Anaemia following initiation of androgen deprivation therapy for metastatic prostate cancer: A retrospective chart review

Abstract

Objective. Haemoglobin levels often decline into the anaemic range with androgen deprivation therapy (ADT). We conducted a chart review of patients receiving ADT for metastatic prostate cancer to assess anaemia-related symptoms.

Methods. 135 stage IV prostate cancer cases were reviewed for treatment type; haemoglobin values before and after treatment; and symptoms of anaemia. Mean haemoglobin levels before and after for all treatment forms, for leuprolide alone, and for combination leuprolide/bicalutamide were calculated and evaluated for significant differences. The numbers of patients developing symptoms were recorded and the effects of specific therapies evaluated.

Results. For all ADT treated patients, mean haemoglobin declined by −1.11 g/dL (p < .0001). Leuprolide-alone treated patients had a mean decline of −1.66 g/dL (p < 0.0001). Leuprolide and bicalutamide combination treatment caused a mean decline of −0.78 g/dL (p = 0.0426). 16 of 43 patients had anemia symptoms. Contingency analysis with Fisher's exact test shows patients receiving leuprolide therapy alone versus other forms of ADT were significantly less likely to have symptoms (χ² = 0.0190).

Conclusions. The present study confirms that ADT results in a significant drop in haemoglobin levels into the anaemic range. A number of patients become symptomatic from this change. Practitioners should monitor haemoglobin levels, and treat symptomatic patients.

Keywords:

• Metastatic prostate cancer
• androgen deprivation therapy
• anaemia
• symptoms

Introduction

Prostate cancer is the most frequently diagnosed cancer in men, and the third leading cause of male cancer death [1]. Currently, androgen deprivation therapy (ADT) is the mainstay of therapy for advanced prostate cancer [2]. Although this approach has been recognized to improve survival [3-5], ADT has numerous, well-recognized side effects. These include erectile dysfunction, decreased bone mineral density, hot flushes, gynaecomastia, decreased penile and testicular size, fatigue and anaemia. Previous studies have shown that patients receiving ADT have a lower quality of life than patients receiving no therapy [6].

As mentioned, a side effect of ADT is a decline in haemoglobin levels, often into the anaemic range. The phenomenon was first described in 1948, when Hamilton reported a series of 6 involuntarily castrated male prisoners with a mean decline in haemoglobin levels of 1 g/dL after 40 days [7]. More recently, Fonseca et al. described a series of 64 patients undergoing orchiectomy for prostate cancer; patients were found to have a statistically significant drop in haemoglobin concentration of 1.2 g/dL on average at 90 days following orchiectomy [8]. Additional reports by Weber et al. [9], and Eri and Tveter [10], detail drops in haemoglobin levels with the use of GnRH-agonist therapy for benign prostatic hyperplasia (BPH). Based on the available data, it is apparent that testosterone levels influence haemoglobin levels – with a decline in testosterone levels, haemoglobin levels predictably fall.

Similar declines in the haemoglobin concentrations of patients undergoing ADT for advanced prostate cancer have been described [11-17]. In these reports, various combinations of therapy have been used, but each study has found a decline in haemoglobin concentration temporally related to the initiation of ADT. The anaemia was generally normocytic, and the mean decline in haemoglobin was approximately 1–2 g/dL over the study periods. Although not all of the studies evaluated patients for other sources of anaemia (e.g., haemolysis, blood loss, bone marrow involvement with cancer, and/or anaemia of chronic disease), most did [12],[14],[16],[17], and these causes of anaemia were not found to be contributing factors. Thus, the anaemia reported was most likely related to an androgen-deprivation effect.

As outlined by Oh [18] in his review of ADT-induced anaemia, little is known about the clinical consequences of this anaemia. Therefore, we asked the question, ‘In patients undergoing ADT for metastatic prostate cancer at Mayo Clinic in Arizona (MCA), is there a significant drop in haemoglobin levels, and if so, do patients become symptomatic?’ To answer this question, we conducted a chart review of patients receiving ADT for metastatic prostate cancer to determine haemoglobin levels before and during treatment, and to assess for anaemia-related symptoms.

