NCCN: Continuing Education
Accreditation Statement
This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.
NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.
This activity is approved for 1.0 contact hour. Approval as a provider refers to recognition of educational activities only and does not imply ANCC Commission on Accreditation approval or endorsement of any product. Accredited status does not imply endorsement by the provider of the education activity (NCCN). Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the post-test with a 70% minimum passing score and complete the evaluation at http://education.nccn.org/node/2399; and 4) view/print certificate.
Release date: September 5, 2012; Expiration date: September 5, 2013.
Learning Objectives
Upon completion of this activity, participants will be able to:
Select the most appropriate patients for ADT according to established indications.
Describe methods to mitigate side effects in order to improve quality of life for men with prostate cancer.
Since Huggins and Hodges1 first recognized the androgen dependence of prostate cancer in 1940, androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic prostate cancer. ADT is also commonly used in combination with external beam radiation therapy (EBRT) for high-risk or locally advanced disease2–4 for durations of 6 months to 3 years. Several large multi-institutional randomized trials have shown survival benefit when ADT is combined with conventional EBRT under these circumstances. Apart from these well-established indications, ADT is commonly used in other scenarios with far less supporting evidence. It may be prescribed as primary treatment in nonmetastatic disease, especially in elderly patients, or in conjunction with brachytherapy. As prostate cancer is the most common cancer in men in the developed world, this wide range of indications exposes ever-increasing numbers of men to the side effects of ADT.5
Adverse Effects of Androgen Deprivation
The side effects of ADT are well documented in the literature. Initially, the most obvious symptoms of sexual dysfunction, loss of libido, and hot flashes were emphasized, but as experience grew the effects of ADT on other systems became apparent. Men on ADT run the risk of developing osteoporosis and have a 23% greater incidence of clinical fractures. They have a tendency to develop obesity, insulin resistance, and diabetes. Alterations in lipids and cardiovascular disease contribute to a 17% increase in cardiovascular-related mortality. Fatigue may be related to anemia, decreased muscle mass, and depression. Cognitive dysfunction has also been documented.6–12
The impact of these adverse effects varies from patient to patient but tends to increase with the duration of treatment, as stated in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer (to view the most recent version, visit NCCN.org).6
The recently recognized metabolic syndrome, characterized by central obesity, elevated triglycerides, reduced high-density lipoproteins, elevated blood pressure, and elevated fasting glucose,13 is present in more than 50% of men with prostate cancer undergoing long-term ADT compared with 22% not receiving ADT. Metabolic syndrome may contribute to all-cause mortality and may also be associated with a shorter time to disease progression. In an observational study of a population-based cohort of 73,196 patients, Keating et al9 found that ADT was associated with a 44% increased risk of diabetes and a 16% increase in myocardial infarction and sudden cardiac death. Although Tsai et al14 also reported that cardiovascular deaths were 2.6 times more common in men on ADT, not all studies concur. A recently published meta-analysis of 4141 patients from 8 randomized trials found no association between ADT and increased cardiovascular death.15 Stratification according to preexisting cardiovascular comorbidity may be important when considering the influence of ADT on cardiovascular death.
Minimizing Exposure to ADT
Low-Risk Patients
No level 1 evidence supports ADT as primary treatment for low-risk prostate cancer, either alone or combined with EBRT. In 2011, Jones et al16 published the results of RTOG 9408, which randomized 1987 men with T1 to T2 disease to either 66 Gy of EBRT alone or combined with 4 months of ADT. At a median follow-up of 9.1 years, the addition of short-term ADT did not improve 10-year overall survival or decrease disease-specific mortality in low-risk disease (Table 1).
