The present study demonstrated that OS and CSS outcomes among mHSPC patients were heterogeneous. Despite no differences in prognosis for groups with high-volume disease according to stratification defined by various guidelines, the prognoses were different among groups with low-volume disease. We confirmed that OS and CSS were related to visceral metastatic sites and metastatic bone spread in mHSPC patients. Of interest, no prognostic difference was found in the CSS between M1a or M1b (low-volume bone metastasis) and M1c patients (no bone metastasis and visceral metastasis, except liver). Notably, this study found that the prognosis of patients with visceral metastasis (except in the liver) depended on the spread of the bone disease.
The current standard treatment for mHSPC is ADT, since the first description of its hormonal dependence in 1941 [13, 14]. In a new treatment paradigm shift, upfront docetaxel and abiraterone acetate administration have been performed in patients with de novo metastasis [7–11]. However, clinicians are confused regarding the selection of initial treatment options, due to the heterogeneity of bone disease spread in patients with visceral metastasis. Although visceral metastases without bone involvement are seldom noted in mHSPC patients, clinicians often see patients with only visceral metastasis in practice [15, 16]. In our cohort, four patients were diagnosed with M1c (lung metastasis without bone metastasis).
This study observed that some mHSPC patients were classified differently according to the several definitions of high-volume disease. Prognoses did not differ among groups with high-volume disease, but significant differences in the prognoses among the groups with low-volume disease were found. These findings suggest that some patients have the probability of missing the opportunity to receive proper initial treatment. Importantly, the concept of high- and low-volume bone metastases has become an essential issue for mHSPC patients in cases utilizing upfront docetaxel and abiraterone acetate [7–11], as well as radiation therapy for primary lesions [17]. In practice, prostate cancer patients are treated based on the recommendations of NCCN guidelines, which categorize mHSPC into high- and low-volume disease according to the presence of visceral metastasis and the degree of bone spread, based on the CHAARTED trial [18]. In particular, the guidelines suggest that radiation therapy is limited for high-volume metastatic disease. This result was recommended based on the STAMPEDE and HORRAD trials [17, 19], which reported that radiation therapy affects survival in cases of low-volume metastases. Therefore, based on our results, careful decisions are needed regarding the use of radiation therapy for primary lesions.
Compared with bone metastasis, visceral metastasis has been shown to confer worst survival, regardless of concomitant bone spread [6]. The study by Gandaglia et al. on 3857 mHSPC patients in the Surveillance Epidemiology and End Results–Medicare database reported that the presence of visceral metastasis should be associated with more aggressive disease; this was observed after stratifying patients according to the metastatic site (lymph node alone, bone, visceral, or bone plus visceral) [20]. Our findings confirmed that visceral metastases conferred the worst survival. Results of additional analyses showed that having visceral metastasis except in the liver did not worsen the prognosis of concomitant bone disease volume.
The presence of liver metastasis have been shown to be a significant predictor of worse prognosis [21]. Armstrong et al. reported that liver metastases were included in the variables with the greatest risk of death [22]. We confirmed that liver metastasis was associated with worse OS and CSS. However, the incidence of liver metastasis with or without bone involvement following prostate cancer diagnosis was relatively low [15]. In our study, there were no patients with liver metastasis and concomitant low-volume bone metastasis.
Regarding the heterogeneous outcomes in mHSPC, our study serves to inform clinical practice by highlighting that the prognosis of patients with an mHSPC diagnosis depends on the presence of liver metastasis and tumor involvement of the bone. In cases with visceral metastasis except liver, CSS survival was associated with bone disease spread. Also, differences in the survival of patients with low-volume bone metastases suggest that physicians should be cautious when deciding on the initial treatment for de novo metastases. To prevent such confusion, the unification of different criteria is necessary and will require a large-scale longitudinal study. Despite the strengths of this study, there are several limitations. Only a relatively small number of patients in this cohort were evaluated by retrospective, observational design. Moreover, several treatment options, such as docetaxel, abiraterone acetate, enzalutamide, and Radium-223, have emerged during the observation period. Therefore, there might be potential biases associated with the implementation of a specific treatment, based on differences in insurance, physician discretion, and patient preference. Nevertheless, we believe that this may reflect clinical practice in the real world.