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ORIGINAL ARTICLE
Year : 2022 | Volume
: 55
| Issue : 5 | Page : 184-189
Nadir prostate-specific antigen as a prognostic factor of 10-year cancer-specific survival of prostate cancer patients with bone metastases
Chi-Feng Hung1, Tsung-Wei Wang2, Cheng-Kuang Yang3, Yung-Cheng Yang4, Yeong-Chin Jou5, Yen-Chuan Ou6
1 Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan
2 Division of Urology, Department of Surgery, Puli Branch of Taichung Veterans General Hospital, Nantou, Taiwan
3 Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
4 Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
5 Department of Urology, Chia-Yi Christian Hospital, Chia-Yi; Department of Health and Nutrition Biotechnology, Asian University, Taichung, Taiwan
6 Division of Urology, Department of Surgery, Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan
Correspondence Address:
Yen-Chuan Ou
No. 699, Sec. 8, Taiwan Blvd, Taichung City 435
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/fjs.fjs_50_22
Background: In Taiwan, the proportion of men with newly diagnosed bony metastatic prostate cancer (PC) is approximately 30%. The present study aims to determine the 10-year cancer-specific survival rate and clinical prognostic factors of men with newly diagnosed bone metastatic PC that were treated with hormone therapy.
Materials and Methods: Between January 1983 and December 2008, 257 patients with bone metastatic PC were identified at initial diagnosis. Clinical and pathological data were collected from their medical chart records. Performance status, body mass index, clinical symptoms, initial serum prostate-specific antigen (PSA), nadir PSA level (nPSA), and treatment modality were reviewed retrospectively. Statistical methods included descriptive statistics, bivariate analyses, Kaplan–Meier survival analyses, and Cox regression analysis for investigating the relationship between the clinical factors and disease survival.
Results: The average follow-up time was 36.4 months (±29.1 months) and the median survival time was 58.1 months. Using Kaplan–Meier survival analyses, the overall 10-year survival rate was 33%. The multivariate Cox regression hazard model revealed that patients with a posttreatment nPSA level >10 ng/mL have a higher probability of death than those with an nPSA <0.5 ng/mL (Hazard ration: 2.63, 95% confidence interval: 1.16–5.97, P = 0.020).
Conclusion: Posttreatment nadir serum PSA level significantly influences the survival of patients with bone metastatic PC. A lower limit of 0.5 ng/mL for the nPSA level is a valuable prognostic factor for survival in patients initially diagnosed with bone metastatic PC and treated with hormone therapy.
Keywords: Metastasis, prognosis, prostate neoplasms, prostate-specific antigen
In Asia, the incidence of prostate cancer (PC) is relatively low compared to Western countries. Despite the use of prostate-specific antigen (PSA) screening for the early detection of metastatic PC, metastatic PC made up of nearly 30% of newly diagnosed patients in Taiwan.[1],[2] Androgen deprivation therapy (ADT) is the initial treatment option for metastatic PC; however, despite this treatment, castration-resistant PC (CRPC) will inevitably develop. Chemotherapy with docetaxel is the standard first-line treatment in patients with metastatic CRPC before the era of new hormone agents, including abiraterone and enzalutamide.[3]
Unfortunately, the prognosis of metastatic PC is dismal, where the 5-year overall survival ranges from 20.5%–34% in Western countries.[1] Interestingly, Taiwanese men with metastatic PC have a higher 5-year survival rate of 49%, which is better than that of their Western counterparts.[1],[4] However, the long-term survival (i.e., 10-year survival) of metastatic PC has never been reported in the literature. We investigated various clinical parameters in patients with newly diagnosed bone metastatic PC and determined the 10-year cancer-specific survival. Several prognostic factors of disease survival were evaluated, including performance status, bone pain, histological grade, nadir PSA (nPSA) level after hormone therapy, and patient age.[5],[6],[7],[8],[9] The aim of the present study was to define the best prognostic factors of metastatic PC after hormone therapy.
Materials and MethodsBetween January 1983 and December 2008, 309 consecutive patients initially diagnosed with bone metastatic PC were treated and followed up at the Taichung Veterans General Hospital (TCVGH). The project was approved by the Institution Review Board of the TCVGH (approval number: CE13240). All deaths, irrespective of cause, and all PC-specific deaths were recorded at least 3 years from the completion of the original study (the follow-up period ended in March 2009). Of all patients, three died from pneumonia and another two patients from sepsis. A total of 52 patients without complete data collection were excluded, and 257 patients were enrolled in this study. All patients obtained histopathologic verification of prostate adenocarcinoma through the prostate and/or bone biopsies. Patient age at diagnosis, initial clinical presentation, performance status, body mass index (BMI), serum PSA levels, biopsy, Gleason score, follow-up duration, and survival status was retrospectively collected and reviewed from the medical charts by a special cancer-registry nurse.
Treatments
Commonly used treatments for metastatic PC include ADT, radiotherapy, chemotherapy, or a combination of these. Early ADT, with or without surgical or medical castration, is the standard initial treatment for newly diagnosed bone metastatic PC. Radiation therapy is a palliative treatment for bone pain. Chemotherapy is the second-line treatment for castration-resistant disease. In this study, a total of 46 patients were treated with chemotherapy. Of these, there were 12 cases that received 12 mg of mitoxantrone over an average of 2.5 courses, and 34 patients that received 75 mg of taxotere every 3–4 weeks over an average of 3.1 courses.
