madman
Super Moderator
Testosterone Therapy in Advanced Prostate Cancer (2022)
Emily Chedrawe, * Aditya Sathe, Josh White, Jesse Ory, and Ranjith Ramasamy
Abstract
Androgen deprivation therapy is a mainstay of advanced prostate cancer (PCa) but the resulting low testosterone levels leave men susceptible to a multitude of adverse effects. These can include vasomotor symptoms, reduced sexual desire and performance, and mood changes. Testosterone therapy (TTh) in advanced PCa has historically been contraindicated since Huggins and Hodges reported that testosterone activates PCa. Although TTh has been demonstrated to be safe in patients who have undergone treatment for localized PCa, there is extremely limited evidence of its safety in advanced PCa. Despite the lack of evidence, some men with advanced PCa still inquire about TTh, and recent publications have described its use. In this article, we review the potential implications of TTh in men with advanced PCa, defined here as biochemical recurrence after localized therapy or metastatic PCa that is either hormone-sensitive or castration-resistant.
Introduction
Testosterone and its relationship with prostate cancer (PCa) progression were first implicated by Drs. Charles Huggins and Clarence Hodges in 1941.1 Testosterone has since frequently been suggested to fuel PCa. Researchers have since found that the relationship between androgens and PCa is more complicated, and likely not linear.2 For instance, men with the lowest levels of testosterone were found to be at increased risk of biopsy-proven PCa compared with other hypogonadal men.3 Furthermore, hypogonadal men who are on testosterone do not appear to have a higher risk of de novo PCa.4 And, in men with localized PCa and curative treatment, multiple studies have shown that giving testosterone therapy (TTh) does not appear to increase the risk of disease progression or recurrence.5–7
Although the U.S. Food and Drug Administration maintains the warning that androgens may increase the risk of PCa and lists known or suspected carcinoma of the prostate as a contraindication, the American Urological Association (AUA) provides a strong recommendation that patients should be informed that there is a lack of evidence to support the previously believed theory that TTh is linked to the development of PCa.8 A Canadian Survey of Urologists found a majority of physicians consider TTh safe in men who underwent radical prostatectomy, radiation therapy, brachytherapy at 96%, 84%, and 86%, and 65% believe it is safe for men on active surveillance.9
Although attitudes regarding the safety of TTh and localized PCa have changed recently, this survey suggests that urologists believe TTh may be less safe in men with PCa with prostate in situ. The use of TTh in advanced PCa, defined as biochemical recurrence after localized therapy (BCR) or metastatic PCa that is either hormone-sensitive (mHSPC) or castration-resistant (mCRPC), is a much more controversial topic and not recommended by current guidelines.9
Nearly half of all men with advanced PCa report high levels of distress and poor quality of life (QOL).10 Low sexuality and hypogonadal symptoms, a consequence of primary treatments and androgen deprivation therapy (ADT), is consistent drivers of poor life satisfaction.11,12 When compared with individuals with localized PCa, those with advanced disease on ADT consistently demonstrate greater severity of sexual dysfunction, hot flashes, low energy, and weight gain.11 Furthermore, men with advanced disease or on ADT are less likely to be offered interventions for sexual dysfunction.11 However, it is unclear whether or not using testosterone in advanced PCa functions the same way as using TTh for men with localized PCa.
Scarce literature is present regarding TTh and advanced PCa. Few researchers have explored this topic since Fowler and Whitmore’s study from 1981 showing 45 out of 67 men with metastatic PCa had unfavorable responses to exogenous testosterone and that the response occurred rapidly within 30 days.13 The safety of TTh in this population is unknown, and by current standards is considered unsafe. Despite this, a research group from Boston recently published a study investigating the safety of TTh in advanced PCa in a cohort of 22 men.12 Our objective is to review the use of TTh in advanced PCa, its implications, and the potential issues of hypogonadism in this disease state.
*Impact of Low Testosterone and Hypogonadal Symptoms in Patients on ADT
*Biochemical Differences of Advanced PCa That Alter Androgen Response
*What Are the Known Clinical Risks and Benefits of TTh in Patients with Advanced PCa?
Conclusion
Given the current understanding of advanced PCa response to androgens, the importance of ADT in PCa treatment, and morbidity and mortality associated with using TTh in advanced PCa, the potential risks of adding TTh in this disease state are significant. Despite this, the impact of hypogonadism on QOL in this cohort is significant, and therapies with fewer side effects or safe treatment options are needed. As newer drugs for advanced PCa develop, we must be cautious not to minimize the importance of QOL in the pursuit of improved survival outcomes. Prospective observational studies in each subtype of advanced PCa would be needed to accurately outline the safety and risks of TTh in this cohort
Nonetheless, a subset of patients may have alternative goals of care and are willing to take these risks for possible improvements in vigor, sexuality, and mood. Alternatively, we have outlined a number of potentially safer strategies, such as intermittent ADT, BAT, and short-acting ADT with relugolix, which could improve hypogonadal symptoms without compromising the morbidity and mortality of advanced PCa. Ultimately, considering our current understanding, TTh has the potential to significantly worsen the prognosis for patients with advanced PCa and is contraindicated for this population. Physicians should continue to provide education for patients that is sufficient for them to make their own decisions.
