Intermittent ADT in Prostate Cancer: A Step-by-Step Approach

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Introduction

Prostate cancer is the leading malignancy diagnosed in the U.S. and the second cause of cancer death in men, after lung cancer.¹ An estimated 240,890 new cases of prostate cancer are anticipated to occur during 2011, and an estimated 33,720 men will die of their disease.¹ Approximately 2.3 million men have prostate cancer; median age at diagnosis is 67 years and median age at death is 80 years.²


The increasing use of prostate-specific antigen (PSA) screening has resulted in most men being diagnosed with asymptomatic, clinically localized cancer.³ Patient age, general health, and tumor characteristics at diagnosis all guide initial treatment for prostate cancer. Based on Gleason score, PSA level, and stage, tumors may be treated with active surveillance, radical prostatectomy, or radiotherapy.³


For men with advanced prostate cancer, defined as PSA recurrence or metastatic disease, American Society of Clinical Oncology (ASCO) 2007 guidelines⁴ and National Comprehensive Cancer Network (NCCN) 2011 guidelines³ recommend luteinizing hormone-releasing hormone (LHRH) agonists or bilateral orchiectomy as first-line therapy. Timing of androgen deprivation therapy (ADT) administration in patients with advanced disease whose only evidence of cancer is a rising PSA may be influenced by PSA velocity, patient anxiety, and adverse events (AEs) associated with treatment.³

Intermittent ADT vs. continuous ADT may reduce AEs without affecting overall survival.³ Recent results from one large, phase 3 randomized trial suggest that treatment with intermittent ADT is noninferior to continuous ADT with significantly better quality of life.⁵ Long-term efficacy of intermittent ADT will be further delineated when results of another large intergroup phase 3 randomized trial are reported.


Androgen Deprivation In Prostate Cancer

The primary goal of ADT is pharmacologic suppression of gonadal testosterone production with medical castration and is achieved primarily with either LHRH analogues or antagonists.⁶ The use of these agents is considered standard of care for advanced, relapsing, and castration-resistant prostate cancer.⁷

In addition, ADT is used in prostate cancer as neoadjuvant or adjuvant treatment in men with locally advanced or high-risk disease undergoing external beam radiation therapy (EBRT);^6,8,9 as adjuvant treatment alone in those with high-risk features (such as extraprostatic extension or high Gleason grade) facing a high risk of recurrence after radical prostatectomy;¹⁰ and routinely in men with metastatic disease.³ Several phase 3 randomized trials have shown that concomitant use of ADT with EBRT can delay metastasis and prolong survival.^9,11

The use of nonsteroidal antiandrogens is based on the premise that adrenal androgens, which are not reduced by LHRH agonists or antagonists, may contribute to the progression of prostate cancer. It is generally agreed that these nonsteroidal antiandrogens are useful in blocking the testosterone flare associated with LHRH analogues. Maximum androgen blockade with nonsteroidal antiandrogens has resulted in a small but statistically significant survival advantage of <5% vs. LHRH monotherapy.¹²

However, quality of life is impaired with respect to sexuality, cognitive function, and thermoregulation when maximum androgen blockade is used.¹³ ASCO guidelines suggest that nonsteroidal antiandrogen monotherapy may be an alternative to castration and is more commonly used in Europe.¹⁴


According to NCCN guidelines, compared with castration alone, no benefit has been proven with combined androgen blockade (medical or surgical castration in combination with an antiandrogen) or triple-androgen blockade (i.e., with the 5-alpha reductase inhibitors finasteride or dutasteride, an antiandrogen, plus medical or surgical castration).³ ASCO guidelines suggest considering combined androgen blockade (i.e., the addition of an antiandrogen to medical or surgical castration), noting that survival—and AEs—are greater.¹⁴


LHRH agents indicated for palliative treatment of men with advanced prostate carcinoma are the gonadotropin-releasing hormone (GnRH) analogues goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin pamoate and the GnRH antagonist degarelix. Antiandrogens indicated for use in combination with LHRH agonists for treatment of metastatic prostate carcinoma are bicalutamide and flutamide; nilutamide is indicated in combination with surgical castration for treatment 
of metastatic prostate cancer (See 
Table below).


Testosterone flare, associated with the use of an initial LHRH agonist alone, can occur in more than 60% of patients.¹⁵ In men with overt metastases or at risk of developing symptoms such as testosterone flare, nonsteroidal antiandrogen therapy should precede or be co-administered with the LHRH agonist and continued in combination for at least 7 days.¹⁵ The GnRH antagonist suppresses androgen production without producing a testosterone surge and has earlier onset of action.¹⁶ It provides rapid and effective castration, which is important for patients with symptomatic metastatic disease as it avoids the flare seen with LHRH agonists.¹⁷ Toxicities of antiandrogen monotherapy include gynecomastia, breast pain, and liver toxicity.¹⁴


Receiving LHRH agonists for ex­tended periods may involve risk of AEs that increase with treatment duration.³ A few weeks after initiation of LHRH agonists, hot flushes, loss of libido, erectile dysfunction, and fatigue coincide with castration levels of testosterone and are commonly reported. Treatment for hot flushes includes low-dose estrogens, megestrol acetate, and cypro­terone acetate.¹⁸ Erectile dysfunction may be treated with phosphodiesterase inhibitors, vacuum devices, or intracavernous therapy; however, lack of libido limits patient enthusiasm for such treatments.¹⁹


Long-term AEs can include bone demineralization, resulting in reduced bone mineral density (BMD) and increased fracture risk,²⁰ anemia, muscle wasting, metabolic syndrome, and depression. It is also suggested that hormone resistance may develop.^6,21


In men with prostate cancer, GnRH agonists have significantly increased the risk for any fracture, hip fracture, and vertebral fractures.²² The relative increase in fracture risk, which can be assessed by the FRAX algorithm,²³ is 21% to 54%.^20,22,24 Many men receive inadequate evaluation and treatment for ADT-related osteoporosis.²⁵ Patients on long-term ADT should be considered for initial T-score and BMD measurement every 2 years if the initial T-score is less than -1.0, or annually if the T-score is between -1.0 and -2.5.⁷ To mitigate adverse effects of ADT on bone, recommended strategies are supplemental calcium (1200 mg daily), vitamin D³ (800-1000 IU daily) for all men aged 50 years and older,³ to slow bone loss. Decreased alcohol consumption, resistance exercises, and smoking cessation are also advised.¹⁹ In men with significant fracture risk on ADT, zoledronic acid 
(4 mg IV annually) and alendronate 
(70 mg PO weekly) can be used.³


Diabetes and cardiovascular disease are common in older men,³ and use of ADT may increase cardiovascular disease risk and/or cause a pattern of metabolic alteration by increasing body weight and reducing insulin sensitivity, resulting in dyslipidemia.²⁶ Therefore, benefits and risks of LHRH agonists should be carefully weighed. Organizations such as the NCCN recommend that patients receiving ADT should be screened for cardiovascular disease³ and undergo periodic blood glucose and/or glycosylated hemoglobin monitoring.^7,26


From the September 01, 2011 Issue of Renal and Urology News