Evaluating the Addition of Total Androgen Suppression to Radiation versus Radiation Alone for Locally Advanced Prostate Cancer
Evaluating the Addition of Total Androgen Suppression to Radiation versus Radiation Alone for Locally Advanced Prostate Cancer
US Oncology Review 2005
Published: October 2008
Published: October 2008
Introduction
The combination of androgen suppression and radiation is becoming the standard treatment for men with locally advanced adenocarcinoma of the prostate.This article will outline the rationale, clinical studies supporting its use, toxicity, and cost associated with the use of combination androgen suppression and radiation in the treatment of men with locally advanced adenocarcinoma of the prostate.
Rationale for Androgen Blockade in Prostate Cancer
Androgens regulate the growth and synthetic activity of the prostate gland.
Testosterone, the primary circulating androgen, is converted to its active form, alphadihydrotestosterone, by 5-alpha-reductase, and forms a complex with the dihydrotestosterone-binding domain of the androgen receptor. This complex then alters the structure of the DNA-binding domain allowing it to reversibly bind DNA sequences and androgen response elements in promoter or enhancer regions of androgenregulated genes. This response can be manifested as stimulation of cell division, inhibition of apoptosis, or cellular differentiation.
Androgen deprivation is one of the oldest treatments for adenocarcinoma of the prostate. Huggins won the 1966 Nobel Prize for Physiology and Medicine for reporting on the effects of androgen deprivation in men with adenocarcinoma of the prostate.1,2 Three effects have been noted when androgen deprivation is combined with radiation in the treatment of adenocarcinoma of the prostate:
• Androgen deprivation will result in tumor volume reduction that could enhance the response of radiation by decreasing the total number of viable clonogens.
• Androgen deprivation may eradicate tumor deposits outside of the radiation field.
• A supra-additive apoptotic effect has been reported in a human prostate cancer cell line when androgen ablation precedes a single fraction of radiation treatment by three days.3
Clinical Trials Evaluating Androgen Deprivation in Patients with Prostate Cancer
The Radiation Therapy Oncology Group (RTOG) has published numerous clinical trials investigating the addition of androgen suppression to radiation in the treatment of locally advanced prostate cancer. RTOG 75–06 was one of the first trials reporting on a possible survival benefit from the use of androgen suppression with radiation.4,5 This trial was designed to compare pelvic irradiation followed by a boost to the prostate with pelvic and periaortic irradiation followed by a boost to the prostate in the treatment of patients with clinical stage C adenocarcinoma with or without pelvic lymph node metastases, or patients with stage A2 and B disease with pelvic lymph node involvement. Patients were not randomized or stratified based upon hormone use, which could be either estrogen and/or orchiectomy. A disproportionally higher percentage of patients receiving hormone use had unfavorable lesions, but it appeared that hormones counteracted the effect of a higher proportion of histologically unfavorable lesions.5 A trend toward improved local control was also noted in patients receiving hormone therapy. Future RTOG clinical trials incorporating androgen suppression as a cytoreductive agent were designed based upon the results of RTOG 75–06.
RTOG 83–07, a phase II clinical trial,was designed to compare the efficacy and toxicity of megestrol acetate with diethylstilbestrol (DES). Hormones were given two months prior to and during radiation in the treatment of patients with bulky stage B (T2B) or Stage C (T3) adenocarcinoma.6 Patients received 44–46 Gray (Gy) to the regional lymphatics followed by a boost of 20–25Gy to the prostate target in 1.8–2.0Gy fractions. DES produced a statistically significant greater median decrease in testosterone compared with megestrol acetate; however, no difference was noted in primary tumor clearance at two years between study arms. Loco-regional recurrence was also comparable between arms at 16% versus 21% at seven years for megestrol acetate and DES respectively, with the rate of distant metastasis also not statistically different between the two arms. Because a clear-cut superiority was not documented between either drug, the RTOG became interested in using a luteinizing hormone-releasing hormone (LHRH), goserelin, and an anti-androgen, flutamide.
References:
1. Huggins C and Hodges C V,"Studies on prostatic cancer: I. the effect of castration on estrogen and of androgen injection on serum
phosphatases in metastatic carcinoma of the prostate", Cancer Res. (1941), 1: p. 293-297.
2. Huggins C, Stevens R E and Hodges C V, "Studies on prostatic cancer: II The effects of castration on advanced carcinoma of the prostate glan", Arch. Surg. (1941), (43): p. 209-223.
3. Joon D L et al, "Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation", Int. J. Radiat. Oncol. Biol. Phys. (1997), 38 (5): p. 1,071-1,077.
4. Pilepich M V et al., Extended field (periaortic) irradiation in carcinoma of the prostate - analysis of RTOG 75-06", Int. J. Radiat. Oncol. Biol. Phys. (1986), 12 (3): p. 345-351.
5. Pilepich M V et al., "Prognostic factors in carcinoma of the prostate analysis of RTOG study 75-06", Int. J. Radiat. Oncol. Biol. Phys. (1987), 13 (3): p. 339-349.
6. Pilepich M V et al.,"Phase II trial of hormonal cytoreduction with megestrol and diethylstilbestrol in conjunction with radiotherapy for carcinoma of the prostate: outcome results of RTOG 83-07", Int. J. Radiat. Oncol. Biol. Phys. (1995), 32 (1): p. 175-180.
7. Pilepich M V et al., "Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31", J. Clin. Oncol. (1997), 15 (3): pp. 1,013-1,021.
8. Lawton C A et al., "Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate", Int. J. Radiat. Oncol. Biol. Phys. (2001), 49 (4): pp. 937-946.
