Research has shown that upfront chemotherapy with first-line ADT significantly improved OS in patients with high-volume metastatic hormone-sensitive prostate cancer.[5] Accordingly, previous studies had identified age, ECOG, Gleason grade group, pretreatment Hb, ALP, LDH, nadir PSA level, TTN and PSADT as prognostic factors for mPCa.[9, 19, 22] Apart from the aforementioned factors, Guangjie et al. demonstrated that patients who exhibited a rapid decrease in PSA levels during the initial ADT phase were at increased risk for progression to CRPC.[16] Masahiko Nakayama et al. introduced the concept that PSA kinetics and early PSA decline were associated differently with time to PSA progression in patients with mCRPC receiving abiraterone acetate. However, the aforementioned study had a limited number of patients and events.[26] Accordingly, the present study found that PSA kinetics was strongly associated with either risk for disease progression or OS. To date, three major clinical trials, namely GETUG-AFU 15, CHAARTED and STAMPEDE, had investigated the role of docetaxel in hormone-sensitive prostate cancer. All three studies had incorporated early chemohormonal therapy into their treatment stagey for mHSPC.[27] Among the overmentioned trials, only CHAARTED had classified the study groups based on tumor volume, subsequently demonstrating a statistically significant improvement in OS for patients with HVD on chemohormonal therapy.[27]
HVD accounted for 54% of our study population, 63% of that in the CHARTEED trial, and 49% of that in previous studies within Taiwan.[20] This indicates that Asian men had a lower prevalence of HVD than the occidental population, which corresponds with our general conception that prostate cancer incidence rates are higher among occidental than among Asian men.[28] The present study found that patients on ADT with HVD had significant shorter OS (30 vs. 43 months) and time to the development of CRPC (13 vs. 26 months) compared to those with LVD. This indicates that regardless of whether patients received chemohormonal therapy[29] or ADT alone, those with HVD had worse prognosis than those with LVD, which agrees with the general consensus that HVD promotes worse prognosis due to disease severity. The current study also found that 58% of the patients progressed to CRPC status, among whom 66% and 48% had HVD and LVD, respectively (p < 0.0001). The findings obtained herein were similar to those presented in previous studies, which demonstrated CRPC status in over 50%, and even 60–70%, of patients with mPCa[16, 20, 22, 30] and showed that over half of the patients with mPCa under ADT eventually progressed to CRPC. Furthermore, the present study found significant differences in PSA kinetics and factors affecting OS and disease progression to CRPC between HVD and LVD. Accordingly, TTN, nadir PSA, level and PSADT were identified as significant predictors of both OS and progression to CRPC in HVD, whereas only PSADT was identified as a significant predictor in LVD. The aforementioned results indicated that among patients with HVD, more attention should be provided to those with faster TTN, higher nadir PSA level and faster PSADT, with such patients possibly becoming suitable candidates for upfront chemotherapy or new generation hormone therapy. However, among patients with LVD, more attention should be provided to those with increasing PSA levels and PSADT considering that TTN, PSA nadir and even PSA reduction rates were not major predictors.
