Clinical Research

Long-term effects of intermittent androgen suppression therapy on lean and fat mass: a 33-month prospective study

Abstract

Background:

To examine changes to whole body and regional lean mass (LM) and fat mass (FM) over 33 months of intermittent androgen suppression therapy (IAST).

Methods:

Phase II cohort study of 72 prostate cancer patients without metastatic bone disease. Patients received flutamide 250 mg tid and leuprolide 22.5 mg three monthly depot for the 9-month initial treatment phase (iTREAT), at which point patients ceased therapy providing PSA <4 ng ml−1 with continued monitoring for further 2 years (POST). AST was recommenced when PSA exceeded pretreatment level or 20 ng ml−1. Body composition was assessed using dual energy X-ray absorptiometry at baseline, completion of treatment phase, and 1 and 2 years post treatment phase (months 21 and 33).

Results:

LM decreased by 1.3 kg and FM increased by 2.3 kg (P<0.001) following iTREAT. During the POST period, there were no further adverse effects on LM or FM, but also no recovery to pretreatment levels. Patients who failed to recover testosterone by month 33 experienced a significant increase in FM compared with those who recovered eugonadal levels of testosterone (10 nmol ml−1; P=0.019). Change in testosterone was moderately correlated to changes in % FM (r=−0.314, P<0.028) and LM (r=0.300, P<0.036) during POST phase. Waist circumference progressively increased over time and by 2 years, POST had not recovered to baseline levels.

Conclusions:

Loss of LM and gain in FM during the 9-month iTREAT was not reversed during 2-year POST, although further deterioration was not observed. Subgroup analysis identified those recovering testosterone showed some body composition improvements. These findings suggest potential benefits of IAST, where testosterone levels are able to recover, to reduce the ongoing adverse effects on body composition, such as the acceleration of sarcopenia and risks associated with metabolic disease.

Introduction

Traditionally, androgen suppression therapy (AST) has been administrated in the latter stage of prostate cancer (for example, presence of metastases).1 However, due to earlier detection of prostate cancer through earlier screening (for example, PSA), patients are undertaking AST in the early stages of the disease and therefore being exposed to testosterone suppression for longer periods of time.2 Additionally, AST is currently used as adjuvant therapy to radical prostatectomy and radiotherapy.3 More than 2000 men in Australia and more than 80 000 in the USA commence on-going AST for prostate cancer each year.4, 5 Although an effective treatment strategy,3 concerns related to the detrimental effects of AST on the musculoskeletal and cardiovascular system have arisen as it can exacerbate the risk of sarcopenia, osteoporosis, obesity, diabetes and cardiovascular complication.6, 7, 8, 9, 10

Intermittent AST (IAST) has been introduced in phase II clinical trials in an effort to reduce AST-related toxicity and possibly delay prostate cancer androgen independence.11 Although improvements in quality of life during off-treatment phases have been observed,12, 13 the effects of intermittent regimens on attenuating the immediate and severe changes in soft tissue (for example, decreased muscle mass and increased fat mass (FM)) have not been evaluated. AST treatment induced reductions in the whole body and regional lean mass (LM) following short-term AST substantially exacerbates the age-related loss of muscle mass (termed sarcopenia), and can further compromise muscle strength, physical function and independent living, particularly in older patients.14, 15, 16 Further, the increase in abdominal obesity following short-term AST15 may be a significant contributing factor for the increased incidence of cardiovascular and metabolic complications in men undergoing AST.8, 10, 17, 18, 19

An Australian wide study (GUOG 98.01) that employed a single regimen IAST program was initiated in 1998. The effect on quality of life, impact on disease control and the short-term effects of maximal androgen suppression on soft tissue and bone physiology of this program have been reported previously.13, 15, 20 In the present report, we extend those findings by examining changes occurring over the subsequent 2 years of the intermittent program in the whole body and regional LM and FM, and abdominal obesity.

Materials and methods

Seventy-two prostate cancer patients aged 44–88 years, participating (out of total 250 patients) in a multi-center trial,12 were accrued at one site (from May 1999 to October 2002) for a sub-study to investigate body composition changes over a 33-month period. Entry criteria were a histological or cytological diagnosis of adenocarcinoma of the prostate and an Eastern Cooperative Oncology Group performance status of 0, 1 or 2. No patient had bone metastases at presentation, but 8.3% had metastatic disease confined to soft tissue. Previous AST did not preclude study entry provided that treatment had been administered more than 2 years ago and given for no more than 6 months. Institutional Ethics Committee approval was obtained and each participant provided written consent.