In elderly patients with localized disease, ADT has been used as primary therapy as an alternative to surgery, radiation, or watchful waiting. A population-based cohort of 19,271 men aged 66 years or older with T1 to T2 prostate cancer was followed for all-cause and prostate cancer-specific mortality. Among those with localized prostate cancer (median age, 77 years), 41% received ADT as monotherapy, whereas the rest were managed conservatively with no surgery, radiation, or ADT in the first 180 days after diagnosis. During the median follow-up of 81 months, 1560 prostate cancer deaths and 11,045 deaths from all causes occurred. Primary ADT was associated with lower 10-year prostate cancer–specific survival (80.1% vs. 82.6%; hazard ratio [HR], 1.17; 95% CI, 1.03–1.33) and similar 10-year overall survival (30.2% vs. 30.3%; HR, 1.00; 95% CI, 0.96–1.05) compared with conservative management. Although ADT improved disease-specific survival in men with poorly differentiated cancer, it had no impact on overall survival even in this subset. Primary ADT in elderly men with localized prostate cancer is not associated with improved survival when compared with watchful waiting.17
Summary of Evidence for ADT According to Risk Categories
ADT is often used to reduce prostate volume before prostate brachytherapy. Although a short course of ADT is usually sufficient (3–6 months), hot flushes and impotence affect quality of life18 and persist after therapy ceases. Beyer et al19 reported a deleterious effect on overall survival for the 20% of 2378 patients who received ADT for downsizing before prostate brachytherapy. At follow-up ranging to 12.6 years (median, 4.1 years), overall survival decreased with increasing age, increasing Gleason score, and ADT use. Other approaches, such as oral antiandrogens and/or 5-α reductase inhibitors, are associated with less sexual toxicity, but prostate volume reduction may be less.
Intermediate-Risk Patients
The role of ADT in the intermediate-risk group is controversial, and is based largely on extrapolation of data from studies in which intermediate- and high-risk patients are combined and treated with conventional EBRT. No prospective randomized data focus exclusively on the use of ADT in an intermediate-risk setting. Likewise, no prospective, randomized data define the role of ADT in the setting of dose-escalated radiotherapy.
In RTOG 9408, analysis of the intermediate-risk group showed that the addition of short-term ADT to EBRT increased 10-year overall survival from 54% to 61% (P = .03) and reduced disease-specific mortality from 10% to 3% (P < .01). Another study by D’Amico et al20 randomized 206 men with intermediate- to high-risk disease to EBRT (70 Gy) with or without 6 months of ADT and found benefits in overall survival (88% vs. 78%; P = .04), cause-specific survival, and biochemical control, but did not stratify by risk categories. However, both of these trials used conventional EBRT doses of 66.6 to 70 Gy. Results should not be extrapolated to patients treated using optimal-dose escalation with EBRT doses greater than 80 Gy or combined with brachytherapy. Whether the same benefits will be seen with optimal dose escalation is unknown; in the absence of pre-existing subclinical micrometastatic disease, a high enough radiation dose to the prostate may obviate the need for ADT.
Ample evidence shows the benefits of dose-escalated radiotherapy in terms of biochemical disease-free survival, local eradication of tumor, and improved freedom from distant metastases through prevention of a second wave of metastatic seeding from uncontrolled recurrent local tumor. Posttreatment prostate biopsies are more frequently negative with escalated doses of radiation, and this not only correlates with freedom from biochemical failure (bNED) but also is the strongest predictor of freedom from distant metastases and cancer death.21 Eradicating the primary tumor is essential to prevent ultimate death from subsequent metastatic disease. Multiple randomized trials of dose escalation with mature follow-up have also shown reduction in biochemical and clinical failure rates comparing 70 with 78 Gy,22 70.2 with 79.2 Gy,23 and 68 with 78 Gy.24
Brachytherapy as a form of dose escalation achieves biologically effective doses much higher than can be achieved with EBRT. Deutsch et al25 reported on a retrospective comparison of biochemical outcomes using an ultra-high dose of conventionally fractionated intensity-modulated radiation therapy (IMRT; 86.4 Gy; n = 470) versus a lower dose of IMRT (50.4 Gy) combined with high-dose-rate brachytherapy (21 Gy/3 fractions; n = 160). The 5-year actuarial prostate-specific antigen (PSA) relapse-free survival was improved for patients treated with the high-dose-rate boost versus IMRT alone, with the most significant benefit being seen for intermediate-risk patients (98% vs. 84%; P < .001).
No prospective randomized trials specifically address the issue of ADT in combination with brachytherapy for intermediate-risk disease, but retrospective data suggest at best an equivocal effect.19,26 In 2010, Stock et al26 analyzed 432 patients treated with optimal dose escalation using combination of EBRT and brachytherapy, 350 of whom received ADT. With a median follow-up of 56 months, ADT did not impact on the 8-year biochemical failure-free rate.
