The standard treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT). This therapy is associated with a multitude of side effects that can impact quality of life. These include vasomotor complications (in particular, hot flushes), sexual dysfunction and gynecomastia, osteoporosis, metabolic syndrome, and depression. Additionally, ADT has been associated with neurocognitive deficits, thromboembolic disease, and cardiovascular disease, although the data regarding the latter associations are mixed. This article summarizes the key side effects associated with ADT and discusses strategies to optimize management.
Metastatic prostate cancer remains a global health challenge. Despite improvements in anticancer therapies, management of the disease is often a struggle to maintain a balance between preserving quality of life and extending survival. Charles Huggins and Andrew Schally laid the groundwork for establishing the critical role of antiandrogen therapies in the management of metastatic prostate cancer. Initially, androgen deprivation therapy (ADT) was achieved via orchiectomy, but by the mid-1980s, the approval of gonadotropin-releasing hormone (GnRH) agonists allowed for medical ADT. Intermittent ADT represents an option for patients with biochemically relapsed prostate cancer, but continuous ADT is the standard initial treatment for metastatic disease. While prolonged disease control can be achieved with this approach, use of ADT is associated with a wide range of side effects (Table) that may significantly reduce quality of life. In this article, we summarize the key side effects associated with ADT and highlight strategies to mitigate them.
Hot flushes are one of the most common and bothersome side effects associated with ADT. Up to 80% of patients undergoing treatment with GnRH agonists will experience hot flushes, with 27% of these patients reporting this symptom as the most significant adverse side effect. Hot flushes are described as an intense feeling of warmth, occasionally associated with nausea and night sweats. Many patients will achieve some improvement in symptom severity as their bodies acclimate to the low testosterone state, although some patients will not acclimate. Therapeutic management is largely extrapolated from studies in breast cancer patients receiving tamoxifen. Randomized clinical trials have demonstrated efficacy of gabapentin and venlafaxine; these agents may be used for this off-label indication in men receiving ADT.[5,6] Low-dose estrogen and progestins can also be considered, but the benefits of this option need to be weighed against the thromboembolic risk associated with estrogen use. Additionally, acupuncture has been shown to be of potential benefit. Conservative strategies to abort hot flushes include sleeping with an open window or drinking cold beverages. Lastly, regular exercise can help decrease frequency and severity of hot flushes; given the benefit of exercise for other ADT side effects and overall health, this recommendation is strongly encouraged. Overall, a stepwise approach is suggested for hot flush management, including exercise, conservative measures, use of venlafaxine or gabapentin, and lastly use of estrogen or progestins as needed, while weighing the potential risks vs benefits of each treatment option.
Sexual Dysfunction and Gynecomastia
Several studies have shown that treatment for clinically localized prostate cancer involving either radical prostatectomy, brachytherapy, or external beam radiotherapy (EBRT) can result in long-term erectile dysfunction.[9,10] Patients receiving neoadjuvant ADT with EBRT were found to have decreased frequency of erection, decreased overall sexual function, and an increase in frequency of hot flushes. In addition, loss of libido is a major consequence of ADT. The degree of erectile dysfunction for patients on ADT is impacted by pretreatment sexual function, as well as by changes in libido; in patients previously able to attain an erection, phosphodiesterase 5 inhibitors, intracavernosal injection therapy, vacuum-assisted devices, or other topical agents may be used. Given the complex interplay between physiology, psychology, stress, and emotion involved in sexual function, a referral to a psychology or counseling service with a focus on sexual health is recommended for interested patients and their partners.
Gynecomastia may arise in conditions of unopposed estrogen activity and can be distressing for cosmetic reasons or because of pain. It may occur with ADT; however, it is more problematic with antiandrogens (specifically at higher doses) due to the buildup of androgens and their consequent peripheral conversion to estrogen in breast tissue. Tamoxifen and breast irradiation are two treatment options; the former is more beneficial as primary prevention, whereas the latter may be of greater use following established gynecomastia.[12,13]
ADT is associated with significant changes in bone. Multiple studies have demonstrated that bone mineral density (BMD) is significantly reduced in men receiving ADT compared with controls. The risk of fracture increases with use of ADT and appears to be dose dependent. Prevention of skeletal-related events (SREs) has been evaluated in multiple randomized clinical trials for patients with nonmetastatic castration-sensitive prostate cancer (CSPC). One study demonstrated a significant decrease in BMD in men receiving ADT alone, while there was no significant change in those who received ADT plus pamidronate. In castration-resistant prostate cancer (CRPC) metastatic to bone, a randomized placebo-controlled trial found that zoledronic acid reduced SREs. Another phase III randomized clinical trial found denosumab to be more effective than zoledronic acid in preventing SREs. Interestingly, in contrast to men with metastatic CRPC, no benefit was seen from osteoclast inhibition in men with CSPC metastatic to bone.
Men who are about to start ADT should be evaluated for risk of osteoporosis, prior fractures, alcohol use, and prior (or current) glucocorticoid use. Serum vitamin D and baseline BMD may be checked to see if bisphosphonates are indicated, with periodic re-evaluation of BMD while on ADT. For all patients starting ADT, it is recommended that they supplement their diet with at least 1,000-mg oral calcium daily and 1,000 IU of vitamin D in an effort to preserve bone integrity and minimize losses; a referral to a registered dietician may further aid in refining both dietary and supplement recommendations. Lastly, an exercise program that includes resistance training and/or weight-bearing exercise is encouraged to further maintain bone strength.
A variety of metabolic changes have been observed with ADT, including weight gain, dyslipidemia, hyperglycemia, and sarcopenia. Weight gain, specifically, is a well-recognized side effect of ADT.[20-22] Retrospective studies have found that men on ADT for nonmetastatic prostate cancer had a median weight gain of 1 to 2 kg after 1 year of treatment. Similar changes in weight have been noted in the metastatic setting.[23-25] When more dramatic, weight gain can have major consequences in terms of both mental and cardiovascular health. A referral to a registered dietician may help with improving diet, while engagement in a structured and formal exercise program can help with reducing or maintaining weight. Many cancer centers offer such programs, and these should be suggested to interested or at-risk patients.
In addition, multiple studies have noted dyslipidemia and increased risk for metabolic syndrome with use of ADT.[26,27] Extrapolating that these changes are associated with increases in cardiovascular risk remains controversial. Loss of lean muscle mass and sarcopenic obesity have been described in several studies. A study of 39 men receiving ADT using CT measurements of the rectus, femoris, sartorius, and quadriceps muscles noted decreases in the cross-sectional area of these muscles. Given the importance of these muscles in gait and balance, studies have explored the association between ADT use and fall risk. One study noted a higher rate of falls in persons treated with ADT, with apparent persistent risk even after ADT is discontinued. Thus, judicious use of ADT and careful evaluation of frail patients and those at risk for complications are recommended when the need for treatment is questionable (eg, biochemical relapse with slowly rising prostate-specific antigen [PSA] levels).
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