Neuroendocrine Serum Tumour Markers in Hormone-Resistant Prostate Cancer
Introduction
Prostate cancer is the most common cancer in men, and represents the second most common cause of cancer-related death in the United States as also in Norway [1]. Initially most tumours present as androgen-sensitive adenocarcinoma, but the histology becomes more undifferentiated along with clinical progression and the development of hormone resistance. The microscopic appearance of so-called neuroendocrine (NE) cells is a part of such dedifferentiation, though these cells occasionally can be found even in the initial histological sections. In recent years much research has dealt with NE cells and their clinical relevance as to prostate cancer. Dependent on patient selection and staining techniques NE cells have been described in 10 to 100 percent in patients with prostatic carcinoma [2], [3], [4], [5].
NE cells may produce specific proteins, which are secreted to the serum. Serum levels of NE proteins may supply prognostic information. Such neuroendocrine tumour markers are chromogranin A (CgA) and neuron-specific enolase (NSE). The clinical significance of these markers has been analyzed in several studies, and CgA and NSE have been shown to have independent prognostic significance in prostate cancer [6], [7], [8]. Serum NSE seems to be most useful as a marker of localized forms of the disease, while the significance of CgA increases in metastatic and progressive disease [7], [9], [10]. High levels of CgA and NSE are usually viewed to be associated with hormoneresistance, mirroring poor prognosis. However, the results have been conflicting [6], [9], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], and more studies are needed which evaluate the clinical significance of these serum markers.
Most NE cells in prostate cancer are considered to be in the G0 phase which correlates with low or absent sensitivity to radiotherapy. Therefore one would expect unchanged or even raised serum levels of NSE or CgA after radiotherapy to metastatic lesions, though so far only one limited study has investigated the kinetics of these markers in relation to palliative external radiotherapy. Ferrero-Pous et al. [24] recorded reduction of NSE in 30% of their patients receiving systemic radionuclide therapy for widespread metastatic prostate cancer. More studies are needed to understand NE cells’ response to irradiation in the human situation.
The primary aim of the present study was to assess the prevalence of elevated serum levels of NSE and CgA in hormone-resistant prostate cancer (HRPC), and to evaluate whether CgA and/or NSE could predict survival in this patient group. In addition we wanted to assess any possible change in levels of NSE or CgA comparing serum levels before and after palliative radiotherapy.
Section snippets
Patients
Each year about 120 patients with symptomatic HRPC are referred to radiotherapy at the Norwegian Radium Hospital (NRH) due to painful bone metastases or symptomatic growing pelvic soft tissue tumours. Symptomatic HRPC was defined as painful and progressing prostate cancer in spite of castration levels of serum testosterone. The present retrospective study includes consecutive patients with symptomatic HRPC if they had been treated from November 1997 to August 2001 and if a pre-radiotherapy
Demographics
A total of 138 patients (median age 72 years, range: 46–88) were eligible for pre-radiotherapy testing (Table 1). In 75 of these patients a post-treatment sample analysis of all three markers was also available. As many as 85 patients had a high level of EOD. The median time from castration to start of radiotherapy was 27.5 months.
Pre-radiotherapy serum values
The median serum PSA was 166 μg/l (range 0.2–3846) (Table 2). Seven patients (5%) had PSA<4 μg/l, and 7 additional patients displayed a PSA serum level between 4 μg/l
Discussion
This study expands the knowledge of neuroendocrine de-differentiation in HRPC. NSE and CgA were elevated in 33% and 58% of the patients respectively, without statistical correlation with each other or with PSA. The level of NSE, was associated with survival, whereas this was not the case for CgA. A new finding was that serum NSE decreased after external beam palliative radiotherapy, corresponding to a significant post-radiotherapy reduction in 79% of the patients with elevated NSE values before
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These three authors have contributed equally.