Anaemia and thrombocytopenia in patients with prostate cancer and bone metastases

Bone metastasis is a common complication in patients with advanced stage prostate cancer and might even be found already at first clinical diagnosis [1, 2]. Depending on the extent of spread, bone marrow function might become compromised, resulting in anaemia und thrombocytopenia [3, 4]. Prognosis after onset of anaemia und thrombocytopenia is not well described in the literature. In addition, factors predicting for these complications are poorly understood. To study the incidence, outcome and risk factors for anaemia and thrombocytopenia in men with prostate cancer and skeletal metastases, a retrospective cohort study was performed.

A retrospective analysis, which included all patients with prostate cancer and bone metastases treated at the authors' institution during 2007 and 2008, was performed. The authors' institution is a community hospital in rural Norway, which is the only oncology care provider and services the complete population of the county, i.e. approximately 236,000 inhabitants. Thus, the 51 consecutive patients included in this study represent an unselected population. Follow-up information was available in all patients. Temporary anaemia, leuko- and thrombocytopenia episodes might result from chemotherapy or radioisotope toxicity, necessitating for example chemotherapy dose reduction. Such toxicity is reversible and not expected to predict short survival. The present analysis did not include reversible events in patients who received chemotherapy or radioisotopes at the time of the event. It is focused on anaemia and thrombocytopenia resulting from disease progression. The cut-off for low Hb was set at 10.0 g/dL as patients with higher values are not expected to receive red blood cell transfusion. Regarding Trc, 50 × 10⁹/L was chosen as higher values will not result in bleeding complications. The normal range for haemoglobin (Hb) was 13.4-17.0 g/dL. The normal range for thrombocytes (Trc) was 130-400 × 10⁹/L. We used the Kaplan-Meier method to generate actuarial survival curves. Patients without event were censored at last clinical follow-up. Survival was calculated from the date of imaging diagnosis of bone metastases (typically by isotope bone scan) or from development of Hb < 10 g/dL. Survival curves were compared with the log rank test. Wilcoxon- and Kruskal-Wallis-tests were used to compare the baseline characteristics between different groups. A p-value ≤ 0.05 was considered statistically significant.

The present study is to our best knowledge the only contemporary series examining the incidence, outcome and risk factors for development of anaemia and thrombocytopenia in patients treated for bone metastases from prostate cancer. To avoid confounding factors, reversible events caused by chemotherapy or radioisotope toxicity were not evaluated. Reversibility was determined by retrospective chart review. Beyond general limitations of retrospective studies, which might contain hidden sources of bias, one should be aware of the limited patient number and thus statistical power. We can not exclude the possibility that a larger study could have identified factors predicting for episodes with Hb < 10 g/dL. However, the data are derived from a representative unselected patient population, actually including all men with bone metastases from prostate cancer in a well defined geographical region. Therefore, it is likely that our findings apply to many men with bone metastases from prostate cancer treated outside of clinical trials by practicing oncologists. We had to arbitrarily define anaemia and thrombocytopenia. Other cut-off values might have been possible, but we decided to consider the probability for red blood cell transfusion and risk of bleeding when choosing Hb < 10 g/dL and Trc < 50 × 10⁹/L. All relevant clinical events were captured when applying these cut-off values. Geenen et al. have previously shown that the white blood cell system did not seem to be affected in patients with metastatic prostate cancer [5]. The present study confirms this result.

Treatment was individualised, taking into account age, organ function, performance status, symptoms etc. The majority of patients (57%) received taxotere after diagnosis of bone metastases and some patients also had second-line treatment with mitoxantrone. Administration of chemotherapy significantly influenced survival. The 2-year rate was 68% in chemotherapy-treated patients versus 41% in others. This difference is only partially attributable to treatment as this was a retrospective study where several sources of bias influenced the choice of treatment. Survival in most patients was 2-3 years, but 4 patients were alive more than 5 years after the detection of bone metastases.

It should also be noticed that androgen deprivation therapy might result in declining Hb, e.g., mean reduction by 1.1 g/dL in the study by Curtis et al. [6]. Beer et al. observed a mean decline of 0.54 g/dL 3 months after starting androgen deprivation therapy [7]. However, the mean level increased in patients with baseline level < 12 g/dL. A decline after 3 months was associated independently with shorter survival and progression-free survival. Already in a previous study, the same group had described an association between anaemia and shorter survival in men with newly diagnosed metastatic prostate cancer [8]. These recent results confirm established prognostic models such as the one developed by Halabi et al., which includes, e.g., Hb, alkaline phosphatase, lactate dehydrogenase and PSA [9]. Because the focus of the present study was on haematological events, detailed analyses of all prognostic factors for survival including alkaline phosphatase and lactate dehydrogenase were not performed. Other authors demonstrated that patients with lower Hb had more advanced disease on bone scan [10]. The time to development of bone metastases (synchronous versus metachronous presentation) and the number of foci on isotope bone scan had no influence on any outcome in the present study. The same holds true for age and distant metastases at non-skeletal sites. While Hb at the time of bone metastases detection was not significant when using the median value as cut-off, an association of Hb ≤ 12.0 g/dL and short survival might be present.

A large number of patients (49%) experienced episodes with Hb < 10 g/dL unexplained by chemotherapy and radioisotope toxicity, but reflecting disease progression. Sixty percent of patients with Hb < 10 g/dL required red blood cell transfusion (29% of all patients in the study). In a previous study, only 10% of patients became anaemic and 7.5% received red blood cell transfusion, but that study was limited to the final year of life and largely to the pre-taxotere era [4]. Notably the decision to transfuse and timing is somewhat subjective and varies from physician to physician. It should also be noted that we did not administer erythropoiesis stimulating agents, which might reduce the need for transfusion, given the debate around these agents and recent recommendations [11‐13]. Median survival from Hb < 10 g/dL was 5.4 months. Thus, this factor predicts when the disease reaches a critical point where the remaining life time is very limited. No risk factors for development of Hb < 10 g/dL could be identified. Five patients (10%) developed episodes with Trc < 50 × 10⁹/L. All of these had previously experienced Hb < 10 g/dL and received red blood cell transfusion. Thus, 5 of 15 patients (33%) who had required transfusion also developed severe thrombocytopenia. Survival after detection of severe thrombocytopenia was short, ranging from 3 weeks to 4 months. Complications such as haematuria, subdural haematoma and the inability to recover from emergency surgery were among the causes of death.

Declining bone marrow function continues to be a common event during the course of prostate cancer with skeletal metastases. It contributes significantly to morbidity and mortality and poses challenges to those involved in palliative care for these patients. The current survival figures after detection of Hb < 10 g/dL and Trc < 50 × 10⁹/L should be regarded as initial estimates, which need to be confirmed in larger studies.