The role of ADT combined with high-dose radiotherapy remains to be defined. Retrospective data suggest a lesser role and do not show a survival benefit. A subset analysis of 883 patients from the RTOG 9406 phase I/II clinical trial of dose escalation evaluated the effect on biochemical and disease-free survival rates from the addition of ADT to dose-escalated radiotherapy (mean dose, 78.5 Gy). After stratifying by risk groups, no difference in bNED or disease-free survival was observed, although in high-risk patients the difference approached significance.27 In 1260 patients with intermediate- to high-risk prostate cancer, Martinez et al28 reported that the addition of a short course of ADT to EBRT and a brachytherapy boost did not improve overall survival, disease-free survival, biochemical control, or local control. In fact, the addition of ADT in this retrospective study correlated with higher rates of metastases and cancer-related deaths. The phase III RTOG 0815 trial is currently addressing the role of ADT with dose escalation through randomizing intermediate-risk patients to dose escalation with or without 6 months of ADT.
High-Risk Patients
The benefit of ADT combined with conventional EBRT in high-risk disease has been established in several randomized trials2–4,29–31 showing improved biochemical, local, and distant control and disease-free and overall survival (Table 2). The EORTC published the 10-year results of a randomized study of 415 patients that assessed the benefit of the addition of 3 years of ADT to conventional EBRT and showed an increase in overall survival (39.8% vs. 58.1%; P = .0004).3 Similarly, Denham et al31 randomized 818 patients to either radiotherapy alone or combined with 3 or 6 months of ADT. The best outcome was achieved with 6 months of ADT. The 10-year follow-up of RTOG 92-02 established that long-term ADT (2 or 3 years) is superior to short-term (4 months).2 RTOG 85-31 showed improved survival for adjuvant ADT after EBRT rather than ADT reserved for relapse.29
However, all of these studies used conventional EBRT doses of 65 to 70 Gy; the potential benefit of ADT combined with an optimal radiation dose has not been defined. Whether an intermediate duration such as 9 to 12 months would provide equivalent benefit remains to be proven, although Stock et al32 reported consistently excellent results in high-risk patients treated with “trimodality” therapy using 9 months of ADT and achieving optimal dose escalation with a combination of EBRT and a brachytherapy boost.
Recurrent Disease
Patients with a rising PSA after definitive treatment are often asymptomatic and have no clinical evidence of disease. Although early intervention increases both cost and side effects, delaying the start of ADT may increase the risk of serious morbidity, such as spinal cord compression.33 Patients with adverse factors such as high Gleason score,34 younger age,35 and short PSA doubling time34,35 should be considered for earlier ADT rather than deferred. Patients without any of the above factors and who have shown a previous response to ADT30 may not require immediate intervention. Selection for deferred ADT may be clarified by 2 recently closed randomized clinical trials: TOAD (Timing of Androgen Deprivation), sponsored by the Trans Tasman Radiation Oncology Group, and ELAAT (Early versus Late Androgen Ablation Trial) by the Ontario Clinical Oncology Group. Both trials closed prematurely but are in the follow-up period and will combine their data on more than 350 patients.
Summary of Level 1 Evidence for Androgen Deprivation Therapy in High-Risk Patients
Once ADT has been initiated, an intermittent approach should be considered. Intermittent androgen deprivation (IAD) is defined as cycles of ADT followed by periods of testosterone recovery. It was first described in the pre-PSA era in 1986 by Klotz et al,36 with cycles defined by symptomatic progression. Laboratory data using androgen-dependent cell lines, such as the Shionogi mouse mammary tumor and the LNCaP cell line, have shown the ability of androgen-dependent cells to undergo repeated cycles of apoptosis secondary to cyclical hormonal withdrawal.37,38 Results of clinical phase II studies have shown feasibility and improvement in quality of life with reduced side effects.39–42 Two international phase III trials described in the following paragraph have been reported recently: one for biochemical recurrence and the other for metastatic disease.
