Pathologic fracture and metastatic spinal cord compression in patients with prostate cancer and bone metastases

Abstract (provisional)

Background
The purpose of this study was to determine the risk factors for and incidence as well as prognostic impact of pathologic fracture (PF) and metastatic spinal cord compression (MSCC) in patients with bone metastases (BM) from prostate cancer.

Methods
Retrospective cohort study including 61 consecutive patients seen at Nordland hospital’s department of oncology between 2007 and 2009. The initial diagnosis of BM might have been made earlier. Twenty-nine patients (48%) received taxotere and 72% zoledronic acid after diagnosis of BM.

Results
Median actuarial survival after diagnosis of BM was 23 months. Six patients (10%) were alive at 5 years. Bone pain at baseline was present in 49% of patients. Eighty-nine percent required external beam radiotherapy and/or radioisotopes after diagnosis of BM. Seventeen patients (28%) developed at least one major skeletal complication, i.e. MSCC or PF (4 of them developed more than one). The actuarial risk was 44% at 4 and 5 years. Most events developed before treatment with zoledronic acid and/or taxotere. Median survival from diagnosis of either MSCC or PF was 11 months (5 months from MSCC). We did not identify statistically significant risk factors for development of major skeletal complications. Serum alkaline phosphatase above median value and age less than or equal to 70 years were the only risk factors approaching significance.

Conclusions
We found high rates of major skeletal complications in this unselected contemporary group of patients. Identification of risk factors might guide the development of early interventions aiming at prevention of MSCC and PF.

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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]. Increasing extent of spread might compromise bone stability, resulting in pathologic facture (PF) [3]. In addition, at least 5-10% of patients might develop metastatic spinal cord compression (MSCC) with or without vertebral fracture [4]. Prognosis after onset of MSCC is limited. Factors predicting for these two major skeletal complications in patients managed by practitioners outside of prospective clinical trials are not completely understood.  To study the incidence,  outcome and risk factors for PF and MSCC 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,  2008 and early 2009 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 61 consecutive patients included in this study represent an unselected population. Follow-up information was available in all patients. The initial diagnosis of bone metastases might have been made before 2007.  Our laboratory provided the following information on normal ranges:  haemoglobin (Hb)  13.4-17.0 g/dL, serum alkaline phosphatase (ALP) <105 U/L, serum lactate dehydrogenase (LDH) <205 U/L and serum calcium 2.15-2.55 mmol/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 other analysed events.  Survival curves were compared with the log rank test.  Afterwards,  statistically significant prognostic factors for survival were examined by multivariate Cox regression analysis (forward stepwise data selection method). Wilcoxon- and Kruskal-Wallis-tests were used to compare the baseline characteristics between different groups.  Risk factors for development of PF and MSCC were evaluated with the Fisher exact test and confirmed by actuarial Kaplan-Meier analyses as these were time-dependent events.  PF was defined as a bone broken,  not by trauma alone, but so weakened by metastatic spread as to break with abnormal ease [5, 6]. MSCC was defined as compression by direct pressure and/or induction of vertebral collapse or instability by metastatic spread that threatens or causes neurological disability [5,  6].

Vertebral deformities (consistent with fracture)  were identified by direct visualisation using the Genant semi-quantitative grading scale [7,  8].  Plain radiography was used except for some patients who had computed tomography scans only.  Synchronous bone metastasis was defined as simultaneous diagnosis of prostate cancer and metastatic spread to the bones.  A p-value =0.05 was considered statistically significant.  No correction for multiple testing was performed.  The study was performed as a retrospective analysis of skeletal complications. As a quality of care analysis where data was fully de-identified, no approval from the Regional Committees for Medical and Health Research Ethics (REK)  was necessary.

Results
The patient characteristics and length of follow-up are shown in Table 1.  Treatment consisted of different types of androgen suppression regimens incl. steroids and palliative external beam radiotherapy in patients with bone pain,  MSCC or surgically stabilized PF.

Administration of other treatments is also shown in Table 1.  Twenty-nine patients (48%) received taxotere after diagnosis of bone metastases and 7 of these also proceeded to second-line treatment with mitoxantrone.  The initial number of bone metastases on radioisotope bone scan was significantly higher in patients with synchronous presentation compared to metachronous presentation,  p=0.05.  Patients with synchronous presentation also had significantly higher median prostate-specific antigen (PSA)  value,  p<0.01,  ALP value (p< 0.01)  and LDH value (p=0.03),  as shown in Table 1.  No other significant differences in baseline characteristics were found between these two groups, which did not differ significantly in overall survival or development of MSCC and PF. 
Median actuarial survival after diagnosis of bone metastases was 23 months. Six patients (10%)  were alive at 5 years.  The parameters shown in Table 2 were examined for their prognostic impact by comparing actuarial survival curves (log rank test).  While Hb at the time of bone metastases detection was not significant when using the median value as cutoff, a significant association between Hb =12.0 g/dL and short survival was found, p=0.03.

The 2-year survival rate in patients with Hb =12.0 g/dL was 25%. Performance status also was significant,  p=0.01.  Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 2 had 33% 2-year survival, those with ECOG 1 43% and those with ECOG 0 77%. In these analyses, age >70 years, ALP above median value, and LDH above median value also predicted for significantly shorter survival, p=0.05. A multivariate analysis confirmed performance status, ALP and LDH as independent prognostic factors for survival, p=0.05.  Chemotherapy-treated patients had a 2-year survival rate of 65%.  Patients managed without chemotherapy because of age,  poor performance status and other contraindications had a 2-year survival rate of 39%  (median survival 29 months with chemotherapy versus 17 months without). 

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Carsten Nieder (.(JavaScript must be enabled to view this email address))
Ellinor Haukland (.(JavaScript must be enabled to view this email address))
Adam Pawinski (.(JavaScript must be enabled to view this email address))
Astrid Dalhaug (.(JavaScript must be enabled to view this email address))

BMC Urology 2010, 10:23   doi:10.1186/1471-2490-10-23
Submission date   2 December 2009
Acceptance date   22 December 2010
Publication date   22 December 2010
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