Methods

To determine the effect of ADT on haemoglobin levels and patient symptoms, we conducted a retrospective chart review of 135 analytic American Joint Committee on Cancer (AJCC) stage IV prostate cancer cases seen at MCA between 1 January 2000 and 30 December 2005. Patients who received their initial diagnosis and all or part of their treatment at MCA, or who were diagnosed elsewhere, but received all or part of their treatment at MCA, were included in the analysis. Patients who received a diagnosis of and treatment for stage IV prostate cancer elsewhere, but came to MCA for a second opinion only (i.e. not for treatment), were excluded from the analysis. The Mayo Clinic Foundation Institutional Review Board approved the conduct of the study.

The following information was collected: type of treatment given (radiation, orchiectomy, hormonal agents and/or chemotherapy); haemoglobin and mean corpuscular volume (MCV) values before and at 3 to 9 months after beginning treatment; creatinine level and glomerular filtration rate (GFR) at 3 to 9 months; and presence or absence of symptoms of anaemia. A patient was considered to have symptoms of anaemia if a chart note referenced ‘fatigue’ or ‘dyspnea on exertion’ at or near the same time at which laboratory values used in the analysis were obtained; symptoms were considered absent if these terms were not found in corresponding chart notes. Where possible and in general, the laboratory values included in the data analysis were values drawn at 6 months; values at either 3 or 9 months were used if a 6 month value was not available. Patients were excluded from the analysis if haemoglobin levels were not checked at the start of treatment or between 3 to 9 months, if they were lost to follow-up, and as noted above.

Statistical analysis was performed using JMP version 6.0. Mean haemoglobin levels before and after 3 to 9 months of all forms of treatment were calculated; a paired T-test was used to evaluate for statistically significant differences. Mean haemoglobin levels before and after 3 to 9 months of treatment for patients receiving leuprolide alone, and for patients treated with combination leuprolide/bicalutamide were also calculated; a paired T-test was used to evaluate for statistically significant differences.

Additional evaluation of treatment effects on patient symptoms was completed. An ‘RX3’ dummy variable was completed to assess the effect of leuprolide therapy alone versus ‘non-RX3’ treatment, which consisted of combined treatment modalities including leuprolide with bicalutamide, or goserilin with bicalutamide, plus or minus radiation therapy. The data was compared against the patient's symptoms, placed in a contingency table, and was tested for statistical significance using Fisher's exact test.

The effect of leuprolide treatment alone on haemoglobin levels was also assessed by the use of multivariate linear regression. The dependent variable was the change in haemoglobin level and the independent variables included symptoms, age, creatinine level and leuprolide therapy. The multivariate regression provides a mechanism to assess the effect of leuprolide therapy alone when adjusted for age, creatinine and patient symptoms.

Results

Of the 135 identified cases, 43 patients had sufficient laboratory data to be included in the analysis. All patients analysed received a form of ADT as part of their treatment (Table I). The majority of patients (n = 32, 74%) received leuprolide alone or in combination with bicalutamide.

Table I.  Number of patients receiving each form of therapy.

Therapy received	Number of patients (n = 43)
External beam radiation and orchiectomy	2
External beam radiation, leuprolide and bicalutamide	2
External beam radiation and leuprolide alone	2
Combination chemotherapy and leuprolide alone	2
Goserilin and bicalutamide	3
Leuprolide alone	11
Leuprolide and bicalutamide	21

As shown in Table II, the average age of patients was 70.12 years. For all forms of treatment, the mean haemoglobin value prior to receiving ADT was 14.12 g/dL. Three to nine months after initiation of therapy, the value was 13.01 g/dL, conveying a mean decline of −1.11 g/dL (95% CI −0.649 to −1.5733, p < 0.0001) (Table II). This value is in the anaemic range (normal haemoglobin = 13.2–17.5 g/dL). MCV at 6 months was 93.5 fL. Average GFR was 69 ml/min/1.73 m².

Table II.  Average age, haemoglobin levels and GFR of patients undergoing ADT.