The National Cancer Institute of Canada launched PR-7 (SWOG JPR-7) in 1999 for patients with a rising PSA after definitive radiotherapy in the absence of metastases, administered as either primary treatment or postsurgical salvage. The trial randomized 690 patients to IAD (8 months of treatment with PSA-determined off-treatment periods) and 696 to continuous ADT. The primary end point was overall survival. Preliminary results were reported at the 2011 ASCO Annual Meeting. With a median follow up of 6.9 years, IAD was found to be noninferior to continuous ADT with respect to overall survival. Benefits were observed in quality of life and the authors concluded that intermittent therapy should be considered in the nonmetastatic setting for men with a rising PSA after primary or postprostatectomy salvage EBRT.43
Metastatic Disease
For the past 7 decades, ADT has been widely used for systemic management of metastatic prostate cancer.1 Although the standard approach is continuous ADT until castration resistance is manifested, the role of intermittent ADT is also being studied. The SWOG 9346 randomized trial of continuous versus intermittent ADT for metastatic prostate cancer closed in 2008. Of 3040 accrued patients, only 1535 were eligible for randomization, having achieved a nadir PSA of less than 4 ng/mL at 7 months. Results were presented at ASCO 2012.44 At a median follow-up of 9.2 years, median overall survival for continuous treatment was 5.8 versus 5.1 years for intermittent (HR for intermittent vs. continuous: 1.09; 95% CI, 0.95–1.24), with rates of grade 3 and 4 adverse events at 30.3% for intermittent and 32.6% for continuous therapy. Intermittent therapy could not be declared as noninferior to continuous.
Mitigating the Side Effects of ADT
The most important strategy to reduce the burden of ADT toxicity is to limit its use to situations where it is clearly indicated. When use of ADT is supported by level 1 evidence, then several strategies can potentially reduce the adverse consequences.
Optimization Before Treatment
The constellation of symptoms associated with ADT should be explained to patients before initiating treatment. Unfortunately, lifestyle recommendations, such as smoking cessation, adopting a healthy diet, and undertaking regular exercise, are offered infrequently. Strategies for symptom management help patients cope and reduce distress,45 although ongoing support may be required to maintain these changes.46 The NCCN Guidelines for Prostate Cancer include strategies on risk reduction, such as those outlined in the following sections (to view the most recent version of these guidelines, visit NCCN.org).6
Monitoring of serum lipid profiles is recommended both before and during treatment; statin drugs are indicated for dyslipidemia.47 Blood pressure should be monitored before and after ADT initiation, and HbA1c and fasting blood glucose levels should also be monitored in patients with diabetes or obesity. The role of the oral biguanide metformin is currently being studied, although preliminary data suggest that metformin together with lifestyle changes may abrogate ADT-induced metabolic syndrome.48 The antineoplastic effect of metformin is also being investigated.
Nutritional Counseling
As weight gain and endocrine dysfunction are common while on ADT, nutritional counseling and diet management are recommended.
Exercise Program
Exercise is important in both weight control and the prevention of bone loss. Resistance exercise develops and maintains skeletal muscle strength and bulk, providing significant functional benefits and improvement in overall health and well-being.45 In a randomized controlled trial, regular sessions of both resistance and aerobic exercise mitigated fatigue compared with usual care.49 A recently published study randomized men on ADT to a 6-month program of metformin, a low-glycemic-index diet, and exercise. Significant reductions were seen in abdominal girth, weight, body mass index, and systolic blood pressure in the intervention arm compared with controls. Biochemical markers of insulin resistance did not differ significantly. The potential benefits of metformin and lifestyle changes in ADT-treated men are being further investigated; effects on overall survival remain to be determined.48
Cognitive Status and Mental Health
A decrease in attention and memory was reported in the ADT arm of a randomized trial10 and cognitive changes have been described during intermittent ADT.11 Although not all studies are in agreement50 and larger sample sizes and longer follow-up are required, patients should nonetheless be advised concerning potential effects on cognitive function. A mental health history should be obtained before initiating ADT, and monitoring for the onset of depressive symptoms is suggested.
Bone Density
The National Osteoporosis Foundation guidelines recommend supplemental calcium (1200 mg daily) and vitamin D (800–1000 IU daily) for all men older than 50 years, and additional treatment for those at higher risk. Bisphosphonates increase bone mineral density and reduce the risk of fracture.51–53 Currently, treatment with either zoledronic acid (4 mg intravenously annually) or alendronate (70 mg orally weekly) is recommended when the absolute fracture risk is significant.6 Denosumab, a human monoclonal antibody against RANK (receptor activator of nuclear factor κB) ligand, has been shown in a phase III randomized trial to increase bone mineral density and reduce new vertebral fractures among men receiving ADT for nonmetastatic prostate cancer.54 When compared with zoledronic acid, denosumab was superior in preventing skeletal-related events. The choice of agent may depend on underlying comorbidities, whether the patient has already received zoledronic acid, and cost considerations.6
Conclusions
The hormonal dependence of prostate cancer provides the option of ADT as a comparatively nontoxic systemic treatment. However, the side effects of castration are not trivial and ADT should be used rationally and only when indicated. Limiting exposure to ADT and systematic efforts to reduce side effects will benefit the quality of life of many men.
The authors (Miren Gaztañaga, MD, and Juanita Crook, MD, FRCPC) have disclosed that they have no financial interests, arrangements, commercial interest conflicts, or affiliations with the manufacturers of any products discussed in this article or their competitors.
EDITOR
Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network.
Ms. Green has disclosed that she has no relevant financial relationships.
CE AUTHORS
Nicole B. Fair, BS, Manager, Continuing Education and Grants
Ms. Fair has disclosed that she has no relevant financial relationships.
Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations
Ms. Gregory has disclosed that she has no relevant financial relationships.
References
- 1↑
Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 2002;167(2 Pt 2):948–951; discussion 952.
- 2↑
Horwitz EM, Bae K, Hanks GE et al.. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:2497–2504.
- 3↑
Bolla M, Van Tienhoven G, Warde P et al.. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11:1066–1073.
- 4↑
Roach M III, Bae K, Speight J et al.. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol 2008;26:585–591.
- 5↑
Cooperberg MR, Grossfeld GD, Lubeck DP, Carroll PR. National practice patterns and time trends in androgen ablation for localized prostate cancer. J Natl Cancer Inst 2003;95:981–989.
- 7
Spry NA, Galvao DA, Davies R et al.. Long-term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33-month observational study. BJU Int 2009;104:806–812.
- 8
Higano C, Shields A, Wood N et al.. Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 2004;64:1182–1186.
- 9↑
Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448–4456.
- 10↑
Green HJ, Pakenham KI, Headley BC et al.. Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int 2002;90:427–432.
- 11↑
Cherrier MM, Rose AL, Higano C. The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. J Urol 2003;170:1808–1811.
- 12↑
D’Amico AV, Denham JW, Crook J et al.. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 2007;25:2420–2425.
- 13↑
Alberti KG, Eckel RH, Grundy SM et al.. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–1645.
- 14↑
Tsai HK, D’Amico AV, Sadetsky N et al.. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99:1516–1524.
- 15↑
Nguyen PL, Je Y, Schutz FA et al.. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011;306:2359–2366.
- 16↑
Jones CU, Hunt D, McGowan DG et al.. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 2011;365:107–118.
- 17↑
Lu-Yao GL, Albertsen PC, Moore DF et al.. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 2008;300:173–181.
- 18↑
Sanda MG, Dunn RL, Michalski J et al.. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250–1261.
- 19↑
Beyer DC, McKeough T, Thomas T. Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005;61:1299–1305.
- 20↑
D’Amico AV, Manola J, Loffredo M 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;292:821–827.
- 21↑
Zelefsky MJ, Reuter VE, Fuks Z et al.. Influence of local tumor control on distant metastases and cancer related mortality after external beam radiotherapy for prostate cancer. J Urol 2008;179:1368–1373; discussion 1373.
- 22↑
Kuban DA, Tucker SL, Dong L et al.. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70:67–74.
- 23↑
Zietman AL, DeSilvio ML, Slater JD et al.. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005;294:1233–1239.
- 24↑
Peeters ST, Heemsbergen WD, Koper PC et al.. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006;24:1990–1996.
- 25↑
Deutsch I, Zelefsky MJ, Zhang Z et al.. Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT. Brachytherapy 2010;9:313–318.
- 26↑
Stock RG, Yalamanchi S, Hall SJ, Stone NN. Impact of hormonal therapy on intermediate risk prostate cancer treated with combination brachytherapy and external beam irradiation. J Urol 2010;183:546–550.
- 27↑
Valicenti RK, Bae K, Michalski J et al.. Does hormone therapy reduce disease recurrence in prostate cancer patients receiving dose-escalated radiation therapy? An analysis of Radiation Therapy Oncology Group 94-06. Int J Radiat Oncol Biol Phys 2011;79:1323–1329.
- 28↑
Martinez AA, Demanes DJ, Galalae R et al.. Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime. Int J Radiat Oncol Biol Phys 2005;62:1322–1331.
