Consistent with a previous study by Si et al. [4], the current study demonstrated longer PFS in the patients receiving ADT plus surgery for mPCA than ADT alone. Of note, we found survival benefit for ADT plus cryosurgery only in patients with low metastatic volume, but not high metastatic volume. In the STAMPEDE trial [3], radiotherapy to the primary tumor did not improve OS in the overall study population. In the subgroup analysis that divided the patients based on the CHAARTED standard, however, radiotherapy increased the OS in the low-volume subgroup. Results in subgroup analysis in our study were consistent with the STAMPED study.
Cox multivariate analysis showed that the patients with positive CTCs at 3 months or 1 year post-treatment had shorter PFS. In the IMMC38 trial, de Bono et al. [7] detected CTCs in 231 CRPC patients receiving chemotherapy with CellSearch system, and showed a close association between shorter OS with higher CTC at both prior to and after treatment. Mandel et al. [14] examined CTCs in 33 patients with hormone-naïve oligometastatic prostate cancer undergoing cytoreductive radical prostatectomy, and found earlier CRPC and shorter OS in patients with CTCs ≥ 2 in 7.5-ml peripheral blood at 6 months postoperatively. The results suggest that high CTC is a risk for poor prognosis, and maybe helpful in selecting hormone-naïve oligometastatic prostate cancer patients for cytoreductive radical prostatectomy. The patients with lower CTCs were suitable candidate for cytoreductive radical prostatectomy. To our best knowledge, this is the first study which found CTC count could identify patients with a poorer prognosis after treatment (cryosurgery or ADT). The patients with positive CTCs at 3 months or 1 year post-treatment had poorer prognosis after treatment (cryosurgery or ADT).
Our study also showed CTC count could determine the degree of response to the treatment. In the current study, the patients receiving ADT plus cryosurgery had lower CTCs at 3 months and 1 year after treatment, and longer PFS than those receiving ADT alone. n comparison to the baseline, the number of CTCs at both 3 and 12 months was lower in the cryosurgery group, but not in the ADT alone group. Lower CTCs in the patients receiving ADT plus cryosurgery was evident in the subgroup analysis that included patients with low metastatic volume only, but not in the subgroup that included the patients with high metastatic volume. Such a finding is consistent with the survival benefit in patients with low metastatic volume only. These results suggested in the patients with low metastatic volume, those receiving ADT plus cryosurgery had lower CTCs and responded better to the treatment than those receiving ADT alone. No similar effect was found in the patients with high metastatic volume.
CTCs could derive from the primary tumor or the metastatic foci. The Higher number of CTCs might be associated with advanced clinical stage and higher metastatic volume [15]. The positive rate of CTCs detected by CellSearch system was 0%-10% in healthy volunteers [16, 17], 5%-38.4% in non-metastatic high risk prostate cancer patients [16–19], 48.5% in oligometastatic prostate cancer [14], and 80% in patients with mCRPC [20]. In our study, the number of CTCs was significantly higher in the patients with high metastatic volume. We hypothesize that since primary tumor represents the major source of CTCs in patients with low metastatic volume, resection of the primary tumor could decrease the number of CTCs, and could be helpful in disease control. In contrast, contribution of the primary tumor to CTCs is relatively small. As a result, the impact of local treatment for primary tumor on patient survival is minimal.
Satkunasivam et al. [5] summarized the mechanisms of survival benefits from local therapy (radical prostatectomy or radiotherapy). First, eradication of the primary tumor eliminates the source of cytokine signaling that prepares niches for eventual sites of metastases and promotes their growth [21]. Second, the primary tumor may remain a source of CTCs that are capable of “self-seeding” the primary organ [22]. Third, local therapy may reduce the number of self-renewing cells that persist after ADT due to the low levels of immature androgen receptors [23]. Local treatment against the primary tumor may induce inflammatory reaction and promote antigen production, which in turn could induce anti-tumor immune responses. Therefore, removal of the primary tumor may reduce metastases [23, 24]. Cryosurgery ablates tumors in situ, leading to the release of tumor proteins and intact tumor associated antigens. Residual tumor antigens may activate anti-tumor immune response in the inflammatory microenvironment [25]. Our current study confirmed that prostate cryosurgery could reduce the source and number of CTCs and then prolong PFS.
The current study has several limitations. As a retrospective analysis, this study has inherent bias in patient selection. Second, the sample size is small. Third, the follow-up was relatively short; we therefore did not analyze cancer-specific survival and OS.