To the best of our knowledge, this was the first study to investigate the feasibility, safety, QOL and oncological outcomes of cryoablation for nonmetastatic CRPC. The clinical outcomes of 16 cases showed that it was safe of cryoablation for nonmetastatic CRPC, and the patients could also gain urinary function QOL and survival benefits. Moreover, we attempted to look for the most appropriate cohort among nonmetastatic CRPC of cryoablation, and found that the patients with obvious lesion in the prostate of preoperative MRI or PSA < 5.33 ng/ml prior to cryoablation had a better survival.
All stages of PCa patients could get benefit from local therapy [6–9]. There was just one study that had investigated the feasibility of local therapy for CRPC patients [9]. Reichard CA et al. [9] performed radical prostatectomy for 14 patients with metastatic CRPC, there were 5 patients experienced either Grade I or II or III complications, additionally, 4 of 9 patients alive at last follow-up had significant voiding symptoms. In the present cohort, just 1 patient developed a postoperative Clavien II complication, and no patients experienced urinary incontinence, indicating cryoablation was safer and quicker of recovery than radical prostatectomy for CRPC patients. In consistent with radical prostatectomy, cryoablation could improve the urinary function QOL. As to clinical oncological outcome, 4 (28.6%) patients has a PSA decrease in the cohort of Reichard CA et al. [9], while 14 (87.5%) patients had a PSA decline in our cohort, which indicated that cryoablation was better than radical prostatectomy, probably for that the patients in the cohort of Reichard CA et al had a more aggressive PCa.
The mechanisms of castration resistance of PCa and cryoablation could give an explanation of our results. First, as the tumor cells of CRPC had a or a lot of mutations [15], the systemic therapy of new drugs such as abiraterone, enzalutamide or docetaxel just had a short effective duration or was invalid, however, the physical damage could kill the tumor cells no matter what the mechanism of castration resistance was. Cryoablation was a type of physical damage, which was achieved through an argon/helium gas-based circulation system, in which, argon can cool down and helium can heat up [12]. For nonmetastatic CRPC, it was very likely that there were tumor cells or lesions of castration resistance in the prostate, thus the cryoablation of prostate was effective. Additionally, we found that the patients with obvious lesion in the prostate of preoperative MRI could get more survival benefit, which was consistent with the mechanism of cryoablation. Second, ADT could inhibit the systemic immune response of PCa patients, which led to the low immune status of CRPC patients. Pu Y et al. [16] observed that the use of medical ADT involving androgen receptor antagonists unexpectedly had a negative effect on the host immune response by inhibiting the initial T cell priming. In contrast, cryoablation could develop an activated systemic immune response, though some studies showed an immunosuppressive response of cryoablation [12], which may be associated with the type of tumor, method of cryoablation and rate of freeze [17]. Slovak R et al. [18] made a review about the immune effects induced by ablative therapy or the combination with immunomodulation, and showed that cryoablation alone could induce more potent immunostimulatory response than radiofrequency, microwave ablation, focused ultrasound and photothermal ablation for the significantly higher post-cryoablation levels of serum interleukin-1, IL-6, NF-κβ, and tumor necrosis factor-α. Accumulating studies confirmed the synergism of cryoablation to immunotherapy for PCa [19–21]. Waitz R et al. [19] provided a preclinical proof-of-concept in the TRAMP C2 mouse model of PCa that CTLA-4 blockade cooperated with cryoablation to augment antitumor immunity and rejection of tumor metastases. Benzon B et al. [20] examined the potential synergism of cryoablation and check point blocking antibodies in an immunocompetent hormone sensitive murine model of PCa, and found that cryoablation could augment the effects of checkpoint blockades in PCa. Si T et al. [21] analysed the data of 12 metastatic CRPC patients treated with combining cryoablation and granulocyte macrophage colony-stimulating factor, showed that the median PSA decline percentage was 69.4% (range: 30.5–92.5%), the tumor-specific T-cell responses were increased at 4 or 8 weeks after treatment, which indicated that combined cryoablation with granulocyte macrophage colony-stimulating factor treatment was an alternative approach for metastatic CPRC. In the present study, we found that the post-cryoablation levels of IL-2 and IL-6 were significantly elevated, and the cryoablation could induce an activated systemic immune response, resulted in promising early oncological outcome.
There are some limitations to our current study. First, this was a retrospective investigation. Second, the sample size was too tiny. Our results need to be validated by prospective research and patient data from multiple medical centers.