Androgen Deprivation Therapy:

Transcription

1 Androgen Deprivation Therapy: Identifying and managing toxicity to support men through prostate cancer treatment Andrew M. McDonald MD, MS University of Alabama at Birmingham Department of Radiation Oncology

2 Goals Review common side effects of ADT Understand their natural course Understand how often these side effects cause a serious detriment to quality of life Review the studies aimed at decreasing the various side effects Make recommendations regarding interventions Be prepared to educate patients better

3 None Disclosures

4 NCCN Guidelines RISK GROUP Intermediate: T2b-T2c or Gleason score 7 or PSA ng/ml High: T3a or Gleason score 8-10 or PSA >20 ng/ml INITIAL RADIOTHERAPY RT ± ADT (4-6 mo) ± brachytherapy or brachytherapy alone RT + ADT (2-3 y) (category 1) or RT + brachytherapy ± ADT (2-3 y) Mohler, JL et al. J Natl Compr Canc Netw 2014 May;12(5): PMID:

5 RTOG Trials RTOG RTOG Jones, CU et al. N Engl J Med 2011 Jul 14;365(2): PMID: Horwitz, EM et al. J Clin Oncol 2008 May20;26(15): PMID:

6 Who else are we using Lupron for?

7 Adverse Effects of ADT Acute - Hot flashes - Sexual dysfunction - Fatigue Late - Loss of bone density - Loss of muscle mass - Gynecomastia - Metabolic syndrome - Heart disease? - Diabetes? 1 In the setting of total androgen blockade.

8 Adverse Effects of ADT Horwitz, EM et al. J Clin Oncol 2008 May20;26(15): PMID:

9 Hot Flashes - Prevalence Spetz, AC et al Schow, DA et al Spetz, AC et al. J Urol 2001 Aug;166(2): PMID: Schow, DA et al. South Med J 1998 Sep;91(9): PMID:

10 Hot Flashes What Works? Gabapentin 1 Medroxyprogesterone 2 1 Loprinzi, CL et al. Ann Oncol 2009 Mar;20(3): PMID: Irani, J et al. Lancet Oncol 2010 Feb;11(2): PMID:

11 Hot Flashes What Doesn t Work? Soy proteins (isoflavones) Venlafaxine Vitolins, MZ et al. J Clin Oncol 2013 Nov 10;31(32): PMID:

12 Hot Flashes Acupuncture? Ashamalla, H et al. Int J Radiat Oncol Biol Phys 2011 Apr;79(5): PMID: Harding, C et al. BJU Int 2009 Jan;103(2): PMID:

13 Sexual Dysfunction - Prevalence Walker, LM et al. Clin Genitourin Cancer 2013 Dec;11(4): PMID:

14 Sexual Dysfunction - Pathogenesis Testosterone primarily regulates sexual interest Not all castrated men become impotent Ability to achieve an erection in response to very strong stimulus may be independent of testosterone Time to tumescence doubled in hypogonadal men Why doesn t erectile function return to normal after ADT is discontinued? Corona, G et al. J Sex Med 2012 Mar;9(3): PMID:

15 RT and Erectile Dysfunction Roach, M 3rd et al. Int J Radiat Oncol Biol Phys 2010 Mar;76(3 Suppl):S PMID: McDonald, AM et al. Urology 2014 Dec;84(6): PMID:

16 PDE-5 Inhibitors RTOG 0215 Overall 13 patients (21%) responded to sildenafil, but not placebo Watkins, BD et al. J Sex Med 2011 Apr;8(4): PMID:

17 Prophylaxis with PDE-5 Inhibitors? Zelefsky, MJ et al. J Urol Sep;192(3): PMID:

18 Exercise and Sexual Interest Cormie, P et al. Prostate Cancer Prostatic Dis 2013 Jun;16(2): PMID:

19 Sexual Counseling

20 Fatigue Prevalence Storey, DJ et al. Ann Oncol 2012 Jun;23(6)L PMID: Kyrdalen, AE et al. Prostate 2010 Sep 15;70(13): PMID:

21 Fatigue Exercise Cormie, P et al. BJU Int 2015 Feb;115(2): PMID: Santa Mina, D et al. J Aging Phys Act 2013 Oct;21(4): PMID:

22 Fatigue Methylphenidate

23 Acute Toxicity Recommendations Hot Flashes Understand natural history Neurontin 300 mg TID and medroxyprogesterone improved vs. venlafaxine Venlafaxine and soy proteins questionably better than placebo Sexual Dysfunction May be more related to decreased libido than erectile dysfunction PDE-5 inhibitors remain first-line despite 20% response rate Encourage physical activity Set expectations before beginning ADT Fatigue Tends to improve after ADT discontinued Physical activity first-line in all patients Methylphenidate can be considered for select patients with very severe symptoms.

24 Bone Density Changes Berruti, A et al. J Urol 2002 Jun;167(6): PMID:

25 Bone Density Fracture Risk Shahinian, VB et al. N Engl J Med 2005 Jan 13;352(2): PMID:

26 Calcium and Vitamin D Calcium: Vitamin D: 1,200 mg/day 800 1,000 IU/day

27 Bisphosphonates Smith, MR et al. N Engl J Med 2001 Sep 27;345(13): PMID:

28 Bisphosphonates Serpa Neto, A et al. Prostate Cancer Prostatic Dis 2012 Mar;15(1): PMID:

29 Denosumab (Xgeva) Smith, MR et al. N Engl J Med 2009 Aug 20;361(8): PMID:

30 Recommendations All men receiving ADT should be counseled regarding adequate calcium and vitamin D intake. Supplemental therapy is recommended for men with a 10 year hip fracture risk of 3% by the FRAX algorithm Denosumab 60 mg SC every 6 months Zolendronate 5 mg IV annually Alendronate 70 mg PO weekly Mohler, JL et al. J Natl Compr Canc Netw 2014 May;12(5): PMID:

31 Loss of Muscle Mass Smith, MR et al. J Clin Oncol 2012 Sep 10;30(26): PMID:

32 Gynecomastia Di Lorenzo, G et al. Lancet Oncol 2005 Dec;6(12): PMID:

33 Gynecomastia Prophylactic RT 10 Gy prescribed to a 5 cm diameter circle centered on the nipple using 6-12 mv electrons. Tyrrell, CJ et al. Int J Radiat Oncol Biol Phys 2004 Oct 1;60(2): PMID:

34 Prophylactic RT Nieder, C Radiat Oncol 2008 Jan 10;3:2. PMID:

35 Prophylactic RT vs. Tamoxifen Perdona, S et al. Lancet Oncol 2005 May;6(5): PMID:

36 Metabolic Consequences Weight gain Increased waist circumference Changes in lipid profile Rise in triglycerides Elevated HDL Diabetes risk increased by 30-40%

37 Metabolic Syndrome JAMA 2001 May 16;285(19): PMID:

38 Late Cardiovascular Outcomes Numerous observational studies published No definitive conclusion met A small majority of studies suggest slightly increased cardiac events but no difference in cardiac mortality Standard risk factors apply Be sure to encourage lipid and glycemic control Encourage follow-up with PCP

39 Exercise Investigated by numerous trials Overall trials have shown that men who regularly exercise are more physically fit No long term outcome studies suggesting that late cardiovascular morbidity/mortality is reduced Should incorporate both strength training and aerobic exercise Monitored programs more successful than handouts

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41 Summary of Evidence Nguyen, PL et al. Eur Urol May;67(5): PMID: