Complications of Androgen Deprivation Therapy: Prevention and Treatment

The myriad effects of androgendeprivation therapy (ADT) inmen were really not appreciateduntil those without metastatic prostatecancer received such treatment.For example, fatigue-now recognizedas a common toxicity of ADT-was once more likely attributed tometastatic disease. Today, however,patients who are otherwise fully functional,healthy, and asymptomatic arebeing treated for a rising prostate-specificantigen level after primary therapy.In these men, the side effects ofADT can be very dramatic and aremore clearly related to the initiationof therapy.Clarification Needed
The article by Holzbeierlein et alprovides a thoughtful review of someof the complications associated withADT and treatment options. The subtitleof the article also refers to theprevention of complications, but thistopic is addressed mainly in the sectionentitled "Prevention of Osteoporosis."However, the concept of "preventionof osteoporosis" should be clarified,as discussed below.Bone Mineral Densityand Bisphosphonates
The authors correctly emphasizethat the loss of bone mineral densitydue to ADT can become significantand that, when osteoporotic fracturesoccur in men, they result in greatermorbidity and mortality than is seenin women with fractures. Althoughmen who are treated with ADT dohave a significant loss of bone mineraldensity, this does not always leadto the development of osteoporosis oreven osteopenia. At present, no prospectivedata are available on the incidenceof osteoporosis in men treatedwith ADT or the resulting fracturerate. It is likely that such data willnever be available because of thewidespread use of bisphosphonates inthis disease.What urologists, medical oncologists,and others treating such patientsshould understand is that a loss ofbone mineral density does not necessarilylead to osteoporosis, that allpatients with osteoporosis do not sustainfractures, and that some men withoutosteoporosis are prone to fractureas well. Therefore, while it behoovesthe physician to monitor for osteoporosisand treat it if it occurs (asone would do with a female patient),there is no established role for preventingloss of bone mineral density by administering a bisphosphonateconcurrently with ADT in men withnormal bone mineral density. Nonetheless,many physicians are initiatingsuch therapy despite the absenceof data on its potential long-term toxicitiesunder these circumstances.'Prophylactic' Therapy
The "prophylactic" use of bisphosphonatesin this setting has been driven,in part, by a misunderstanding ofthe reports by Smith et al on the effectsof pamidronate or zoledronicacid on bone mineral density in patientswithout bone metastases beforeand after 1 year of ADT.[1,2] Theserandomized prospective studies bothshowed that ADT alone caused significantloss of bone mineral density,whereas ADT plus a bisphosphonatecould prevent loss of bone mineraldensity (pamidronate) or actually increasethis parameter (zoledronicacid).These investigators did not recommendthat bisphosphonate therapy beadministered to all patients who arestarting ADT, although many haveinterpreted their data in this manner.Certainly men with osteoporosis atbaseline before the initiation of ADTshould be treated with bisphosphonates,but others should merely be monitored periodically with dualenergyx-ray absorptiometry (DXA)or quantitative computed tomography(Q-CT). Hence, a better subheadfor this section of the article byHolzbeierlein et al would have been"Monitoring and Treating Patients forOsteoporosis."While this is the current state ofthe art, the inhibition of bone turnovermay one day be shown to preventor delay the onset of bonemetastases. Padalecki et al have demonstratedthat zoledronic acid preventsbone metastases in a metastatic prostatecancer model.[3] At present, thereare no human data showing that bonemetastases can be prevented with bisphosphonatetherapy, although studiesto assess this possibility are underdevelopment in the cooperative groupsetting. If bisphosphonate therapy isshown to prevent or delay bone metastases,its use as "prophylaxis" whenstarting ADT would be justified.Exercise Benefit
Holzbeierlein et al do mention exerciseas a lifestyle modification thatcan be recommended to patients onADT, but it should be emphasizedthat exercise has great potential toprevent or minimize many of the complicationsof such therapy. A singlerecent prospective randomized studyin prostate cancer patients treated withADT showed that a program of supervisedresistance exercises (vs noexercise) increased upper and lowerbody strength, improved quality oflife, and decreased fatigue after only12 weeks.[4]Although resistance exercise hadbeen shown to elevate mood, buildmuscle, and reduce body fat in healthyolder men,[5-11] there is a paucity ofdata on the benefits of exercise inprostate cancer patients per se. Nevertheless,exercise has been studied inthe context of many of the complicationsreferred to in the article in othersettings. For example, resistance exercisehas been shown to increase bonemineral density.[12] Muscle strengthand mass are also enhanced with resistance training.[12] Presumably,basal metabolism increases with resistanceexercising,[13] and this, inturn, results in loss of body fat massand an increase in lean body mass.[14]Resistance training has been shownto improve glycemic control in diabetics.[14] This is important becauseADT has been shown to increase insulinlevels, with glucose intolerancedeveloping after only 3 months oftherapy.[15] Androgen deprivationtherapy has also been shown to alterlipid profiles,[16] and resistance exerciseimproves high-density lipoproteinlevels.[17]In addition, resistance exerciseimproves aerobic capacity and endurance.[18] Aerobic exercise, whichhas been studied mainly in breast cancerpatients, improves many measuresof "biopsychosocial" functioning includingcardiovascular fitness, bodycomposition, self-esteem, mood states,and fatigue.[19-23] To my knowledge,aerobic exercise interventions havenot been studied in prostate cancerpatients.Conclusions
Holzbeierlein et al conclude thatpatients should be informed of thepotential effects of ADT and that lifestylemodifications such as exercise,diet, and vitamin supplementationshould be recommended. Althoughthis is good advice in theory, mostphysicians do not really know whatto tell their patients about exercise,diet, or vitamin supplementation. Anutritionist will estimate a patient'sdaily dietary intake of calcium andvitamin D and make specific recommendationsfor supplementation.Healthy dietary habits and recommendationsfor weight loss can also bemade, if necessary.With respect to exercise, a balancedprogram of aerobic and resistance exercisesshould be recommended. Aphysical therapist or licensed personaltrainer-ideally one with a fitnessrelatedacademic degree and experience-should be consulted to instructthe patient in such a program. Unfortunately,reimbursement for suchservices is lacking. This deserves furtherattention, as exercise has farreaching potential benefits (beyondalleviating the side effects of ADT)and could actually extend overallsurvival.More research is clearly needed tobetter understand and counteract theadverse effects of ADT. However, recognizingthat these adverse affectscould actually decrease survival inmen who would otherwise live formany years underscores the need todistinguish those without metastaseswho will benefit from ADT from thosein whom therapy can be delayed.

