madman
Super Moderator
Abstract
Introduction: Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET).
Methods: We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed.
Results: Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. The median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture.
Conclusions: These initial observations indicate TTh was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.
Introduction
The diagnosis of prostate cancer (PCa) has been considered an absolute contraindication for testosterone (T) therapy (TTh) for decades, based on the belief that TTh ‘‘activates’’ PCa growth, first asserted by Huggins and Hodges.1 In 1981, Fowler and Whitmore reported that 45 of 52 men with metastatic PCa who received testosterone demonstrated an ‘‘unfavorable response’’ within 30 days.2 Since the standard treatment for advanced PCa is to lower serum T with androgen deprivation therapy (ADT), it seemed logical that raising serum T promotes PCa growth. For these reasons it has been widely believed that raising testosterone is likely to cause rapid disease progression, morbidity, and death in men with PCa.
However, a growing literature has challenged this concept. Multiple case series have demonstrated low rates of PCa progression or recurrence in men after radical prostatectomy (RP),3,4 radiation therapy,5 and in men on active surveillance.6,7 Population-based studies have failed to show that the use of TTh is associated with worse PCa outcomes.8 The apparent paradox whereby ADT causes disease regression in PCa yet TTh appears to not cause worse PCa outcomes are resolved by the saturation model,9 describing a growth the curve in which maximal androgenic stimulation of PCa is achieved at low serum T concentrations, with little to no additional stimulation occurring at higher serum T concentrations. There is extremely limited evidence regarding saturation in advanced PCa, consisting of an absence of prostate-specific antigen (PSA) progression with TTh in a case report,10 and an inverted U-curve in PCa cell lines in vitro exposed to progressively increasing androgen concentrations, with maximal growth achieved at near-physiological concentrations followed by growth inhibition at higher concentrations.11 However, positive results from the use of bipolar androgen therapy (BAT) in men with castrate-resistant PCa,12 and a modified BAT protocol (mBAT)13 indicate that elevating serum testosterone is not necessarily harmful.
Whereas there has been growing evidence for the benefits of TTh in the general population of men with testosterone deficiency,14 and moderate experience in men with PCa after definitive local therapy or with the low-risk disease on active surveillance, there is scant published experience with the use of TTh in men with nonlocalized PCa in clinical practice. We present in this study our initial observations of TTh in a set of men with advanced PCa treated with TTh. These men all specifically sought TTh, for a number of reasons, including prior experience with TTh, adverse experience with ADT, or belief that a robust serum T concentration would be beneficial for their health despite known concerns that TTh would hasten PCa growth.
*Discussion To the best of our knowledge, this is the first reported clinical series in the PSA era of outcomes with TTh specifically in men with BCR or MET in a clinical setting, and not part of a formal trial
*There are several important limitations to this study, including its retrospective nature, multiple forms of TTh treatment, and small sample size. In addition, PCa is a heterogeneous disease, and this report includes those with Gleason scores ranging from 6 to 9, which may cloud the interpretation of results. Nonetheless, these preliminary results indicate that TTh does not appear to cause precipitous PCa progression in men with BCR and MET. There may be a role for TTh in selected men with BCR, MET, or high-risk diseases willing to accept the theoretical risk of hastened disease progression in return for enhanced quality of life.
Conclusion
TTh in men with BCR, MET, and high-risk PCa was associated with symptomatic benefits and low rates of complications, although the interpretation of these results must be tempered by a small sample size and a heterogeneous population. Well-designed prospective studies are needed to provide better evidence for the potential use of TTh in similarly affected individuals. In the meantime, these results may provide clinicians with a framework to counsel patients who prioritize quality of life over longevity.
Introduction: Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET).
Methods: We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed.
Results: Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. The median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture.
Conclusions: These initial observations indicate TTh was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.
Introduction
The diagnosis of prostate cancer (PCa) has been considered an absolute contraindication for testosterone (T) therapy (TTh) for decades, based on the belief that TTh ‘‘activates’’ PCa growth, first asserted by Huggins and Hodges.1 In 1981, Fowler and Whitmore reported that 45 of 52 men with metastatic PCa who received testosterone demonstrated an ‘‘unfavorable response’’ within 30 days.2 Since the standard treatment for advanced PCa is to lower serum T with androgen deprivation therapy (ADT), it seemed logical that raising serum T promotes PCa growth. For these reasons it has been widely believed that raising testosterone is likely to cause rapid disease progression, morbidity, and death in men with PCa.
However, a growing literature has challenged this concept. Multiple case series have demonstrated low rates of PCa progression or recurrence in men after radical prostatectomy (RP),3,4 radiation therapy,5 and in men on active surveillance.6,7 Population-based studies have failed to show that the use of TTh is associated with worse PCa outcomes.8 The apparent paradox whereby ADT causes disease regression in PCa yet TTh appears to not cause worse PCa outcomes are resolved by the saturation model,9 describing a growth the curve in which maximal androgenic stimulation of PCa is achieved at low serum T concentrations, with little to no additional stimulation occurring at higher serum T concentrations. There is extremely limited evidence regarding saturation in advanced PCa, consisting of an absence of prostate-specific antigen (PSA) progression with TTh in a case report,10 and an inverted U-curve in PCa cell lines in vitro exposed to progressively increasing androgen concentrations, with maximal growth achieved at near-physiological concentrations followed by growth inhibition at higher concentrations.11 However, positive results from the use of bipolar androgen therapy (BAT) in men with castrate-resistant PCa,12 and a modified BAT protocol (mBAT)13 indicate that elevating serum testosterone is not necessarily harmful.
Whereas there has been growing evidence for the benefits of TTh in the general population of men with testosterone deficiency,14 and moderate experience in men with PCa after definitive local therapy or with the low-risk disease on active surveillance, there is scant published experience with the use of TTh in men with nonlocalized PCa in clinical practice. We present in this study our initial observations of TTh in a set of men with advanced PCa treated with TTh. These men all specifically sought TTh, for a number of reasons, including prior experience with TTh, adverse experience with ADT, or belief that a robust serum T concentration would be beneficial for their health despite known concerns that TTh would hasten PCa growth.
*Discussion To the best of our knowledge, this is the first reported clinical series in the PSA era of outcomes with TTh specifically in men with BCR or MET in a clinical setting, and not part of a formal trial
*There are several important limitations to this study, including its retrospective nature, multiple forms of TTh treatment, and small sample size. In addition, PCa is a heterogeneous disease, and this report includes those with Gleason scores ranging from 6 to 9, which may cloud the interpretation of results. Nonetheless, these preliminary results indicate that TTh does not appear to cause precipitous PCa progression in men with BCR and MET. There may be a role for TTh in selected men with BCR, MET, or high-risk diseases willing to accept the theoretical risk of hastened disease progression in return for enhanced quality of life.
Conclusion
TTh in men with BCR, MET, and high-risk PCa was associated with symptomatic benefits and low rates of complications, although the interpretation of these results must be tempered by a small sample size and a heterogeneous population. Well-designed prospective studies are needed to provide better evidence for the potential use of TTh in similarly affected individuals. In the meantime, these results may provide clinicians with a framework to counsel patients who prioritize quality of life over longevity.
