Glucocorticoids (dexamethasone, hydrocortisone, triamcinolone, prednisone

Glucocorticoids - ≥ 2nd line treatment.

Hydrocortisone, Dexamethasone, Prednisone, Triamcinolone

Howard Hansen

12 April 2008

Low-dose corticosteroids

Low-dose corticosteriods can be used as an independent second line hormone therapy. They are often combined with chemotherapy or with ketoconazole or aminoglutethimide(Cytaden).

Triamcinolone is another glucocorticoid to consider and is discussed elsewhere. Included on the triamcinolone page is a great deal of additional information on glucocorticoids.

In addition, see the paper on chemo-sequencing where Aishman has given some information on where glucocorticoids might fit into a treatment plan.

Corticosteriods diminish adrenal androgen production by an indirect negative feedback loop (suppress ACTH(corticotropin) = reduced adrenal androgens).

A review paper by Fakih M et al (12) gives a good overview and is recommended as a supplement to this paper.

Table 1 below lists various clinical trial results for glucocorticoids -- hydrocortisone, prednisone, triamcinolone and dexamethasone. Table 2 lists the equivalency (strength) of these glucocorticoids relative to one another.

Table 1. Steroid use in prostate cancer
Study	Steroid	mg/day	n	PSA RR(≥50% decrease) (%)	Duration of response
Kelly WK et al, (13) J Clin Onc 1995.	Hydrocortisone	40	30	20	16 weeks.
Small EJ, et al (1), 2000.	Hydrocortisone	40	231	16	MST 9.2 mos.
Kantoff et al, (2), 1999.	Hydrocortisone	45	116	22	MST 12.6 mos. MTP 2.3 mos.
Tannock et al, (3), 1996.	Prednisone	10	81	22	4.0 mos?
Gregurich et al (14) 2000 ASCO	Prednisone	5 BID	60	24	Median TTP 3.8 mos.
Fosså et al, (4), 2001.	Prednisone	5mg 4x/day.	101	21	MTP 3.4 mos; MST 10.6 mos.
Fosså SD et al, (4.1), 2007.	Prednisolone	5mg x 2	50	26	Median PFS 4mos.; Median OS 18mos.
Sartor O, et al (4.2), Urology 1998.	Prednisone	10mg 2x/day	29	34	Median PFS 2 mos. (range 0-11. Median survival 12.8 mos.
Storlie et al, (5), Cancer 1995.	Dexamethasone	1.5(.75mg BID)	38	61	Median 245 days; range 99-660.
Nishiyama T et al, (7), IJU 1998.	Dexamethasone	1.5->.5	16	43 (3 of 7 patients)	4 mos., range 2-15 mos. Of the 3 responders, their responses lasted > 6 mos.
Nishimura et al, (8), Cancer 2000.	Dexamethasone	.5-2	37	62	Median of 9 mos.
Srinivas et al, (6), Urology 2006.	Triamcinolone	4mg, 2xday	24	29 and another 21% had stable disease.	7.5 mos.

PSA prostate-specific antigen; PFS progression free survival; OS overall survival; TTP time to progression; n number of patients; MST median survival time; MTP median time to progression.

When Should glucocorticoids be Used?

W. Oh in his review of second-line hormone therapies(11), states that due to the relatively low response rates and the short duration of responses, low-dose glucocorticoids should be used after other, more effective, secondary hormonal therapies have been tried.

Fakih et al (12), suggest their use in the palliative setting or on failure of primary chemotherapy in HRPC disease. See the triamcinolone paper for other suggestions.

Equivalency in mg of different glucocorticoids

Table 2. Equivalency in milligrams (mg) of the different glucocorticoids.

Dexamethasone	Triamcinolone	Prednisolone and Prednisone	Hydrocortisone	Cortisone
.75 mg=	4 mg=	5 mg=	20 mg=	25 mg

Do glucocorticoids affect PSA when combined with Taxotere?

