madman
Super Moderator
Background and purpose
To determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT).Materials and methods In 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly.T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed.
Results
Overall, 87.4% (167/191), 75.9% (293/386), 54.8% (181/330) and 43.2% (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p<0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules,respectively (p<0.001) and was significantly faster for those with a normal T at baseline (p<0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery.
Conclusions
Testosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT.
Introduction
Androgen deprivation therapy (ADT) is an effective, commonly used treatment in localised prostate cancer1. In the National Comprehensive Cancer Network guidelines Version 1.20242, the recommendation of ADT plus radiotherapy (RT) for unfavorable intermediate risk prostate cancer (IRPC) is listed as category 2a evidence and as category 1 evidence for high-risk prostate cancer (HRPC). However, ADT is also associated with a long list of hypogonadal side effects that significantly affect patients’ quality of life3, including hot flashes 4, fatigue 5, anemia 6, decrease muscle strength, increase body fat 7-8 depression, anxiety9-10, metabolic syndromes 11, decrease penile and testicular size 12, sexual dysfunction 13-14, increase of cardiovascular risk 15,osteoporosis and bone fractures 16-17-18-19.
Despite these known potential harmful outcomes, there is a lack of prospective data in the literature on the kinetics of testosterone (T) recovery after ADT use. Addressing T recovery, also involves considering the actual place of T replacement therapy in patients remaining persistently hypogonadal after ADT 20.
Based on the long-term follow-up of two randomised trials in localised prostate cancer, we report herein our prospectively collected data on T recovery in patients with IRPC and HRPC treated with RT and different duration of ADT.
Discussion
To our knowledge, this report represents the largest prospectively collected data on T recovery after both a short or prolonged ADT use in patients with localised prostate cancer and a long-term follow-up. Previous series reported in the literature are mainly from retrospective data, involving small number of patients with non-uniform clinical stages, a variety of regimens and duration of ADT and, most importantly, without an adequately acceptable T measurement frequency and/or baseline T documentation 23-24-25-26-27. Moreover, the definition of T recovery varied significantly and included return to supra or non-castrate level, out of hypogonadism after ADT withdrawal 5, a T >50 ng/dl 24, supra castrate level, recovery to baseline and/or normal T levels 25-26, and back to normal T with low T cut-off 27. Overall,most studies report that older patients receiving a longer duration of ADT have more prolonged T recovery rates after ADT cessation 23-25-26.
Our report is unique because it also includes a cohort of randomised patients receiving RT alone who had their T measured in a similar manner to those receiving combined RT plus ADT. The lack of added ADT to this cohort, allowed us to assess the potential impact of RT on T changes. As reported, most patients (94%) with baseline normal T maintained a normal T over time after completion of RT, indicating the small, if any, impact of RT alone on T level. Pickles et al 28 have reported similar rates in 666 patients with prostate cancer treated with RT alone. Thus, we can use this cohort as a reference for T variation over a prolonged period. The small percentage of this cohort developing abnormal T over time can be explained by a natural decline of T with advancing age, as shown by several reports 29- 30-31-32
Our study confirms that the prolonged use of ADT significantly affects and delays T recovery rates, even after a long term follow-up. This important side effect related to the hormonal treatment should not be overlooked, considering its detrimental impact on quality of life and the potential aggravation of associated medical issues that a prolonged castration status may have in this, generally, elderly population. Lifestyle modifications should be discussed with these patients, including alcohol and caffeine consumption, smoking cessation, healthy food habits, exercise, optimal calcium and vitamin D intake. Because of the potential development of osteoporosis and the known bone fracture risk after ADT 18-19, long term bone health surveillance including a bone density scan should be performed and appropriate therapy 33-34-35-36 given if osteoporosis or fracture shall be prevented.
Moreover, we performed multivariable analyses with logistic regression or with competing risks using ADT durationas outcomes variable and determined that a normal T at baseline is indeed a strong predictor for T recovery. On MVA, other factors affecting an optimal T recovery included age and medical comorbidities.
