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Keywords:

  • Flutamide;
  • finasteride;
  • advanced prostate cancer;
  • anaemia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objective

To determine the effect of combined finasteride and flutamide therapy on haemoglobin and haematocrit values in men with advanced prostate cancer.

Patients and methods

Nineteen men, previously untreated by hormone therapy, with histologically confirmed adenocarcinoma of the prostate and clinical evidence of advanced disease, were treated with combined finasteride (5 mg/day) and flutamide (750 mg/day) for at least 6 months. Complete blood counts were performed before initiation and after 6 months of therapy.

Results

After 6 months of finasteride and flutamide therapy both haemoglobin levels and haematocrit decreased in all men, with a mean (sd, range) decrease of 16 (10, 3–42) g/L and 4.6 (2.7, 0.8–9.9)%, respectively.

Conclusion

Combined finasteride and flutamide therapy significantly lowers haemoglobin and haematocrit levels in men with advanced prostate cancer, and further study of this effect is warranted.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Androgens stimulate haematopoiesis by activating haematopoietic stem cells and by stimulating the production of erythropoietin [1]. Before the discovery of recombinant erythropoietin, androgens were used clinically to improve haematocrit levels in anaemic patients [2[3]–4]. The erythropoietic effects of androgens may explain why men generally have higher haematocrit levels than age-matched women [1]. Haemoglobin or haematocrit levels have been used as a prognostic factor in men with metastatic prostate cancer, but until recently the impact of hormonal ablation on these indices has not been appreciated [5].

Novel hormone regimens have been studied in an attempt to find effective potency- and libido-sparing therapy for men with advanced prostate cancer [6[7][8]–9]. We have recently reported that the combination of finasteride and flutamide significantly lowers serum PSA levels in most men with advanced prostate cancer, despite resultant rises in serum testosterone levels [10]. Finasteride is a 5α-reductase inhibitor that is widely used for the treatment of BPH and has not been associated with the development of symptomatic anaemia [11]. Flutamide is an oral antiandrogenic agent for which anaemia is an uncommonly reported side-effect [12]. In the present report we describe the impact of combined finasteride and flutamide therapy of 6 months’ duration on haemoglobin and haematocrit levels in men with advanced prostate cancer.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Twenty-four men with histologically proven adenocarcinoma of the prostate and clinical evidence of advanced disease, previously untreated by hormone therapy, were enrolled in an investigational protocol approved by the Human Studies Committee. As previously described [10] these men were initially treated with finasteride (5 mg daily) only. Flutamide (250 mg three times a day) was added when serum PSA levels stabilized after finasteride therapy. Combined finasteride and flutamide therapy was continued unless men were unable to tolerate the agents or if there was disease progression (as indicated by rising serum PSA levels).

All men were evaluated with complete blood counts and liver enzyme assay before initiating therapy; these tests were repeated every 6 months until therapy was discontinued. Complete blood counts after 6 months of therapy were not available for five men (two who died from unrelated causes, two who were receiving conventional hormone therapy because they were intolerant of flutamide, and one who was lost to follow-up). The median age range) of the 19 men included in this report was 72 (62–92) years. Of these 19 men, 14 were treated because of a rising serum PSA level after potentially curative therapy (EBRT in eight, radical prostatectomy in five and cryotherapy in one), and five had untreated metastatic disease (three stage D2, one stage D1 and one stage D0). Before hormone therapy, the median (range) PSA level was 17.1 (4.0–289.0) ng/mL in these 19 men; in 17 men, the serum PSA was <2.0 ng/mL and was <1.0 ng/mL in 13 after 6 months of finasteride and flutamide therapy. None of the men experienced liver dysfunction during the study.