At baseline, prostatic disease extent was categorized into one of the three categories: (1) locally advanced disease without evidence of metastatic disease but not considered suitable for or declining radical treatment, (2) metastatic soft tissue disease and PSA>10 ng ml−1 without evidence of bone metastasis on nuclear medicine bone scan and (3) local disease following radical prostatectomy, or radical radiotherapy associated with a rising PSA2 ng ml−1, measured on three consecutive occasions at intervals of at least 1 month or more apart and without evidence of metastatic disease.

Treatment and follow-up program

Patients were assessed at 3-month intervals for 33 months. AST was achieved by a maximal androgen suppression program, employing Flutamide (Eulexin) 250 mg tid for 9 months and Leuprolide (Lucrin) 22.5 mg depot at baseline, 3 and 6 months. After the initial treatment phase (iTREAT phase) of testosterone suppression of 9 months, the patients ceased therapy (POST phase), providing their PSA level was below 4 ng ml−1. AST was recommenced when the PSA exceeded 20 ng ml−1, or exceeded the presenting PSA if less than 20 ng ml−1, or for clinical activity of disease. Patients who recommenced treatment during the POST phase continued follow-up in the study.

Body composition

Whole body bone mineral-free LM, FM and percent fat were derived by DXA (Hologic Discovery W, Waltham, MA, USA). From the whole body scan, upper limb, lower limb and trunk, LM and FM were derived by manipulating segmental lines according to anatomical landmarks.21 A vertical line extended between the head of the humerus and glenoid fossa separated the upper limb from the trunk, while an oblique line through the femoral neck separated the lower limb from the pelvis. Upper limb LM and lower limb LM were then summed to derive appendicular skeletal muscle.22 Measures were undertaken at baseline, at the completion of the initial 9-month period of androgen suppression, and then 1 and 2 years after the end of the initial treatment period (months 21 and 33). The DXA system used has been shown to be highly reliable. The Hologic DXA scanner used demonstrates coefficients of variation ranging from 0.2 to 3.5% with intra-class correlations ranging from 0.99 to 1.00.23

Anthropometric measures

Anthropometric measures were undertaken at every 3-month visit. Central adiposity was assessed by waist circumference (WC), and hip circumference (HC) was also determined.24 WC was measured at the level of the narrowest point between the lower costal (rib) border and the iliac crest. In the absence of obvious narrowing, measurement was taken at the midpoint between these two landmarks. HC was measured at the level of the greatest posterior protuberance of the buttocks, which usually corresponds anteriorly to the level of the symphysis pubis. The technical error of WC measures are 1.31 cm for intra-measurer error and 1.56 cm for inter-measurer error.25 For hip measurement, the technical error is 1.23 cm for intra-measurer error and 1.38 for inter-measurer error.25 WC and HC are more precise than other anthropometric measures (for example, skinfolds)26 and has been shown to be reliably associated with risk of chronic disease.27

PSA and testosterone

PSA and testosterone were assessed using standard procedures as previously described.15 PSA and testosterone were assessed using a Abbott Architect Immunoassay analyzer, with reagents and instruments supplied by Abbott Diagnostics (Perth, WA, Australia).

Statistical analyses

Data were analyzed using the SPSS statistical software package (version 18.0, SPSS, Chicago, IL, USA). Analyses included standard descriptive statistics, unpaired t-tests, repeated measures analysis of variance (ANOVA) and analysis of covariance (ANCOVA). Where appropriate, the LSD post-hoc procedure with Bonferroni adjustment for multiple comparisons was undertaken to locate the source of significant differences. Association between variables was determined by Pearson correlation and simple linear regression analysis. An alpha level of 0.05 was set as the criterion for statistical significance and results are given as the mean±s.d.

Results

Baseline characteristics of the cohort are shown in Table 1. The flow of patients through the study is shown in Figure 1. Seventy-two patients from a single site completed body composition analysis at the beginning of the study. At 33 months, 49 patients remained available for body composition assessment. The main reasons for dropout during the follow-up period were major illness or death, and developing androgen independence. The median time taken for serum testosterone to recover to eugonadal level of 10 nmol ml−1 during the POST period was 9 months from the end of the iTREAT phase; however, 26% failed to recover at 2 years. The median POST time to retreatment was 18 months, and at 2 years, 59% had commenced a further course of ADT. As expected, recommencing ADT during the post therapy period caused testosterone to again fall to castrate levels.