The answer turns out to be no. There have been three studies that provided this answer. Petrylak (9) in two trials of Taxotere + Emcyt stated that "Dexamethasone...does not appear to significantly contribute to the response rate of estramustine and docetaxel." Petrylak gave decadron 60mg orally 3x/day every 3 weeks until progression(at which time they got taxotere and emcyt). For the 12 men entered, they only received from 1 to 5 cycles before progression, none had a >50% decrease in PSA, 11 progressed by PSA and 1 by measurable soft tissue disease.

Weitzman (10) reported that dexamethasone @ 20 mg/6 hours X 3 doses every 3 weeks before starting Taxotere + Emcyt "...does not significantly contribute to the PSA response rate of estramustine and docetaxel."

Thus using decadron intermittently(every 21 days) rather than as a continuous therapy, as most studies of glucocorticoids have done, does not do much, if anything, PSA-wise.

References

1. Small EJ, Meyer M, Marshall ME, et al: Suramin therapy
for patients with symptomatic hormone-refractory prostate
cancer: results of a randomized phase III trial comparing
suramin plus hydrocortisone to placebo plus hydrocortisone.
J Clin Oncol 18: 1440–1450, 2000.

2. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone
with or without mitoxantrone in men with hormone refractory
prostate cancer: results of the Cancer and Leukemia
Group B 9182 study. J Clin Oncol 17: 2506–2513, 1999.

3. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy
with mitoxantrone plus prednisone or prednisone alone
for symptomatic hormone-resistant prostate cancer: a Canadian
randomized trial with palliative end points. J Clin Oncol 14: 1756–1764, 1996.

4. Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L , Collette L., Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group, J Clin Oncol. 2001 Jan 1;19(1):62-71.

4.1. Fosså SD, Jacobsen AB, Ginman C, Jacobsen IN, Overn S, Iversen JR, Urnes T, Dahl AA, Veenstra M, Sandstad B, Eur Urol. Weekly docetaxel and prednisolone versus prednisolone alone in androgen-independent prostate cancer: a randomized phase II study, 2007 Dec;52(6):1691-8. Epub 2007 Feb 8. Comment in: Eur Urol. 2007 Dec;52(6):1698-9.

4.2. Sartor O et al; Effect of prednisone on prostate-specific antigen in patients with hormone-refractory prostate cancer; Urology 1998 Aug;52(2)252-6.

5. Storlie JA, Buckner JC, Wiseman GA, et al: Prostate
specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma, Cancer 76: 96–100, 1995.

6. Srinivas S, Krishnan AV, Colocci N, Feldman D, Phase II study evaluating oral triamcinolone in patients with androgen-independent prostate cancer, Urology. 2006 May;67(5):1001-6.

7. Nishiyama T, Terunma M; Hormone/antihormone withdrawal and dexamethasone for hormone-refactory prostate cancer; Int J Urol 1998 Jan;5(1):44-7

8. Nishimura et al; Low doses of oral dexamethasone for hormone-refractory prostate carcinoma; Cancer 2000 Dec 15;89(12):2570-76

(9) Petrylak DP; Docetaxel (Taxotere) in hormone-refactory prostate cancer; Semin Oncol 2000 Apr;27(2 Suppl 3):24-29

(10) Weitzman et al; Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer; J Urol 2000 Mar; 163(3): 834-7.

(11) WK Oh, "Secondary Hormonal Therapies in the Treatment of Prostate Cancer," Urology 60[Suppl 3A]:87-93, 2002.

(12) Fakih M, Johnson CS, Trump DL, Glucocorticoids and treatment of prostate cancer: a preclinical and clinical review, Urology. 2002 Oct;60(4):553-61.

(13) Kelly WK, Curley T, Leibretz C, Dnistrian A, Schwartz M, Scher HI, Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer, J Clin Oncol. 1995 Sep;13(9):2208-13.

(14) Mary Gregurich, M Gregurich, L Asmar, Phase III Study of Mitoxantrone/Low-Dose Prednisone Versus Low-Dose Prednisone Alone in Patients with Asymptomatic Hormone-Refractory Carcinoma of the Prostate, Proc Am Soc Clin Oncol 19: 2000 (abstr 1321).