9. Pilepich M V et al., "Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate", Int. J. Radiat. Oncol. Biol. Phys. (2001), 50 (5): pp. 1,243-1,252.
10. Bolla M et al., "Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin", N. Engl. J. Med. (1997), 337 (5): pp. 295-300.
11. Bolla M et al.,"Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial", Lancet (2002), 360 (9327): pp. 103-106.
12. Hanks G E et al., "Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02", J. Clin. Oncol. (2003), 21 (21): pp. 3,972-3,978.
13. D Amico A V et al., "6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial", JAMA (2004), 292 (7): pp. 821-827.
14. Valicenti R K et al.,"RTOG 94-06: is the addition of neoadjuvant hormonal therapy to dose-escalated 3D conformal radiation therapy for prostate cancer associated with treatment toxicity?", Int. J. Radiat. Oncol. Biol. Phys. (2003), 57 (3): pp. 614-620.
15. Herr H W and O Sullivan M,"Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy", J. Urol. (2000), 163 (6): p. 1,743-1,746.
16. Krahn M et al.,"Patient and community preferences for outcomes in prostate cancer: implications for clinical policy", Med. Care (2003), 41 (1): p. 153-164.
17. Stege R,"Potential side-effects of endocrine treatment of long duration in prostate cancer", Prostate Suppl. (2000), 10: p. 38-42.
18. Daniell H W, "Osteoporosis after orchiectomy for prostate cancer", J. Urol. (1997), 157 (2): p. 439-444
19. Neymark N et al.,"Estimating survival gain for economic evaluations with survival time as principal endpoint: a cost-effectiveness analysis of adding early hormonal therapy to radiotherapy in patients with locally advanced prostate cancer", Health Econ. (2002), 11 (3): p. 233-248.
20. Konski A, Sherman E, Krahn M, Bremner K, Beck J R and Watkins-Bruner D,"Economic analysis of a Phase III clinical trial evaluating the addition of total androgen suppression (TAS) to radiation versus radiation alone for locally advanced prostate cancer (RTOG 86-10)", submitted Int. J. Radiat. Oncol. Biol. Phys. (2004).
2. Huggins C, Stevens R E and Hodges C V, "Studies on prostatic cancer: II The effects of castration on advanced carcinoma of the prostate glan", Arch. Surg. (1941), (43): p. 209-223.
3. Joon D L et al, "Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation", Int. J. Radiat. Oncol. Biol. Phys. (1997), 38 (5): p. 1,071-1,077.
4. Pilepich M V et al., Extended field (periaortic) irradiation in carcinoma of the prostate - analysis of RTOG 75-06", Int. J. Radiat. Oncol. Biol. Phys. (1986), 12 (3): p. 345-351.
5. Pilepich M V et al., "Prognostic factors in carcinoma of the prostate analysis of RTOG study 75-06", Int. J. Radiat. Oncol. Biol. Phys. (1987), 13 (3): p. 339-349.
6. Pilepich M V et al.,"Phase II trial of hormonal cytoreduction with megestrol and diethylstilbestrol in conjunction with radiotherapy for carcinoma of the prostate: outcome results of RTOG 83-07", Int. J. Radiat. Oncol. Biol. Phys. (1995), 32 (1): p. 175-180.
7. Pilepich M V et al., "Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31", J. Clin. Oncol. (1997), 15 (3): pp. 1,013-1,021.
8. Lawton C A et al., "Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate", Int. J. Radiat. Oncol. Biol. Phys. (2001), 49 (4): pp. 937-946.
9. Pilepich M V et al., "Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate", Int. J. Radiat. Oncol. Biol. Phys. (2001), 50 (5): pp. 1,243-1,252.
10. Bolla M et al., "Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin", N. Engl. J. Med. (1997), 337 (5): pp. 295-300.
11. Bolla M et al.,"Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial", Lancet (2002), 360 (9327): pp. 103-106.
12. Hanks G E et al., "Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02", J. Clin. Oncol. (2003), 21 (21): pp. 3,972-3,978.
13. D Amico A V et al., "6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial", JAMA (2004), 292 (7): pp. 821-827.
14. Valicenti R K et al.,"RTOG 94-06: is the addition of neoadjuvant hormonal therapy to dose-escalated 3D conformal radiation therapy for prostate cancer associated with treatment toxicity?", Int. J. Radiat. Oncol. Biol. Phys. (2003), 57 (3): pp. 614-620.
15. Herr H W and O Sullivan M,"Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy", J. Urol. (2000), 163 (6): p. 1,743-1,746.
16. Krahn M et al.,"Patient and community preferences for outcomes in prostate cancer: implications for clinical policy", Med. Care (2003), 41 (1): p. 153-164.
17. Stege R,"Potential side-effects of endocrine treatment of long duration in prostate cancer", Prostate Suppl. (2000), 10: p. 38-42.
18. Daniell H W, "Osteoporosis after orchiectomy for prostate cancer", J. Urol. (1997), 157 (2): p. 439-444
19. Neymark N et al.,"Estimating survival gain for economic evaluations with survival time as principal endpoint: a cost-effectiveness analysis of adding early hormonal therapy to radiotherapy in patients with locally advanced prostate cancer", Health Econ. (2002), 11 (3): p. 233-248.
20. Konski A, Sherman E, Krahn M, Bremner K, Beck J R and Watkins-Bruner D,"Economic analysis of a Phase III clinical trial evaluating the addition of total androgen suppression (TAS) to radiation versus radiation alone for locally advanced prostate cancer (RTOG 86-10)", submitted Int. J. Radiat. Oncol. Biol. Phys. (2004).