PSA level has been the most widely used biomarker for evaluating disease progression and predicting survival in clinical practice. Furthermore, several retrospective clinical studies and even some meta-analyses have determined that PSA kinetics, including PSA response, nadir PSA level, TTN, or PSADT, predicted OS or disease progression.[9, 10, 13, 24] Among such factors, nadir PSA levels and TTN have been considered important predictors of survival and progression period. Generally, a faster decline in PSA levels has been associated with more cancer cell death, which promotes a more favourable prognosis and survival.[31] However, reports have shown that rapidly decreasing PSA levels during initial ADT was a risk factor for early progression to CRPC.[16] Accordingly, a recent study introduced the novel concept suggesting that tumor-regulating fibroblasts play an important role in the mechanisms associated with TTN after primary ADT.[32] Other studies have also demonstrated that rapidly decreasing PSA levels may be associated with transcriptional outcomes of ADT rather than cancer cell death. Moreover, heterogeneous prostate cancer cells, including hormone-resistant prostate cancer cells and hormone-sensitive prostate cancer cells, often coexist in the same patient. The rapid decline in PSA levels may indicate downregulation of PSA expression in hormone-sensitive prostate cancer cells, which are regulated by androgen via the androgen receptor pathway,[33] though it is doubtful that whether hormone-sensitive prostate cancer cells account for more of the cancer cells in HVD than in LVD, it might be a possible explanation for patient with HVD have shorter TTN and faster time to disease progression, even shorter OS. Moreover, longer TTN and lower PSA nadir levels during ADT have been known to be associated with significantly longer OS and period of disease progression.[10, 11, 13, 24, 30] Despite the lack of internationally accepted PSA nadir or TTN cutoff points for predicting disease progression or survival outcomes until present, observed tendencies have suggested that higher PSA nadir levels and shorter TTN promoted a shorter disease progression period and poor prognosis and survival of patients with mPCa receiving ADT.[9]
PSADT predicts outcomes has been known for nearly 30 years, and it may closely indicate changes in prostate tumor volume, an independent predictor of biochemical relapse among patients that either underwent radical prostatectomy or endocrine treatment.[34] Doctor D’Amico et al. demonstrated that patients with PSADT > 12 months have lower risk of prostate cancer death within 5 years of relapse.[35] Moreover, Kelloff et al. reported that PSADT was a predictor of tumor response to medication in patients with prostate cancer and suggested that significant changes in PSADT may be used to support the approval of newer treatment.[36] Despite the considerably wide distribution of PSADT values, studies have suggested that it may still be useful for strategies after relapse and that patients with advanced or relapsed disease who have rapid PSADT should receive more aggressive or earlier treatment.[37, 38] Tomioka,S. et al. also reported that post-treatment PSADT ≤ 2 months may be a predictor for decreased survival and was associated with poor prognosis among patients with prostate cancer and bone metastasis.[39] The present study identified lower cutoff point of PSADT than before as a useful clinical predictor in patients with mPCa receiving ADT, regardless of whether they had HVD (PSADT < 2 months) or LVD (PSADT < 4 months). The possible cause of short median PSADT in our study is that the PSA nadir level is low, so that the doubled PSA level could be reached easily. In addition, PSA level is checked more frequently in our study than in other studies, so the PSADT may also be influenced. Although PSADT cannot be evaluated during the early stages of ADT, it may still be a clinically effective predictor of disease progression and OS.
Previous reports have showed that PSA-producing CRPC cells have the ability to grow under low androgen environments and may be present in heterogeneous prostate cancer with bone metastases.[29, 40] Moreover, CRPC cells may exhibit faster PSA decline under ADT compared to androgen-dependent prostate cancer cells due to the rapid reduction in PSA, which may be affected via the downregulation of PSA expression, regulated by androgen through androgen receptors, rather than cancer cell death. Another explanation is that the rapid removal of androgen-dependent prostate cancer cells may provide a suitable environment for CRPC cells.[29, 33] Given that HVD has been associated with a higher CRPC rate and more severe bone metastases and disease status compared to LVD, TTN and PSA nadir might be more effective predictors for OS and disease progression in HVD rather than in LVD.
The current study has some limitations worth noting. The most important limitation is our exclusion of patients who received chemotherapy or radiotherapy, however those with subsequent hormone therapy, including abiraterone or enzalutamide after CRPC were not excluded, which may have affected our results with regard to OS. Second, given that this was a single-centre retrospective study, our results may not be generalisable to other populations. Moreover, considering that CGMH is a medical centre in Taiwan, the disease severities of our study population may be higher than those of general population. Lastly, not all PSA parameters and factors, including Gleason score, Hb, Ca and ALP, were regularly assessed at our institution, which might have influenced our results.