Saturday, June 29, 2019

How much prednisone is needed with abiraterone?

Abiraterone (Zytiga) inhibits the enzymes necessary for the adrenal glands to produce androgens. The adrenals are the secondary source of androgens after the testicles. Unfortunately, the same enzyme is needed for the adrenals to produce cortisol, so a glucocorticosteroid (in the form of prednisone, dexamethasone, or methylprednisolone) has to be replaced when taking abiraterone. When abiraterone is prescribed for men with metastatic hormone-sensitive prostate cancer, 5 mg once daily (5 mg qd) or sometimes 2.5 mg twice daily (2.5 mg bid) is taken for replacement. When abiraterone is prescribed for men with metastatic castration-resistant prostate cancer, 5 mg twice daily (5 mg bid) is taken with it, because the anticipated duration of taking the steroids is shorter. Recently it was found that switching from prednisone to dexamethasone 0.5 mg once a day (0.5 mg qd) can extend the duration of abiraterone effectiveness (see this link).

The danger of taking too little corticosteroid to replace what is lost is a condition called a syndrome of secondary mineralocorticoid excess. This occurs because the pituitary gland reacts to the lack of cortisol by producing a hormone called ACTH. ACTH increases the production of mineralocorticoids (like aldosterone), hormones that increase blood pressure, lower potassium and cause edema in the limbs.

The danger of taking too much corticosteroid may include insulin resistance, a decrease in lean body mass, increase in fat accumulation, and decrease in bone mineral density. It is also immunosuppressive, and may cause tissue breakdown (catabolysis) and gastritis. Adverse effects increase with dose and duration of use.

Glucocorticosteroids have been found to have independent anti-cancer activity (see this link). The effect is short-lived as resistance eventually arises. It is also given to mitigate some of the side effects of chemotherapy ike emesis/nausea and peripheral edema.

Attard et al. conducted a randomized clinical trial among men taking 1000 mg/day abiraterone for metastatic castration-resistant prostate cancer at 22 hospitals in 5 countries in 2013-2014.

  • 41 received it with prednisone 5mg bid (P5 bid)
  • 41 received it with prednisone 5 mg qd (P5 qd)
  • 40 received it with prednisone 2.5 mg bid (P2.5 bid)
  • 42 received it with dexamethasone 0.5 mg qd (D0.5 qd)


The primary outcome measured was mineralocorticoid excess through 24 weeks of treatment as indicated by elevated blood pressure or a blood test for low potassium (hypokalemia). They also measured serum levels of ACTH, which gets elevated if there is not enough glucocorticoid. For side effects of too much glucocorticoid, they measured insulin resistance, loss of lean body mass, gain of body fat, and loss of bone mineral density. For the benefits, they measured suppression of androgen precursors, the % of patients in whom PSA declined by at least 50%, the duration of radiographic progression-free survival, and the patient-reported change in quality of life.



P5 bid
P5 qd
P2.5 bid
D0.5 qd
Mineralocorticoid excess
29%
63%
40%
30%
(95% confidence range)
17%-46%
47%-77%
26%-56%
17%-46%
Grade 3 hypertension
7%
22%
13%
7%
Grade 3 hypokalemia
0%
7%
0%
0%
Change in ACTH (pmol/L)
-1.1
9.0
4.0
-1.8
Change in fasting serum insulin (insulin resistance)
Not statistically significant
Not statistically significant
Not statistically significant
significant
Change in lean body mass
-6%
-3%
-6%
Not statistically significant
Change in total body fat
12%
Not statistically significant
Not statistically significant
19%
Change in bone mineral density
Not statistically significant
Not statistically significant
Not statistically significant
-2%
Androgen precursor suppression
-81%
Not statistically significant
Not statistically significant
-88%
PSA declined by ≥ 50%
63%
78%
60%
88%
Radiographic Progression-free survival
18.5 months
15.3 months
12.8 months
26.6 months
Quality of Life change
Not statistically significant
Not statistically significant
Not statistically significant
Not statistically significant

Although sample sizes were not large enough to directly compare the treatments, the data suggest that P5 bid and D0.5 qd do a good job of preventing mineralocorticoid excess, whereas P5 qd does not. P5 bid and D0.5 qd seem to cause body changes. D0.5 qd seems to have superior oncological effectiveness.

There was tremendous individual variation. It seems prudent to start with the prescribed dose (P5 bid) and monitor body changes, or to start at the lower dose (P5 qd) and to monitor blood pressure and potassium levels.



Evidence for Dose Escalation in Adjuvant/Salvage Radiation

It is well known that prostate cancer is relatively radio-resistant compared to other kinds of cancer. While dose escalation (most recently by increasing the biologically effective dose using hypofractionated dose (more that 2.0 Gy per session) delivery or brachytherapy boost therapy) has become the mainstay in primary radiation therapy, doses delivered for adjuvant or salvage radiation has stayed about 10 Gy lower. Recently, Dr. King's analysis of the dose responsiveness of salvage radiation questioned this supposition (see this link). While his mathematical arguments provide us with intriguing plausibility, only clinical evidence from a randomized clinical trial can change practice.

We now have Level 1 evidence that expanding the adjuvant/salvage treatment field to include the pelvic lymph nodes improves the oncological outcomes in men with higher PSA at the time of salvage radiation.

Link et al. conducted a small, retrospective study among 120 locally advanced (stage T3/4) post-prostatectomy patients at the University of Heidelberg between 2009 and 2017. All were lymph node negative.

  • 43 received whole pelvic radiation therapy (WPRT)- 62% received 79.3 Gy to the prostate
  • 77 received radiation to the prostate bed only (PBO)- 70% received 79.3 Gy to the prostate
  • Biologically equivalent dose (2 Gy) to the prostate was 79.3 Gy ("high dose") if they had positive margins or PET/CT/MRI imaging-detectable prostate bed tumors (62% of patients), 71.4 Gy ("low dose") if they had negative margins (38% of patients).


Median freedom from biochemical failure was:

  • longer among those who got the higher dose: 76 months vs 21 months
  • longer among those who received WPRT vs PBO: 68 months vs 32 months


There is a lot of overlap in treatments, so it is impossible to tease out the effect that each had on the oncological outcomes. Almost all of those who received the escalated dose also had positive margins - a known factor for predicting success of adjuvant/salvage radiation. Also, almost all men who had adjuvant radiation had positive margins and dose escalation - adjuvant radiation has proven to be more successful than "wait-and-see" in 3 major randomized clinical trials.

Toxicity increased with both dose and size of the treatment field. Grade ≥ 2 toxicity was reported by:

  • 3.4% among those who received low dose and PBO
  • 12.5% among those who received high dose and PBO
  • 15.4% among those who received low dose and WPRT
  • 36.7% among those who received high dose and WPRT
  • No reports of Grade 3 gastrointestinal toxicity
  • 13% Grade 3 urinary toxicity among high dose patients, none among low-dose patients


This is a far cry from the randomized clinical trial we need for practice-changing dose escalation for adjuvant/salvage radiation. However, we can't rule out that there is no oncological benefit to dose escalation. It remains unknown what proportion of these high-risk patients would have done just as well with lower doses and smaller treatment fields. The increase in toxicity with dose and treatment field means that patients ought not jump into this without understanding the risks and discussing them with their radiation oncologists.