Disclosures:

The author receivesclinical research support from Novartis.

References:

1.

Smith MR, McGovern FJ, Zietman AL, etal: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer.N Engl J Med 345:948-955, 2001.

2.

Smith MR, Eastham J, Gleason DM, et al:Randomized controlled trial of zoledronic acidto prevent bone loss in men receiving androgendeprivation therapy for nonmetastatic prostatecancer. J Urol 169:2008-2012, 2003.

3.

Padalecki SS, Carreon MR, Grubbs B, etal: Androgen deprivation causes bone loss andincreased prostate cancer metastases to bone:Prevention by zoledronic acid (abstract SU072).J Bone Miner Res 17:S310, 2002.

4.

Segal RJ, Reid RD, Courneya KS, et al:Resistance exercise in men receiving androgendeprivation therapy for prostate cancer. J ClinOncol 21:1653-1659, 2003.

5.

Dupler TL, Cortes C: Effects of a wholebodyresistive training regimen in the elderly.Gerontology 39:314-319, 1993.

6.

Treuth J, Ryan AS, Pratley RE, et al: Effectsof strength training on total and regionalbody composition in older men. J Appl Physiol77:614-620, 1994.

7.

Fiatarone MA, O’Neill EF, Ryan ND, etal: Exercise training and nutritional supplementationfor physical frailty in very elderly people.N Engl J Med 330:1769-1775, 1994.

8.

Pyka G, Lindenberger E, Charette S, et al:Muscle strength and fiber adaptions to a yearlongresistance training program in elderly menand women. J Gerontol 49:M22-M27, 1994.

9.

McCartney N, Hicks AL, Martin J, et al:Long-term resistance training in the elderly:Effects on dynamic strength, exercise capacity,muscle, and bone. J Gerontol A Biol Sci MedSci 50:B97-B104, 1995.

10.

Ades PA, Ballor DL, Ashikaga T, et al:Weight training improves walking endurance inhealthy elderly persons. Ann Intern Med124:568-572, 1996.

11.

Rejeski WJ, Brawley LR, Shumaker SA:Physical activity and health-related quality oflife. Exerc Sport Sci Rev 24:71-108, 1996.

12.

Vincent KR, Braith RW: Resistance exerciseand bone turnover in elderly men andwomen. Med Sci Sports Exerc 34:17-23, 2002.

13.

Willey KA, Singh MA: Battling insulinresistance in elderly obese people with type 2diabetes: Bring on the heavy weights. DiabetesCare 26:1580-1588, 2003.

14.

Castaneda C, Layne JE, Munoz-OriansL, et al: A randomized controlled trial of resistanceexercise training to improve glycemic controlin older adults with type 2 diabetes. DiabetesCare 25:2335-2341, 2002.

15.

Smith JC, Bennett S, Evans LM, et al:The effects of induced hypogonadism on arterialstiffness, body composition, and metabolicparameters in males with prostate cancer. J ClinEndocrinol Metab 86:4261-4267, 2001.

16.

Smith MR, Finkelstein JS, McGovernFJ, et al: Changes in body composition duringandrogen deprivation therapy for prostate cancer.J Clin Endocrinol Metab 87:599-603,2002.

17.

Hurley BF, Hagberg JM, Goldberg AP, etal: Resistive training can reduce coronary riskfactors without altering VO2max or percent bodyfat. Med Sci Sports Exerc 20:150-154, 1988.

18.

Vincent KR, Braith RW, Feldman RA,et al: Improved cardiorespiratory endurance following6 months of resistance exercise in elderlymen and women. Arch Intern Med162:673-678, 2002.

19.

Segal R, Evans W, Johnson D, et al:Structured exercise improves physical functioningin women with stages I and II breast cancer:Results of a randomized controlled trial. JClin Oncol 19:657-665, 2001.

20.

Mock V, Burke MB, Sheehan P, et al: Anursing rehabilitation program for women withbreast cancer receiving adjuvant chemotherapy.Oncol Nurs Forum 21:899-907, 1994.

21.

Winningham ML: Walking program forpeople with cancer: Getting started. CancerNurs 14:270-276, 1991.

22.

Dimeo FC: Effects of exercise on cancer-related fatigue. Cancer 15:92(6suppl):1689-1693, 2001.

23.

Winningham ML, MacVicar MG,Bondoc M, et al: Effect of aerobic exercise onbody weight and composition in patients withbreast cancer on adjuvant chemotherapy. OncolNurs Forum 16:683-689, 1989.