.

As I continue to monitor the well being of many prostate cancer patients on ADT, I can say with very little doubt that men can live long and strong while undergoing hormone therapy.

With one caveat…

You must follow a lifestyle and exercise regimen that supports your body.

Many of my patients on ADT are “crushing it” by practicing a prescribed exercise and nutritional regimen gathered from the science I’ve researched.

Not only is prostate cancer successfully managed when combining ADT with lifestyle, but the quality of life is also exceptional. I am not exaggerating.

Should I be on ADT? What would you do if you were me?

I’m often asked by patients, “What would you do if you were in me? Would you go on ADT?”

Such question reminds me of a line in one of the few books I read from cover to cover in high school (I wasn’t a big reader then), To Kill a Mockingbird by Harper Lee…

“You never really understand a person until you consider things from his point of view, until you climb inside of his skin and walk around in it.”

In other words, I am not you. And I have not been diagnosed with PSA recurrence after initial treatment for prostate cancer with curative intent.

That said, I do read many scientific papers on prostate cancer, have extensive clinical experience with patients battling this disease, and have opinions about prostate cancer treatments and quality of life.

Here’s what I’d say…

I am a sucker for a good quality of life. I’d choose the quality of life over longevity in most cases. Much would depend on the severity and length of time of adverse effects from ADT.

Thus, every case is different.

If God forbid, I am diagnosed with aggressive, stage 4 lung cancer; it is likely that I will choose no medical treatments as experience and data show not a significant survival rate and poor quality of life with the available treatments for such disease and numerous others alike.

But I digress. We are talking about prostate cancer.

Men on ADT in my clinical experience are doing exceptionally well, likely because they are following my nutritional and exercise advice – at least, that’s what I’d like to think. Getting on ADT for the right patient and based on the scientific data supporting its use in improving survival is a good option.

Exercise Prescription for men on Hormone Deprivation Therapy or Androgen Deprivation Therapy (ADT) to treat Prostate Cancer

The goal for men on ADT and applying lifestyle and exercise program are:

  1. Minimize adverse and unwanted side effects from ADT treatment
  2. Create a hostile biological environment for cancer in the body to support medical treatment
  3. Optimize quality of life despite ADT.

Wow! That’s a lot. Can we accomplish all that?

Yes, it is. And yes you can.

The right lifestyle and exercise program like the CaPLESS method can minimize about 80% of those side effects. I am not kidding.

Low libido, impotence (or let’s call it sexual dysfunction. Impotence sounds a bit harsh) and hot flashes are non-life threatening and more difficult to overcome.

Most other life-threatening side effects  are greatly reduced.

Studies on Exercise while on Hormone Deprivation Therapy or ADT.

In one study of 2,700 male health care professionals (average age 70 years) with non-metastatic prostate cancer and found that those participating in vigorous physical activity for a duration ≥3 hours/week demonstrated a 49% lower risk of all-cause mortality and a 61% lower risk of death specifically from prostate cancer, compared with men who did 1 1 hour/week of vigorous activity. (Kenfield et al. 2011)

A systematic review of ten studies (five randomized and five uncontrolled clinical trials) examined the effects of exercise on patients receiving ADT. This paper demonstrated that physical performance was improved by exercise. Randomized controlled trials found exercise to be consistently beneficial for muscular performance: reported as increases in muscular strength and increases in upper and lower limb strength, compared with the control population. (Gardner et al. 2014)

Body composition (the amount of fat compared to muscle in the body) is a component of many studies investigating exercise effects on prostate cancer patients on ADT and resistance training has been shown to either increase lean body mass or not decline. Loss of muscle mass is a common scenario amongst ADT patients. (Galvão et al. 2010)

An observational study reported in 2006 looking at over 70,000 men observed 11% increase in myocardial infarction risk and a 16% increased risk of coronary heart disease and death from cardiac arrest in the study of prostate cancer patients receiving ADT, versus those not on hormone therapy. (Keating et al. 2006)

We would want to avoid those cardiovascular problems while on ADT, right?

