The Question:
When do you start androgen deprivation therapy (ADT) in men who have had treatment to their prostate (prostatectomy and/or radiation therapy) and their PSA starts to rise again in the future? If we scan the patient (CT, MRI, etc) and we don’t find any concerning lesions suggestive of metastatic prostate cancer, what should be our next step?
The guidelines are quite clear that patients with metastatic disease seen on imaging studies, ADT is usually recommended to start right away. But for the scenario I mentioned above (where no lesions are seen but the PSA is continuing to rise) the guidelines do not tell us when to start ADT (see NCCN guideline, below.)
What Is ADT?
Androgen deprivation therapy include any of a number of drugs that reduce the fuel the drives the progression of most prostate cancers, testosterone. Often called chemical castration, the effects mimic those in men who have had both testicles removed (orchiectomies, also known as surgical castration.)
- Possible side-effects of ADT include:
- Hot flashes
- Decreased libido and erectile dysfunction (not being able to have an erection)Loss of energy, general weakness
- Breast enlargement and tenderness
- Irritability
- Emotional disturbance including depression
- Headache
- Itching, dry skin, rash
- Gastrointestinal issues: diarrhea, nausea, vomiting
- Loss of muscle mass
- Weight gain (mainly due to increased body fat)
- Shrinkage of testicles
- ‘Metabolic syndrome’ (increased risk of diabetes, heart disease, and cholesterol)
- Long-term use (over a year) may lead to:
- Osteoporosis
- Lower blood counts or anemia
ADT is usually continued indefinitely (continuously or intermittently) once it is started.
Surgical castration is another option for patients who don’t want to take the medications, and there are data that suggest that orchiectomy may be associated with a lower risk of bone fractures, blood clots, diabetes and cardiac events.
The Best Data We Have To Date:
This was an observational study of patients (n=2096) who were treated with either radical prostatectomy or radiotherapy (external beam radiotherapy or brachytherapy) and had a subsequent PSA relapse, defined as:
- a PSA ≥ 0.2 ng/mL if the primary treatment was radical prostatectomy, or
- three rising PSA levels one month apart if the primary treatment was radiation-based
Patients were either started on ADT at PSA relapse (immediate initiation) or at disease progression (deferred initiation). They defined progression as cancer relapse based on any of the following criteria:
- Metastatic disease seen on any imaging study
- PSA doubling time <12 months for PSA≥ 10 ng/mL
- PSA doubling time ≤ 6 months based on 3 consecutive measurements obtained ≥ 2 months apart
What they found was that there was absolutely no difference in survival in the two approaches (immediate or deferred ADT initiation); see the figure below.
The authors concluded:
“In summary, our study provides evidence on the when to start ADT question. In the absence of randomized trial results, our findings suggest that starting ADT at PSA relapse does not have a major impact on overall survival compared with deferred ADT initiation at disease progression.”
The authors concluded:
The results suggest that only a subgroup of patients, especially those with high-risk disease with a long life expectancy, may benefit from early ADT.
The main predictors for unfavourable outcomes were:
- PSA doubling time <12 mo
- Gleason scores 8-10
They also found that an intermittent ADT strategy appears reasonable.
The investigators randomized 142 men to the immediate therapy arm and 151 to the delayed therapy arm.
Median follow-up was 5 years.
- 16 (11%) men died in the immediate therapy arm
- 30 (20%) died in the delayed therapy arm
- 5-year overall survival was 86% in the delayed therapy arm versus 91% in the immediate therapy arm
The authors concluded:
“Immediate receipt of ADT significantly improved overall survival compared with delayed intervention…”
The Bottomline:
Based on the above data, if there is any survival advantage at all with the immediate ADT approach at PSA recurrence, the absolute benefit would be likely less than 10%.
For patients who have no evidence of metastatic disease on imaging studies and have a long life-expentancy (>10 years), it may be reasonable to delay starting ADT unless they have or develop any of these high-risk criteria for rapid disease progression:
- PSA doubling time <12 months for PSA≥ 10 ng/mL
- PSA doubling time ≤ 6 months based on 3 consecutive measurements obtained ≥ 2 months apart
We don’t have black and white rules on when to start ADT in this group of patients, so these points should be considered a starting point for a discussion with you and your physicians.
PSA Doubling Time Calculator (MSKCC)– This is a great tool to help you more accurately calculate your PSA doubling time when you have multiple PSA values.