Average age	70.12 years
Haemoglobin beginning	14.3 g/dL
Haemoglobin after 3 to 9 months	13.0 g/dL
Average GFR at 3 to 9 months of therapy	69 ml/min/1.73 m^2

For patients treated with leuprolide alone (n = 11), the mean haemoglobin value prior to receiving leuprolide was 14.81 g/dL. Three to nine months after initiation of therapy, the value was 13.15 g/dL, conveying a mean decline of −1.66 g/dL (95% CI −1.1966 to −2.1125, p < 0.0001), and also in the anaemic range (Table III). For patients treated with leuprolide and bicalutamide (n = 22), the mean haemoglobin value prior to receiving the combination was 13.93 g/dL. Three to nine months after initiation of therapy, the value was 13.15 g/dL, conveying a mean decline of −0.78 g/dL (95% CI −0.0289 to −1.5424, p = 0.0426), and again in the anaemic range (Table III).

Table III.  Effect of treatment on haemoglobin levels.

Treatment	Number of patients	Mean haemoglobin (g/dL) decrease	Haemoglobin (g/dL) decrease range
Leuprolide alone	11	−1.66*	−0.9–−2.8
Leuprolide with bicalutamide	21	−0.78^†	−0.2–−3.4

*p < .0001.

^†p = 0.0426.

Overall, 16 patients were identified to have symptoms from anaemia. Only one of the 16 patients reporting anaemia symptoms was treated with leuprolide alone (Table III); the remaining 10 patients receiving leuprolide alone had no symptoms from anaemia. The other 15 patients reporting symptomatic anaemia were on multi-agent therapy, including leuprolide with bicalutamide (9 patients, Table III), or goserilin with bicalutamide, plus or minus radiation therapy. Contingency analysis with Fisher's exact test shows that patients receiving leuprolide therapy alone were significantly less likely to have symptoms from anaemia than patients receiving other forms of therapy (p = 0.0190).

On linear regression with multivariate analysis, the independent variables for symptoms, leuprolide therapy, and age are statistically significant and are associated with a reduction in the patient's haemoglobin. The independent variable for creatinine was added to the regression to account for the effect of renal function on haemoglobin, but was not statistically significant after factoring for age, leuprolide therapy and symptoms (Table IV).

Table IV.  Linear regression analysis of change in haemoglobin.

Parameter estimates
Term	Estimate	Prob > |t|
Intercept	5.870113	0.0015
Symptom	−0.675482	0.0075
Age	−0.048364	0.0455
Leuprolide therapy	−0.697754	0.015
Creatinine	−0.688939	0.1244
R-squared	0.33

Discussion

Testosterone and its metabolites have long been recognized for their stimulating effects on erythropoietin levels, haem synthesis and erythroid colony-forming cells within the bone marrow. More recently, reports of anaemia resulting from ADT for advanced prostate cancer have appeared. The present study confirms that ADT results in a significant drop in haemoglobin levels into the anaemic range. In addition, the data show a number of patients become symptomatic from this change.

All patients analysed here received a form of ADT as part of their treatment for stage IV prostate cancer. A significant drop in haemoglobin levels of approximately 1 g/dL was observed, with mean haemoglobin levels in the anaemic range at 3 to 9 months following initiation of therapy. Mean MCV was in the normocytic range. It is possible that the decline in haemoglobin values could be due to a combination of factors besides androgen deprivation alone, including radiation or chemotherapy effects. However, a similar decline in haemoglobin levels was observed in the 32 patients receiving hormonal agents alone (leuprolide alone or in combination with bicalutamide), thereby indicating that ADT by itself can lead to the decline in haemoglobin. Anaemia of chronic disease, blood loss or bone marrow involvement by tumor are possible contributing factors, although previous studies controlling for these factors have not found them to play a role [8],[12],[14],[16],[17].

For patients treated with leuprolide therapy alone, multivariate linear regression analysis shows that haemoglobin declines when controlled for age, creatinine and symptoms. This finding agrees with the results of a study by Eri and Tveter. In their study of 50 patients receiving leuprolide therapy for BPH, a mean decline in haemoglobin of 0.8 g/dL at 6 months was observed [10]. Similarly, Weber et al. reported a haemoglobin decline of 1.1 g/dL at 6 months in a study of 10 men receiving the GNRH-agonist nafarelin for BPH [9].