Emily Chedrawe, * Aditya Sathe, Josh White, Jesse Ory, and Ranjith Ramasamy
Abstract
Androgen deprivation therapy is a mainstay of advanced prostate cancer (PCa) but the resulting low testosterone levels leave men susceptible to a multitude of adverse effects. These can include vasomotor symptoms, reduced sexual desire and performance, and mood changes. Testosterone therapy (TTh) in advanced PCa has historically been contraindicated since Huggins and Hodges reported that testosterone activates PCa. Although TTh has been demonstrated to be safe in patients who have undergone treatment for localized PCa, there is extremely limited evidence of its safety in advanced PCa. Despite the lack of evidence, some men with advanced PCa still inquire about TTh, and recent publications have described its use. In this article, we review the potential implications of TTh in men with advanced PCa, defined here as biochemical recurrence after localized therapy or metastatic PCa that is either hormone-sensitive or castration-resistant.
Introduction
Testosterone and its relationship with prostate cancer (PCa) progression were first implicated by Drs. Charles Huggins and Clarence Hodges in 1941.1 Testosterone has since frequently been suggested to fuel PCa. Researchers have since found that the relationship between androgens and PCa is more complicated, and likely not linear.2 For instance, men with the lowest levels of testosterone were found to be at increased risk of biopsy-proven PCa compared with other hypogonadal men.3 Furthermore, hypogonadal men who are on testosterone do not appear to have a higher risk of de novo PCa.4 And, in men with localized PCa and curative treatment, multiple studies have shown that giving testosterone therapy (TTh) does not appear to increase the risk of disease progression or recurrence.5–7
Although the U.S. Food and Drug Administration maintains the warning that androgens may increase the risk of PCa and lists known or suspected carcinoma of the prostate as a contraindication, the American Urological Association (AUA) provides a strong recommendation that patients should be informed that there is a lack of evidence to support the previously believed theory that TTh is linked to the development of PCa.8 A Canadian Survey of Urologists found a majority of physicians consider TTh safe in men who underwent radical prostatectomy, radiation therapy, brachytherapy at 96%, 84%, and 86%, and 65% believe it is safe for men on active surveillance.9
Although attitudes regarding the safety of TTh and localized PCa have changed recently, this survey suggests that urologists believe TTh may be less safe in men with PCa with prostate in situ. The use of TTh in advanced PCa, defined as biochemical recurrence after localized therapy (BCR) or metastatic PCa that is either hormone-sensitive (mHSPC) or castration-resistant (mCRPC), is a much more controversial topic and not recommended by current guidelines.9
Nearly half of all men with advanced PCa report high levels of distress and poor quality of life (QOL).10 Low sexuality and hypogonadal symptoms, a consequence of primary treatments and androgen deprivation therapy (ADT), is consistent drivers of poor life satisfaction.11,12 When compared with individuals with localized PCa, those with advanced disease on ADT consistently demonstrate greater severity of sexual dysfunction, hot flashes, low energy, and weight gain.11 Furthermore, men with advanced disease or on ADT are less likely to be offered interventions for sexual dysfunction.11 However, it is unclear whether or not using testosterone in advanced PCa functions the same way as using TTh for men with localized PCa.
Scarce literature is present regarding TTh and advanced PCa. Few researchers have explored this topic since Fowler and Whitmore’s study from 1981 showing 45 out of 67 men with metastatic PCa had unfavorable responses to exogenous testosterone and that the response occurred rapidly within 30 days.13 The safety of TTh in this population is unknown, and by current standards is considered unsafe. Despite this, a research group from Boston recently published a study investigating the safety of TTh in advanced PCa in a cohort of 22 men.12 Our objective is to review the use of TTh in advanced PCa, its implications, and the potential issues of hypogonadism in this disease state.
*Impact of Low Testosterone and Hypogonadal Symptoms in Patients on ADT
*Biochemical Differences of Advanced PCa That Alter Androgen Response
*What Are the Known Clinical Risks and Benefits of TTh in Patients with Advanced PCa?
Conclusion
Given the current understanding of advanced PCa response to androgens, the importance of ADT in PCa treatment, and morbidity and mortality associated with using TTh in advanced PCa, the potential risks of adding TTh in this disease state are significant. Despite this, the impact of hypogonadism on QOL in this cohort is significant, and therapies with fewer side effects or safe treatment options are needed. As newer drugs for advanced PCa develop, we must be cautious not to minimize the importance of QOL in the pursuit of improved survival outcomes. Prospective observational studies in each subtype of advanced PCa would be needed to accurately outline the safety and risks of TTh in this cohort
Nonetheless, a subset of patients may have alternative goals of care and are willing to take these risks for possible improvements in vigor, sexuality, and mood. Alternatively, we have outlined a number of potentially safer strategies, such as intermittent ADT, BAT, and short-acting ADT with relugolix, which could improve hypogonadal symptoms without compromising the morbidity and mortality of advanced PCa. Ultimately, considering our current understanding, TTh has the potential to significantly worsen the prognosis for patients with advanced PCa and is contraindicated for this population. Physicians should continue to provide education for patients that is sufficient for them to make their own decisions.