A paired t-test was used to test for significant change in haemoglobin and haematocrit levels after 6 months of therapy and to determine if there was a significant difference in haemoglobin and haematocrit changes in men who had undergone prior definitive therapy, compared with those who had not. Pearson correlation coefficients were used to evaluate the association of the change in testosterone with the change in haemoglobin, and with the change in haematocrit.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The mean haemoglobin and haematocrit levels before and after therapy for the 19 men included in the analysis are shown in Table 1. After 6 months of finasteride and flutamide therapy, both haemoglobin level and haematocrit decreased significantly in all men (Fig. 1). In 13 of the 19 men, the haemoglobin level decreased by at least 10 g/L and in nine the haematocrit decreased by at least 4%. The haemoglobin level was <120 g/L and haematocrit ≤ 35% in only one of 19 men before therapy, but were below these thresholds in five men after 6 months of finasteride and flutamide therapy. The changes in haemoglobin and haematocrit were not dependent on whether the men had previously received potentially curative therapy (P>0.05). The mean (sd) testosterone level rose significantly from 410 (175) μg/mL to 550 (314) (P<0.05). There was no significant correlation between changes in testosterone and changes in haemoglobin (r=0.04, P>0.05) or haematocrit (r=−0.15, P>0.05).

Table 1.  Haemoglobin level and haematocrit in 19 patients with advanced prostate cancer before and after 6 months of finasteride and flutamide therapy Thumbnail image of
image

Figure 1. The correlation between (a) haemoglobin and (b) haematocrit levels before and after 6 months of combined therapy.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The erythropoietic effects of testosterone have been recognized for many years, but it is only recently that evidence for the anaemic effects of hormonal therapy in patients with prostate cancer have been described. Several reports have shown that combined androgen ablation lowers haemoglobin and haematocrit levels in most men. For example, Asbell et al. [13] reported that haemoglobin level decreased by a median of 28 g/L after 4 months of combined flutamide and Zoladex therapy. The relative contribution of each agent could not be determined from that study. However, Strum et al. [5] reported that haemoglobin levels decreased less in men with prostate cancer treated by orchidectomy or LHRH agonists alone than in those treated with combined LHRH agonists and flutamide, and that flutamide had a greater potential to produce anaemia than had bicalutamide.

The present study shows that 6 months of combined finasteride and flutamide lowers haemoglobin and haematocrit levels significantly in men with prostate cancer, even though serum testosterone levels increased. Haematocrit levels fell by > 1 point in 18 of 19 men, by >3 points in 12 and by >4 points in eight. Before treatment, one man was anaemic (i.e. haemoglobin level <120 g/L and haematocrit <35%), but five were anaemic after 6 months of combined therapy. The decrease in haematocrit was independent of baseline testosterone level, the change in testosterone level during therapy, and whether men had undergone prior definitive therapy or not. As the present study was not randomized, we cannot confirm that finasteride and flutamide caused the anaemia in these men. However, as only two men had disease progression during the initial 6 months of combined therapy, the anaemia was probably caused by the therapy rather than disease progression.

The relative contribution of each agent cannot be assessed; both finasteride and flutamide have been used as single agents in several large studies, and anaemia has not been a reported side-effect of either agent. However, no study to date has been designed to assess directly the impact of finasteride or flutamide on haemoglobin and haematocrit levels, and a significant yet clinically undetectable difference may have been missed.

The clinical significance of the decrease in haemoglobin and haematocrit in this study is unknown. No patient complained specifically of symptoms associated with anaemia and none required blood transfusions. However, the impact on quality of life, energy level and general feeling of well-being was not specifically addressed. It is possible that these relatively small decreases in haemoglobin and haematocrit levels could be associated with worsening fatigue and muscle weakness.

The role of combined finasteride and flutamide in the management of advanced prostate cancer has not yet been defined. However, it has been suggested that this form of novel hormone therapy is most appropriate for patients with advanced prostate cancer, who have good performance status, who are sexually active and have low-volume disease (i.e. biochemical recurrence after radical prostatectomy or radiation therapy). It is worth considering that these men may be alive for many years and the anaemic effects of prolonged therapy could be particularly detrimental to this group of patients.

In conclusion, the results of this preliminary study suggest that 6 months of combined finasteride and flutamide therapy significantly lowers haemoglobin and haematocrit levels in men with advanced prostate cancer. As anaemia may be an important side-effect of oral antiandrogen therapy, it should be evaluated in a large prospectively controlled study.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Supported in part by a grant from Merck and Co., and Schering Corp.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References