Our study raises the question of the potential benefit and safety of use of T replacement therapy in persistently hypogonadal patients (low T with attributable symptoms) post-ADT and without evidence of disease recurrence. The saturation model 37 based on androgen receptors in prostate cancer cells already saturated at low level of T, would theoretically prevent exogenous T impacting on prostate cancer cells growth, supporting the use of T replacement therapy in these situations. Retrospective data in the literature confirm the safety of the use of T replacement therapy after active surveillance 38, prostatectomy 39-40, radiation therapy 41-42 and brachytherapy 43-44. Despite several caveats from the retrospective methodology, including small series, mainly low risk or intermediate favorable risk prostate cancers, short follow up, lack of Gleason score report and objective measures to properly evaluate symptoms of hypogonadism 23-24-25-26-27-28, there appears to be a major trend to consider T replacement therapy in patients cured from prostate cancer with the goal of improving hypogonadism symptoms and quality of life.
Our study has limitations including the potential variability in T measurement assays among the institutions participating in our trials. We also acknowledge that variation in T level is related to several factors beyond age and ADT duration, including cultural and geographical location, exercise, obesity, comorbid conditions and circadian rhythms 48-49-50. For these reasons, we are aware that some T that were called abnormal may indeed represent a borderline normal T due, for example, to a diurnal variation. To overcome some of these limitations, we opted to use a straight forward definition of T recovery (return to normal level) and for abnormal T value (defined as below the normal range). Despite these potential caveats, strengths of the current study include the randomisation aspect of both trials (preventing patient selection to different ADT duration arms), the availability of a baseline T measurement prior to ADT and rigorous and controlled T measurements during follow-up schedule for all patients. Furthermore, it has an arm that received no ADT and, importantly, it is the largest study looking at T kinetics over a long-term followup.
Conclusion
In patients with localised prostate cancer treated with different ADT duration, our prospective data provide investigators and patients useful information and guidance on the frequency of an initial normal T level measurement, on the probability of testosterone recovery post medical castration, and on the time required for a full recovery to a normal gonadal status. The testosterone recovery rate after exposure to ADT is dependent on several factors including duration of the hormonal manipulation, a normal baseline T, age, and medical comorbidities. Longer ADT duration is the most important variable affecting T recovery kinetics that may last for a long time after hormonal cessation. Special attention should be addressed to patients considered cured from prostate cancer, but with a continuing low testosterone level and symptoms of hypogonadism. Consideration of T replacement therapy after careful evaluation and strict follow up seems to be an attractive option that requires further studies. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT and in facilitating the design of treatment optimization in future trials.
To determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT).Materials and methods In 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly.T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed.
Results
Overall, 87.4% (167/191), 75.9% (293/386), 54.8% (181/330) and 43.2% (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p<0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules,respectively (p<0.001) and was significantly faster for those with a normal T at baseline (p<0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery.
Conclusions
Testosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT.
Introduction
Androgen deprivation therapy (ADT) is an effective, commonly used treatment in localised prostate cancer1. In the National Comprehensive Cancer Network guidelines Version 1.20242, the recommendation of ADT plus radiotherapy (RT) for unfavorable intermediate risk prostate cancer (IRPC) is listed as category 2a evidence and as category 1 evidence for high-risk prostate cancer (HRPC). However, ADT is also associated with a long list of hypogonadal side effects that significantly affect patients’ quality of life3, including hot flashes 4, fatigue 5, anemia 6, decrease muscle strength, increase body fat 7-8 depression, anxiety9-10, metabolic syndromes 11, decrease penile and testicular size 12, sexual dysfunction 13-14, increase of cardiovascular risk 15,osteoporosis and bone fractures 16-17-18-19.
Despite these known potential harmful outcomes, there is a lack of prospective data in the literature on the kinetics of testosterone (T) recovery after ADT use. Addressing T recovery, also involves considering the actual place of T replacement therapy in patients remaining persistently hypogonadal after ADT 20.
Based on the long-term follow-up of two randomised trials in localised prostate cancer, we report herein our prospectively collected data on T recovery in patients with IRPC and HRPC treated with RT and different duration of ADT.
Discussion
To our knowledge, this report represents the largest prospectively collected data on T recovery after both a short or prolonged ADT use in patients with localised prostate cancer and a long-term follow-up. Previous series reported in the literature are mainly from retrospective data, involving small number of patients with non-uniform clinical stages, a variety of regimens and duration of ADT and, most importantly, without an adequately acceptable T measurement frequency and/or baseline T documentation 23-24-25-26-27. Moreover, the definition of T recovery varied significantly and included return to supra or non-castrate level, out of hypogonadism after ADT withdrawal 5, a T >50 ng/dl 24, supra castrate level, recovery to baseline and/or normal T levels 25-26, and back to normal T with low T cut-off 27. Overall,most studies report that older patients receiving a longer duration of ADT have more prolonged T recovery rates after ADT cessation 23-25-26.