- 29↑
Pilepich MV, Winter K, Lawton CA et al.. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285–1290.
- 30↑
D’Amico AV, Moul JW, Carroll PR et al.. Intermediate end point for prostate cancer-specific mortality following salvage hormonal therapy for prostate-specific antigen failure. J Natl Cancer Inst 2004;96:509–515.
- 31↑
Denham JW, Steigler A, Lamb DS et al.. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 2005;6:841–850.
- 32↑
Stock RG, Ho A, Cesaretti JA, Stone NN. Changing the patterns of failure for high-risk prostate cancer patients by optimizing local control. Int J Radiat Oncol Biol Phys 2006;66:389–394.
- 33↑
Loblaw DA, Virgo KS, Nam R et al.. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007;25:1596–1605.
- 34↑
Pound CR, Partin AW, Eisenberger MA et al.. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–1597.
- 35↑
D’Amico AV, Kantoff P, Loffredo M et al.. Predictors of mortality after prostate-specific antigen failure. Int J Radiat Oncol Biol Phys 2006;65:656–660.
- 36↑
Klotz LH, Herr HW, Morse MJ, Whitmore WF Jr. Intermittent endocrine therapy for advanced prostate cancer. Cancer 1986;58:2546–2550.
- 37↑
Bruchovsky N, Rennie PS, Coldman AJ et al.. Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res 1990;50:2275–2282.
- 38↑
Sato N, Gleave ME, Bruchovsky N et al.. Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. J Steroid Biochem Mol Biol 1996;58:139–146.
- 39↑
Goldenberg SL, Gleave ME, Taylor D, Bruchovsky N. Clinical experience with intermittent androgen suppression in prostate cancer: minimum of 3 years’ follow-up. Mol Urol 1999;3:287–292.
- 40
Higano CS, Ellis W, Russell K, Lange PH. Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 1996;48:800–804.
- 41
Malone S, Perry G, Eapen L et al.. Mature results of the Ottawa phase II study of intermittent androgen-suppression therapy in prostate cancer: clinical predictors of outcome. Int J Radiat Oncol Biol Phys 2007;68:699–706.
- 42↑
Bouchot O, Lenormand L, Karam G et al.. Intermittent androgen suppression in the treatment of metastatic prostate cancer. Eur Urol 2000;38:543–549.
- 43↑
Crook JM, Malone S, Horwitz E et al.. A phase III randomized trial of intermittent vs. continuous androgen suppression for PSA progression after radical therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013) [abstract]. J Clin Oncol 2011; 29(Suppl):Abstract 4514.
- 44↑
Hussain M, Tangen CM, Higano CS et al.. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): results of S9346 (INT-0162), an international phase III trial [abstract]. J Clin Oncol 2012;30(Suppl):Abstract 4.
- 45↑
Lebret T, Coloby P, Descotes JL et al.. Educational tool-kit on diet and exercise: survey of prostate cancer patients about to receive androgen deprivation therapy. Urology 2010;76:1434–1439.
- 46↑
Moyad MA. Promoting general health during androgen deprivation therapy (ADT): a rapid 10-step review for your patients. Urol Oncol 2005;23:56–64.
- 47↑
Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 2003;61(2 Suppl 1):32–38.
- 48↑
Nobes JP, Langley SE, Klopper T et al.. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int 2011;109:1495–1502.
- 49↑
Segal RJ, Reid RD, Courneya KS et al.. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. J Clin Oncol 2009;27:344–351.
- 50↑
Alibhai SM, Breunis H, Timilshina N et al.. Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer. J Clin Oncol 2010;28:5030–5037.
- 51↑
Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med 2007;146:416–424.
- 52
Michaelson MD, Kaufman DS, Lee H et al.. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 2007;25:1038–1042.
- 53↑
Smith MR, Eastham J, Gleason DM et al.. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003;169:2008–2012.
- 54↑
Smith MR, Egerdie B, Hernandez Toriz N et al.. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361:745–755.
- 55
Stock RG, Cesaretti JA, Hall SJ, Stone NN. Outcomes for patients with high-grade prostate cancer treated with a combination of brachytherapy, external beam radiotherapy and hormonal therapy. BJU Int 2009;104:1631–1636.
- 56
Bolla M, de Reijke TM, Van Tienhoven G et al.. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360:2516–2527.