Although there are no studies I can find specifically to evaluate the effect of exercise on ADT-induced cardiovascular events, there is a large body of evidence supporting the role of physical activity in the prevention and management of cardiovascular disease in the general population. (Thompson et. Al 2003)

Osteoporosis ( bone fragility), is a major side effect of ADT can lead to bone fractures, and bone fractures lead to 37% of deaths in older men. (Ebeling; 2008)

A study of 8,833 men aged 18–64.9 years used computed tomography to show an inverse relationship between adiposity (BMI and visceral and subcutaneous adiposity) and bone quality (Zhang et al. 2015)

Studies show that resistance training in older men and women, where only high-intensity, and not moderate-intensity, strength training resulted in increased bone mineral density. (Vincent et al. 2002)

METABOLIC SYNDROME WHILE ON ADT

Metabolic syndrome defined by weight gain, especially waist gain; fasting glucose 100 mg/dL or higher, peripheral insulin resistance; and increased diabetes risk increase the risk of heart disease and stroke, in addition to diabetes as is a common side effect when ADT.

Results from a randomized pilot study assessed the impact of over six months of combined metformin, a low-glycemic-index diet, and exercise in 20 prostate cancer patients at ADT initiation and compared this with 20 men who were on ADT alone. The metformin and exercise group had decreased abdominal girth, weight, BMI, and systolic blood pressure, compared with the group on ADT treatment alone, although insulin-resistant biochemical markers were not significantly different. In this small study, however, it was not possible to separate the metformin and dietary effects from the exercise components. (Nobles et al. 2012)

63 prostate cancer patients were randomized to receive either a 3-month aerobic and resistance exercise program or usual care, concomitant to initiation of ADT. Patients receiving the exercise-based intervention demonstrated significant reductions in ADT-associated metabolic effects, including decreased whole body fat mass, abdominal fat, and percentage fat, compared with the usual care control group. (Cormie et al. 2015)

C-reactive protein, an inflammation marker commonly elevated in metabolic syndrome, showed a clinically meaningful reduction in a randomized controlled trial of exercise in 57 men on ADT (Galvão et al. 2010)

Exercise Prescription while on ADT

Exercise four hours a week in moderate to high intensity. Anyone on ADT must include weight resistant exercise, two to three times a week, where you push and pull weight against gravity.

Types of exercises used in some studies include:

Leg presses 

Leg extensions

Leg curls 

Lat pull downs

Biceps curls (with dumbbell)

Triceps extension

These are the main strength training exercises performed on many of the studies listed above showing benefit.

Strength training movements I strongly recommend include:

Kettlebell training – Pavel on this video sounds like a military agent. He is the best at kettlebells and one of the most knowledgeable on physical strength. 

(Me and a friend after Kettlebell training)

Squats

Deadlifts

Benchpress

The Press

Pushups

Pull-ups

 

If the above movements and exercises sound foreign then consider hiring a physical trainer if able to. Not only can a trainer help you with the movements but also help prevent injuries.

If an injury occurs during any movements mentioned above, all bets are off, you will not or cannot get the benefit of the exercise.

Listen…

Fear should not stop you from trying and consistently training with the exercises mentioned.

Prostate cancer has to be fought with courage.

The most important point in doing any of the above exercises is to first master the technique of that movement. That is one of two ways you prevent injuries from doing those exercises. The other is avoiding doing too much weight too soon. Yes, you should challenge yourself and increase the weight you push or pull, but it must be done incrementally.

Again, hiring a personal trainer can be priceless if your pockets allow.

Last 3 Blog Posts:

Traditional Chinese Medicine treatment for Erectile Dysfunction

Why I’m Into Intermittent Fasting

Does Eating Chicken Cause Prostate Cancer

 

Resource:

Much of the research for this blog post is from Moyad et al; 2016

Nutrition while on ADT – Advanced ADT Support

 

References:

Kenfield SA, Stampfer MJ, Giovannucci E, Chan JM. Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study. J Clin Oncol. 2011;29(6):726–732.

Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. J Clin Oncol. 2014;32(4):335–346

Thompson PD, Buchner D, Pina IL, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity) Circulation. 2003;107(24):3109–3116.

Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448–4456.

Ebeling PR. Clinical practice. Osteoporosis in men. N Engl J Med. 2008;358(14):1474–1482

Galvão DA, Taaffe DR, Spry N, Joseph D, Newton RU. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol. 2010;28(2):340–347.

