To the Editor,
A successful prostatectomy involves removal of all prostatic tissue leading to unmeasurable PSA blood levels. In case of disease recurrence, the PSA will eventually begin to rise. This can either be due to a local relapse, lymph node involvement or distant metastases. The most widely used definition of biochemical failure is that of the American Urological Association (AUA). This is defined as a serum PSA ≥ 0.2 ng/ml confirmed by a second determination. Unfortunately there is no method available to date that is capable of differentiating between patients with a true local recurrence and those where the disease is located outside of the prostate/seminal vesicle bed. The former group is expected to benefit from local radiotherapy and thus it would be ideal to be able to develop methods to identify these patients. Current practice involves the use of several prognostic factors, such as surgical margins, PSA doubling time and seminal vesicle involvement to identify patients with high probability of local recurrence that would benefit from salvage radiotherapy [Citation1–4].
According to a meta-analysis by King, including 41 studies on salvage radiotherapy, around 54% of patients receiving radiotherapy (70 Gy) attain relapse-free survival after 3–5 years [Citation5]. This also means that a large proportion of these patients only experience side effects without any treatment benefit either due to a local treatment failure, or perhaps more commonly, undetectable disease outside of the prostate/seminal vesicle bed at the time of treatment. Development of methods to identify patients who already have disease deposits that are not covered with traditional salvage radiotherapy would allow one to either intensify this treatment (e.g. hormonal therapy or lymph-node irradiation) or to inhibit it altogether in case of distant metastases.
It has been shown that circulating tumour cells (CTCs) can be identified in patients with metastatic prostate cancer [Citation6]. Whether it is possible to detect these cells at an earlier disease stage, i.e. before distant metastases can be confirmed by imaging modalities, is not well studied. Lowes et al. reported that patients with PSA recurrence had CTCs in the blood in 73% of the cases at pre-treatment [Citation7]. Interestingly patients with CTCs were less likely to respond to treatment. This could indicate that presence of CTCs in blood could be used as a predictive factor during treatment of patients with a recurrent prostate cancer.
The aim of this study was to prospectively evaluate the prevalence of CTCs in patients with PSA recurrence and correlate it to treatment outcome.
Material and methods
Patients
Sixty-one patients were included in this prospective observational trial. All patients had a PSA recurrence after radical prostatectomy. All patients were judged to have a local recurrence and any evidence of disease outside of the prostatic/seminal vesicle bed was an exclusion criteria. No additional prostate cancer treatment was allowed before or during radiotherapy.
Blood sampling and CTC analysis
The samples were collected for all patients at baseline (within one hour before start of radiotherapy). For each patient blood was drawn into 7.5 ml CellSave® preservative tubes (Veridex). The CTC sample was always preceded with a separate blood test to minimise risk of contamination of epithelial cells and then turned eight times for blending. During transport the sample was kept at room-temperature (15–30°C). Food and Drug Administration (FDA) approved CellSearch® method (Veridex, Raritan, NJ, USA) for capturing and enumerating CTCs was used for sample analysis. The method has previously been described by Allard et al. [Citation8]. All samples were kept at room temperature and analysed within 72 hours from sample extraction at the Department of Oncology and Pathology, Clinical Sciences, Lund University, Sweden.
Results
Patient characteristics
Sixty-one patients were included in the study. None of the patients had received hormone therapy. The median PSA value at treatment start was 0.27 (IQR: 0.17–0.36) ng/ml. For further baseline patient characteristics see .
Table I. Patient characteristics.
Follow-up and treatment outcome
The median follow-up time was 13.6 months (IQR 12.6–20.0 months). Forty-five patients (73%) had a declining PSA at six months post-radiotherapy as compared to baseline (PSA response) and in 15 cases (25%) PSA was rising (PSA progress). One patient did not reach six months follow-up as he developed and died of disseminated cholangiocarcinoma. His PSA was < 0.1 ng/ml at three months. At last follow-up 35 patients (57%) had PSA < 0.1 ng/ml, 22 (36%) had rising PSA and in four cases PSA nadir was not reached. Nine patients initiated hormonal treatment due to PSA progression and three patients developed prostate cancer distant metastases during follow-up.
CTCs
CTCs were detected in two study samples from two separate patients whereof one later was shown to have disseminated malignancy in the GI-tract and hence the CTCs were not assumed to stem from prostate cancer recurrence. The other patient belonged to the PSA response category (PSA < 0.1 ng/ml) at six months (last follow-up).
Discussion
According to this prospective observational trial, CTCs are with current state of the art methodology only exceptionally detectable in patients with early biochemical relapse at low PSA levels.
Our results are in contrast to previous work by Lowes et al. [Citation7] in a similar patient population. The reason for this discrepancy is unclear. We have used the same well calibrated system by CellSearch® (Veridex, Raritan, NJ, USA). Our laboratory has a long experience with this type of analyses and reports CTC detection rates in other patient materials similar to data presented in the literature.
In conclusion CTCs are according to our results not yet sufficiently useful as a predictive tool for treatment of patients with an early PSA recurrence after prostatectomy. We assume that CTCs are unlikely to be detected with current methods in the majority of patients with early relapse which is reflected in the fact that no CTCs were detected in the non-responding group included in this study.
Acknowledgements
We would like to thank Gertrud Strömbäck, Hanna-Karin Göransson and Anna-Maria Lind, Department of Radiotherapy, and Anna Weddig at the Clinical Research Unit at the Department of Oncology, Skåne University Hospital for gathering and processing the blood samples and Kristina Aaltonen, Sara Baker and Kristina Lövgren at the Department of Oncology and Pathology for undertaking the CellSearch-based CTC analysis. We acknowledge financial support from Berta Kamprad Cancer Foundation.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
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