Table 1 Distribution of patients according to descriptive variables, disease extent and performance status (n=49)
Figure 1
figure1

Flowchart of patients through the study period. MI, myocardial infarction.

Effects of the treatment on body composition and abdominal obesity

Changes to each assessed parameter are shown in Figure 2. Both lean and fat measures showed significant deterioration over the iTREAT phase with a decrease in whole body LM of 1.3 kg (P<0.001) and an increase in whole body FM of 2.2 kg (P<0.001). There was no recovery during the 2-year POST phase, although overt further worsening was not apparent. A similar pattern was observed across all sub-regions and for the anthropometric measures of central abdominal obesity (Table 2). When comparing those who were retreated during the POST phase with those who escaped retreatment, there was a significant group difference (P=0.029) for whole body FM at month 33, but not for whole body LM (P=0.452).

Figure 2
figure2

Whole body lean and adipose tissue changes (kg) from baseline to 33 months in all the patients (n=49). FM, fat mass; LM, lean mass.

Table 2 Whole body and regional composition, hip and waist changes at baseline, 9 months (iTREAT phase), 21 and 33 months

Effects of the testosterone recovery on LM and FM

As previously reported,28 testosterone recovery showed significant variance, with several patients remaining persistently hypogonadal. We dichotomized the group into eugonadal and hypogonadal patients according to whether the recovering testosterone exceeded 10 nmol ml−1 in the 24 months following cessation of ADT and explored the impact of this factor on our outcome measures (Table 3).

Table 3 Whole body and regional composition changes from 9 months (iTREAT phase) to 33 months (POST phase) for patients not recovering testosterone (n=35) and patients recovering testosterone (n=14; mean±s.d.)

There was a significant difference (P<0.05 for all; except trunk fat, P=0.076) between the two subgroups for whole body, upper limb, lower limb, trunk and % FM with those not recovering testosterone experiencing some gain in FM compared with those reaching eugonadal levels. Further, LM appeared to partially recover in patients recovering testosterone compared with those not recovering; with differences between groups approaching statistical significance (whole body, P=0.095; upper body, P=0.059; appendicular skeletal muscle, P=0.083). WC was not different between the two subgroups. Change in testosterone during the POST phase was moderately correlated to change in % FM and LM during the POST phase, with lower levels of testosterone associated with greater gain in % FM (r=−0.314, P<0.028) and higher levels of testosterone associated with accretion of whole body lean tissue (r=0.300, P<0.036).

Discussion

Four compelling findings arise from our study, (1) both LM and FM indices deteriorated significantly over the 9-month iTREAT phase, (2) although further deterioration appeared to be arrested following cessation of AST, recovery was not observed in POST, (3) dichotomizing the group according to testosterone recovery during POST identified divergent soft tissue responses, with continuing deterioration in persistently hypogonadal patients versus some limited improvement in those becoming eugonadal and (4) WC increased progressively from baseline to 33 months clearly indicating an increased risk factor for metabolic syndrome irrespectively of testosterone recovery.

Our findings confirm the changes in whole body composition that accompany AST (iTREAT) reported by others9, 29, 30 with whole body FM increasing by 9.4–11%, and LM decreasing by 2.7 to 4.0% following the first year of AST. Only limited information exists regarding long-term AST on body composition outcomes. Levy et al.31 reported continued loss of LM and increase in FM following 2 years of interrupted AST that was accompanied by a reduction in physical function (for example, gait speed), and a recent meta-analysis shows a dose–response relationship between unfavorable changes in body composition and AST treatment duration.16 These long-term body composition results following continued AST differ with our overall findings during IAST, where further losses of LM and gains in FM did not occur up to 2 years post treatment. This is a very significant outcome as IAST may reduce long-term treatment-induced toxicities related to body composition even though the rapid LM loss and FM gain in our cohort during the 9-month iTREAT was not reversed during the POST period. Such a treatment strategy may prevent the exacerbation of sarcopenia that can potentially further compromise muscle function and independent living, particularly in older prostate cancer patients. Therefore, our findings support additional benefits of IAST that are beyond those previously reported for quality of life10, 11, 12 as it may reduce the risk of further adverse body composition effects.