Zhang P, Peterson M, Su GL, Wang SC. Visceral adiposity is negatively associated with bone density and muscle attenuation. Am J Clin Nutr. 2015;101(2):337–343.

Vincent KR, Braith RW. Resistance exercise and bone turnover in elderly men and women. Med Sci Sports Exerc. 2002;34(1):17–23.

Nobes JP, Langley SE, Klopper T, Russell-Jones D, Laing RW. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int. 2012;109(10):1495–1502.

Cormie P, Galvao DA, Spry N, et al. Can supervise exercise prevent treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy: a randomized controlled trial. BJU Int. 2015;115(2):256–266

DA, Taaffe DR, Spry N, Joseph D, Newton RU. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol. 2010;28(2):340–347.

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by Dr. Geo

6 comments… add one
  • Stephen B. Strum MD, FACP 03/30/2018, 6:00 PM

    I read Dr. Geo’s viewpoint from beginning to end and although I agree with the importance of exercise I would say with a major degree of certainty that exercise, per se, is not going to make a major change in what I term the Androgen Deprivation Syndrome (ADS). We described this “spectrum” of possible clinical signs, symptoms, laboratory and imaging findings in men on testosterone lowering treatments i.e. ADT. In fact, our group was the first to describe in detail AAD (anemia of androgen deprivation) and later on the resolution of severe anemia using very low dose erythropoietin aka Epogen, Procrit. Men on ADT often lose the “combativeness” associated with testosterone. With that loss comes a more sedentary lifestyle and the risk of significant weight gain, lipid and fatty acid abnormalities. Given that testosterone drives so many of the body’s functions, it takes a multi-pronged approach to deal with whatever specific androgen deprivation adverse side-effects that an individual may be challenged with. For example, bone loss due to ↓ testosterone with associated ↑ in bone resorption markers (BRMs) such as urine DpD (deoxypyridinoline) is best treated with a drug like denosumab (Xgeva®). Although resistant exercises will help, the multi-pronged approach is more likely to work. Alkalinization of urine with something as simple as sodium bicarbonate or potassium citrate has also shown to help improve bone mineral density (BMD). Some men experience severe hot flashes and one injection of deep-provera 400 mg i.m. often completely knocks out this symptom; but it should only be used if symptoms are moderate to severe. Twenty years ago we published an abstract in ASCO (American Society of Clinical Oncology): Strum SB, Scholz MC, McDermed JE: The Androgen Deprivation
    Syndrome: the incidence and severity in prostate cancer patients receiving
    hormone blockade. Proc Amer Soc Clin Oncol 17:316A, 1998. If there is interest I can post that abstract in a separate comment.

    Reply
    • Dr. Geo 03/31/2018, 6:14 PM

      Thank you for your informative comment Dr. Strum. I agree that treating adverse events from ADT (and even treating prostate cancer) is a multi-pronged approach. In my practice is see very little anemia from patients on ADT, for some odd reason.Additionally, my patients, by enlarge, but not all, are increasingly disciplined in following the lifestyle practices and training regimen I prescribe. Likely I have a homogenous group as well. Lastly, the exercise program has to be prescriptive for it to work. Mild exercises with low intensity would offer little benefit compared to moderate to high-intensity exercises that include weight resistance. This is critical for men to do well while on ADT. Please share your abstract. And thanks again for your contribution to this important conversation.

      Reply
  • John 03/31/2018, 1:23 PM

    Kettlebell video is great! I’ll start incorporating it into my workouts. Happy Easter to you and your family! John

    Reply
    • Dr. Geo 03/31/2018, 6:00 PM

      Kettlebell training is one of my favorites for increasing strength and athleticism.Good luck with your training and let us know how you do, John.

      Reply
  • Richard Gonzalez 04/02/2018, 12:57 PM

    Dr Geo,

    Please define “Study participants had confirmed PC that was castration-resistant.”

    Richard Gonzalez

    Reply
    • Dr. Geo 04/02/2018, 6:52 PM

      Great question, Richard. Castrate resistant prostate cancer (CRPC) is when a patient is treated with Androgen Deprivation Therapy (ADT) for prostate cancer, PSA goes down to virtually zero, often for about two years (every case is different), then PSA starts rising indicating a relapse of prostate cancer, despite ADT. Thus, prostate cancer becomes resistant to ADT. Does that explain it?

      Reply

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