Our report is unique because it also includes a cohort of randomised patients receiving RT alone who had their T measured in a similar manner to those receiving combined RT plus ADT. The lack of added ADT to this cohort, allowed us to assess the potential impact of RT on T changes. As reported, most patients (94%) with baseline normal T maintained a normal T over time after completion of RT, indicating the small, if any, impact of RT alone on T level. Pickles et al 28 have reported similar rates in 666 patients with prostate cancer treated with RT alone. Thus, we can use this cohort as a reference for T variation over a prolonged period. The small percentage of this cohort developing abnormal T over time can be explained by a natural decline of T with advancing age, as shown by several reports 29- 30-31-32
Our study confirms that the prolonged use of ADT significantly affects and delays T recovery rates, even after a long term follow-up. This important side effect related to the hormonal treatment should not be overlooked, considering its detrimental impact on quality of life and the potential aggravation of associated medical issues that a prolonged castration status may have in this, generally, elderly population. Lifestyle modifications should be discussed with these patients, including alcohol and caffeine consumption, smoking cessation, healthy food habits, exercise, optimal calcium and vitamin D intake. Because of the potential development of osteoporosis and the known bone fracture risk after ADT 18-19, long term bone health surveillance including a bone density scan should be performed and appropriate therapy 33-34-35-36 given if osteoporosis or fracture shall be prevented.
Moreover, we performed multivariable analyses with logistic regression or with competing risks using ADT durationas outcomes variable and determined that a normal T at baseline is indeed a strong predictor for T recovery. On MVA, other factors affecting an optimal T recovery included age and medical comorbidities.
Our study raises the question of the potential benefit and safety of use of T replacement therapy in persistently hypogonadal patients (low T with attributable symptoms) post-ADT and without evidence of disease recurrence. The saturation model 37 based on androgen receptors in prostate cancer cells already saturated at low level of T, would theoretically prevent exogenous T impacting on prostate cancer cells growth, supporting the use of T replacement therapy in these situations. Retrospective data in the literature confirm the safety of the use of T replacement therapy after active surveillance 38, prostatectomy 39-40, radiation therapy 41-42 and brachytherapy 43-44. Despite several caveats from the retrospective methodology, including small series, mainly low risk or intermediate favorable risk prostate cancers, short follow up, lack of Gleason score report and objective measures to properly evaluate symptoms of hypogonadism 23-24-25-26-27-28, there appears to be a major trend to consider T replacement therapy in patients cured from prostate cancer with the goal of improving hypogonadism symptoms and quality of life.
Our study has limitations including the potential variability in T measurement assays among the institutions participating in our trials. We also acknowledge that variation in T level is related to several factors beyond age and ADT duration, including cultural and geographical location, exercise, obesity, comorbid conditions and circadian rhythms 48-49-50. For these reasons, we are aware that some T that were called abnormal may indeed represent a borderline normal T due, for example, to a diurnal variation. To overcome some of these limitations, we opted to use a straight forward definition of T recovery (return to normal level) and for abnormal T value (defined as below the normal range). Despite these potential caveats, strengths of the current study include the randomisation aspect of both trials (preventing patient selection to different ADT duration arms), the availability of a baseline T measurement prior to ADT and rigorous and controlled T measurements during follow-up schedule for all patients. Furthermore, it has an arm that received no ADT and, importantly, it is the largest study looking at T kinetics over a long-term followup.
Conclusion
In patients with localised prostate cancer treated with different ADT duration, our prospective data provide investigators and patients useful information and guidance on the frequency of an initial normal T level measurement, on the probability of testosterone recovery post medical castration, and on the time required for a full recovery to a normal gonadal status. The testosterone recovery rate after exposure to ADT is dependent on several factors including duration of the hormonal manipulation, a normal baseline T, age, and medical comorbidities. Longer ADT duration is the most important variable affecting T recovery kinetics that may last for a long time after hormonal cessation. Special attention should be addressed to patients considered cured from prostate cancer, but with a continuing low testosterone level and symptoms of hypogonadism. Consideration of T replacement therapy after careful evaluation and strict follow up seems to be an attractive option that requires further studies. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT and in facilitating the design of treatment optimization in future trials.