Given the intermittent regimen of our program, some patients received additional cycles of retreatment while others did not during the POST period. We found that men not reaching eugonadal levels of testosterone during the POST period experienced continued gains in FM compared with those recovering testosterone. This is an important finding as the increase in FM and abdominal obesity following short-term AST may be an independent risk factor for the increased incidence of cardiovascular and metabolic complications in men undergoing AST.8, 17, 18, 19 Further, there was some recovery in the whole body and regional LM at 2 years POST in those recovering testosterone, although this did not reach statistical significance.

As regular assessment of body composition by DXA may not always be available to clinicians to monitor patterns of FM and LM alterations during AST, we also included routine measures of abdominal obesity, such as WC and HC, as they are correlated with FM changes by DXA and have been extensively reported in large epidemiological studies on cardiovascular and metabolic diseases.32 Importantly, WC greater than 102 cm is a key criteria for metabolic syndrome diagnosis by the Adult Treatment Panel III report.33 Cross-sectional studies have showed that nearly 80% of prostate cancer patients on ADT have WC 102 cm, over 60% have hyperglycemia, and more than 50% of these patients have metabolic syndrome.34 In our series, WC increased continuously from baseline to 33 months (101 cm to nearly 104 cm), clearly indicating an increased risk factor for metabolic syndrome. Further, these changes were not different between those recovering and not recovering testosterone by month 33.

Currently, there is no established treatment to reverse body composition alterations during AST. Physical exercise, in particular resistance training, may be an important countermeasure against LM loss during AST and other risk factors for metabolic complications.35 We have previously shown that resistance exercise can be safely undertaken by patients on AST without elevating testosterone36 and can have significant anabolic and physical functioning effects.37, 38, 39 Although long-term studies using exercise are yet to be conducted, exercise may be an important countermeasure to the increased risk for AST-associated cardiovascular and metabolic disease.40 For example, in non-prostate cancer patients, it is well known that increased levels of physical activity reduces the risk of type 2 diabetes in a dose–response manner,41 and lifestyle interventions have been shown to significantly reduce the risk of type 2 diabetes in at-risk populations.42

Several limitations of this study are worthy of comment. Our patients were a convenience sample who gave consent to be in the study; therefore, some element of selection bias may be present. Nonetheless, as previously reported, they appear typical of Australian men presenting for AST.13 Second, it may be argued that more frequent DXA scanning during the 2-year POST period should have been undertaken; however, there is no reason to believe that departures from the patterns in LM and FM that we observed would have occurred with more frequent scanning. Lastly, a stronger experimental design may have been the use of a randomized trial that included prostate cancer patients not allocated to AST. However, from a clinical standpoint, this may not be in the best interest of the patient, especially given the length of the study.

In summary, intermittent androgen suppression therapy may be an important strategy in the therapeutic management of prostate cancer patients by attenuating fat gain and muscle loss associated with androgen suppression. Our findings demonstrate further benefits to IAST, beyond those of quality of life,13 where reduction of adverse effects on body composition and the progression of sarcopenia may reduce the risk for frailty, physical dependence, and cardiovascular and metabolic disease. Lifestyle interventions, including exercise, should be considered in the POST period as a supportive care intervention to aid recovery and reduce the risk of metabolic syndrome.

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Acknowledgements

We would like to thank Abbott Australasia and Schering-Plough for their financial support in running the study. DAG is funded by a Movember New Directions Development Award obtained through Prostate Cancer Foundation of Australia’s Research Program. We would also like to thank the Genito Urinary Oncology Group NSW and Urology Research Centre Perth for their support and direction, Spry JI and Leutenegger S (Perth) for data management and additional analysis, and the following doctors from Perth who contributed patients to the study: Joseph D, Rowling C, Stanley J, Low A, Vivian J, Cassidy B, Chelvanayagam D, Davies R, Harper CS, Hill I, La Bianca S, Mander J, McRae P, Shannon T and Weinstein S.

Clinical Trial Registry: a phase II study to assess the effect of intermittent androgen blockade in the treatment of advanced prostate cancer; ACTRN12608000170325; http://www.ANZCTR.org.au/ACTRN12608000170325.aspx

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Correspondence to D A Galvão.

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Spry, N., Taaffe, D., England, P. et al. Long-term effects of intermittent androgen suppression therapy on lean and fat mass: a 33-month prospective study. Prostate Cancer Prostatic Dis 16, 67–72 (2013). https://doi.org/10.1038/pcan.2012.33

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Keywords

  • body composition
  • intermittent androgen suppression
  • testosterone
  • obesity
  • sarcopenia

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