Feasibility of androgen-deprivation and radiation therapy with docetaxel for localized high-risk prostate cancer

Prostate cancer (PC) is the most common cancer in men and the leading cause of cancer-related deaths in developed countries. Most PC-related deaths are caused by metastatic disease, and approximately 10% of newly diagnosed PC cases have distant metastases (1). Although the prognosis of localized PC is generally good, high-risk PC has a significantly worse prognosis than low- and intermediate-risk PC, with a 15-year PC-specific mortality rate of 26–37% (2). Although each guideline defines high risk slightly differently, treatments for high-risk or locally advanced PC include radical prostatectomy + extended pelvic lymph node dissection or radiotherapy (RT) + long-term androgen deprivation therapy (ADT). Stereotactic ablative radiation therapy (SABR) has been reported as a useful treatment for oligometastatic PC (3). Because relapse occurs despite these treatments, many strategies have been considered to improve outcomes. STAMPEDE trial showed that the addition of abiraterone with prednisolone to ADT improves the prognosis of hormone-sensitive metastatic PC patients (4). Furthermore, STAMPEDE and CHAARTED trials showed that the addition of docetaxel to ADT improves the prognosis of castration-sensitive metastatic PC patients (5,6). Therefore, docetaxel therapy was considered a promising strategy, and the phase III NRG Oncology Radiation Therapy Oncology Group (RTOG) 0521 trial was conducted (7). In an interim analysis of the RTOG 0521 trial, the docetaxel group (ADT + RT + docetaxel) significantly improved the 4-year overall survival (OS) compared with the control group (ADT + RT) in patients with high-risk nonmetastatic PC (4-year OS: 93% vs. 89%, respectively). In addition, the disease-free survival (DFS) rate improved, and the distant metastasis rate decreased in the docetaxel group. However, long-term follow-up (median follow-up of survivors, 10.4 years) showed no significant differences in OS, DFS, or distant metastasis rates between the two groups (7). This study suggests that docetaxel should not be used in high-risk localized PC. The results are very interesting and provide valuable knowledge for both patients and physicians. However, the 4-year OS was significantly prolonged in the docetaxel group, making it difficult to believe that there is no benefit from docetaxel.

Various studies other than the RTOG 0521 trial have also reported that docetaxel provides no clinical benefit for nonmetastatic PC (7). However, the definition of high-risk PC in each study varied. In the RTOG 0521 trial, 52.8% of the cases had a Gleason’s score (GS) of ≥9, and 16% had a GS of 7 (7). Thus, a fairly wide range of cases was included among the high-risk PC. Because the prognosis of patients with high-risk PC, including Gleason pattern 5, is poor, it may be possible to identify patients who would benefit from docetaxel by further narrowing down the range of cases (8). GS is a very useful prognostic factor for PC; however, it may be possible to identify cases using serum markers. Various serum biomarkers for PC have been reported (9). These include microRNA, androgen receptor mutant, bone metabolism, neuroendocrine, and metabolite biomarkers, which may guide treatment selection and sequencing in an era of personalized therapy (9).

Lactate dehydrogenase (LDH), which regulates the conversion of pyruvate to lactate, is a known prognostic factor in advanced PC (8). LDH is a tetrameric enzyme consisting of three different monomeric subunits, such as LDH-A, which is involved in docetaxel resistance (10). In the future, it may be possible to extract cases in which docetaxel is beneficial using LDH values.

CCL2 is a 13-kDa protein composed of 76 amino acids, also known as monocyte chemotaxis protein-1, and was first discovered among CC chemokines in 1989. Several recent studies have reported on the role of CCL2 in various cancers, including PC, which has attracted much attention. Previously, we showed that the suppression of AR signaling not only inhibits PC cell proliferation and prostate-specific antigen (PSA) secretion but also promotes CCL2 secretion to enable PC cell metastasis. These results suggest that CCL2 is a useful biomarker for PC. In 379 patients, we analyzed serum CCL2 levels measured during CCL2 prostate biopsy and long-term observation (median follow-up, 110.4 months) (11). Analysis of patients with nonmetastatic castration-sensitive PC (nmCSPC) showed that CCL2 is a predictor of OS and castration-resistant PC-free survival in nmCSPC (11). CCL2 is a prognostic factor for nmCSPC and may be useful in identifying patients with high-risk nmCSPC. In a basic study, CCL2 levels of the wild-type PC cell line (DU145), docetaxel-resistant PC cell line (DU145-TxR), and cabazitaxel-resistant PC cell line (DU145 TxR/CxR) were examined, and DU145-TxR DU145 TxR/CxR had significantly higher CCL2 levels than DU145 (12). CCL2 treatment of DU145 resulted in cabazitaxel tolerance, and CCR2 (specific receptor for CCL2) antagonist treatment of DU145-TxR/CxR also reduced cabazitaxel tolerance (12). CCL2-mediated docetaxel resistance was also reported. The inhibition of CCL2 activity has antitumor effects, and the combination of CCL2 inhibition and docetaxel enhanced the therapeutic effect of docetaxel (13). CCL2 may not only be a biomarker of high-risk nmCSPC but may also be a predictor of response to taxane-based chemotherapy.

miRNAs are endogenous short non-coding RNAs that bind to complementary messenger RNAs and repress gene expression post-transcriptionally. Changes in miRNA expression can affect important cellular processes such as cell cycle, proliferation, apoptosis, and epithelial-to-mesenchymal transition (EMT) (9). Various miRNAs have been reported as biomarkers in PC (9). miRNA-21 levels were higher in docetaxel-resistant castration-resistant prostate cancers (CRPCs) than in docetaxel-sensitive CRPCs (14). In addition, miRNA-200 and miRNA-17 levels were associated with improved PSA response and OS in CRPCs treated with docetaxel (15). These miRNAs may be involved in the mechanism of docetaxel resistance and may serve as biomarkers of docetaxel resistance.

Previous studies have shown that docetaxel should not be used for broadly defined high-risk localized PC. Docetaxel is not recommended to improve the prognosis of high-risk localized PC. As mentioned earlier, narrowly defined high-risk PC that would benefit from docetaxel may be identified using various biomarkers; thus, future studies are required.

Acknowledgments

Funding: None.

Footnote

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