Furthermore, the development of anaemia in patients receiving combined androgen deprivation with leuprolide and bicalutamide is similar to that found in several additional studies. Asbell et al. studied 131 men with locally advanced prostate cancer taking flutamide plus zoladex for 2 months, followed by continued combined androgen deprivation with radiation. A mean haemoglobin decline of 2.8 g/dL at 4 months was observed [12]. Strum et al. described 133 patients receiving leuprolide plus flutamide, or other combinations of GnRH-agonists plus antiandrogens, with a mean haemoglobin decline of 1.8 g/dL at 3 months [17]. Ornstein et al. report 19 men with advanced prostate cancer who received finasteride plus flutamide for 6 months; a significant drop in haemoglobin of 1.6 g/dL was found [13]. Bogdanos et al. treated 42 patients with stage C or stage D1 prostate cancer with leuprolide plus flutamide; haemoglobin decreased significantly, by an average of 1.5 g/dL [14]. Qian et al., in their study of 136 patients with varying stage prostate cancer treated with bilateral orchiectomy plus flutamide, observed a significant haemoglobin decline of 2.3 g/dL at 6 months [15]. Finally, Choo et al. followed 72 patients with non-metastatic prostate cancer treated with radical prostatectomy followed by 6 weeks of radiation therapy and then 2 years of nilutamide and busereline as adjuvant therapy; a mean haemoglobin decline of 0.83 g/dL at 24 months was found [16].

The development of anaemia following initiation of ADT is thought to be due to a loss of the erythropoietic stimulating effects of androgens. Stem cells within the bone marrow have testosterone receptors, which, when exposed to 17-keto derivatives of androgens, cause expression of genes that differentiate the stem cells into erythroid colony forming cells [16]. With a decline in androgen levels produced by GnRH-agonists and/or testosterone antagonists, bone marrow stem cells are no longer exposed to this stimulus, and thus a decline in the number of new erythrocytes produced from the bone marrow (and hence a decline in the measured haemoglobin value) results.

The consequence of fewer erythrocytes produced is, of course, anaemia, which often causes a patient to have symptoms. However, limited data on the numbers of patients developing symptoms of anaemia while on ADT are available. To address this lack of knowledge, the present study included a review of the numbers of patients developing anaemia symptoms while on ADT. We found that 16 of the 43 patients analysed (37%) developed symptoms. Additionally, patients receiving leuprolide alone were significantly less likely to have symptoms of anaemia than patients given combination forms of therapy. This overall number of symptomatic patients is much higher than reported in other studies. No patients were found to have symptoms of anaemia in the Ornstein et al. study [13]. Only 17 patients (13%) developed symptoms of anaemia in the Strum et al. study [17], and six patients (14%) in the Bogdanos et al. study developed symptoms [14].

To account for this difference, we propose the following: it is possible that patients selected to be treated with single agent therapy in our study may have had less advanced disease, and hence better overall health status, than those patients given combination ADT plus or minus combination chemotherapy/radiation. Such patients may have been less likely to report symptoms. This theory also may explain why more patients treated with combination leuprolide and bicalutamide were symptomatic than those treated with leuprolide alone, despite a lower mean decrease in these patients' haemoglobin.

Regardless of the actual number of patients that may become symptomatic from anaemia while on ADT, a certain number will. For such patients, current guidelines recommend red blood cell transfusions as necessary and strong consideration of treatment with erythropoietin for haemoglobin values less than 10 g/dL [19]. Erythropoietin treatment resulted in symptom improvement in several studies [14],[16],[17]. Given that patients may develop symptoms, practitioners should be careful to monitor haemoglobin levels periodically.

There are several limitations to the present study that must be mentioned. The patients included in the analysis received a wide variety of treatments, and because of this heterogeneity, the development of anaemia observed can be attributed only to ADT in general, not to any particular hormonal treatment. Also, the data set included a small number of patients, thus limiting the power of the study. Furthermore, there are inherent flaws in retrospective chart reviews, including non-randomization of patients and non-blinding of the observers. However, the data reported here is in line with that of several previous studies, as outlined.

ADT is a widely used treatment modality for advanced prostate cancer. A now well-reported side effect of this therapy is a decline in haemoglobin levels, generally within 2 to 6 months of therapy initiation, and often into the normocytic-anaemic range. A certain number of men receiving ADT will develop symptoms related to their anaemia. Therefore, haemoglobin levels should be monitored after starting ADT, and patients should be screened for anaemia symptoms.

Acknowledgements

We thank Jorge Rakela MD, and Keith J. Cannon MD, Department of Internal Medicine, MCA, for their support.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.