Statistical analysis
Patients were divided into two groups: the survival and mortality groups. Comparisons of nominal or ordinal variables between the two groups were determined by the Chi-square test, whereas differences in continuous variables were determined through the paired t-test. The Cox proportional hazards model (i.e., backward regression method) was used to determine the significant clinical predictors of bone metastatic PC. Overall survival and cause-specific survival were assessed using univariate and multivariate Cox proportional hazards regression models with covariates for age, PSA levels at diagnosis, nPSA levels, and the adverse treatment modality. Multivariate survival analyses were carried out with the IBM SPSS Statistics version 24.0 (IBM Corp. Released 2016. Armonk, NY, USA)-Cox program, and P values were assessed by the Wald statistic. Cancer-specific survival was calculated using the Kaplan–Meier method and comparisons were made using the log-rank test. A P < 0.05 was considered significant. An additional Cox regression analysis of overall survival was performed with covariates for the PSA nadir levels.
ResultsThe clinical characteristics of the study cohort are summarized in [Table 1]. Briefly, the average age of PC onset was 72 years old. The median time to reach nPSA levels after hormone therapy was 7.1 months. The mean treatment duration of ADT to CRPC status is 12.8 ± 16.3 months. Among the patients, 116 (45.1%), 79 (30.7%), and 62 (24.1%) had treatment duration of ADT to CRPC from <12, 12 to 24, and ≥24 months, respectively. The majority of men that received treatment for advanced disease had a good performance status (0, 1) (81.9%). In regard to BMI, 10.6% of patients were underweight, and the mean BMI was 23 ± 3.3 kg/m2. Two hundred and fifty-two patients (98.05%) had testosterone levels below 0.5 ng/ml after hormonal therapy. A total of 149 patients (58%) received combined androgen blockade, of which, 60.3% underwent surgical castration. Finally, 46 patients (17.9%) received chemotherapy.
Table 1: Clinical characteristics of patients with newly diagnosed bone metastatic prostate cancerComparisons of the study variables between the two groups are summarized in [Table 2]. There were no significant differences noted in BMI, performance status, Gleason score, and nPSA levels between the two groups. However, there were significant differences in pretreatment PSA and treatment modalities between the survival and mortality groups. The 5- and 10-year cancer-specific survival rates, which were determined using the Kaplan–Meier method, were 60% and 33%, respectively, for all 257 patients [Figure 1]. It was also found that pretreatment PSA [Figure 2], nPSA [Figure 3], and treatment modalities have significant effects on survival duration. Therefore, all of the variables listed above were put into a Cox proportional hazard model for further analysis. The findings of the univariate and multivariate Cox proportional hazard model analyses are presented in [Table 3]. It was determined that the statistically significant prognostic factors of overall survival were nPSA levels >10 ng/ml (P = 0.020) and maximum androgen blockade therapy (P = 0.016). The mean survival time was longer in patients with nPSA levels <0.5 ng/ml (P = 0.038).
Figure 1: Overall survival curve of patients with bone metastatic prostate cancer
Figure 2: Survival curves of patients with bone metastatic prostate cancer according to their pretreatment PSA level. Blue: PSA <100 ng/ml, Orange: PSA of 101–300 ng/ml, Red: Nadir PSA >300 ng/ml. PSA: Prostate-specific antigen
Figure 3: Survival curves of patients with bone metastatic prostate cancer according to their nadir PSA levels. Blue: Nadir PSA <0.5 ng/ml, Green: Nadir PSA of 0.5–10 ng/ml, Orange: nadir PSA >0.5 ng/ml. PSA: Prostate-specific antigen
Table 2: Comparisons of the clinical characteristics of patients with newly diagnosed bone metastatic prostate cancer according to survival
Table 3: Univariate and multivariate Cox proportional hazard model analyses of patients with newly diagnosed bone metastatic prostate cancer Discussion Of all Taiwanese men with newly diagnosed PC, more than 30% have metastatic PC.[1],[2] Despite this, it appears that Taiwanese men with metastatic PC may have better survival compared to Western men (e.g., 5-year survival of 49% vs. 20.5%–34%, respectively).[1],[4] While the basis for this difference remains unknown, it may be related to differences in clinical treatment. In addition, it was identified that racial differences may account for the differences in survival of patients with PC to some extent.[1],[10],[11] That is, significant differences in certain somatic genomic factors that are either induced by specific environmental and/or genetic risk factors may underlie the regional/ethnic differences and thereby affect the clinical incidence of PC.[12] In the present study, the 10-year long-term follow-up data suggest that patients with newly diagnosed bone metastatic PC that were treated with combined androgen blockade have an overall survival advantage.
It is well known that ADT is beneficial for the treatment of bone metastatic PC. Our study demonstrated a positive association between survival status and hormone therapy. Similar findings were also reported in several previous studies.[13],[14],[15] Some studies, on the other hand, suggest that chemotherapy is the preferred treatment modality for newly diagnosed bone metastatic PC, as CRPC inevitably develops following initial treatment with ADT.[3] Docetaxel is the standard first-line treatment in patients with metastatic CRPC before the era of novel hormone agents, including abiraterone and enzalutamide. However, in our study population, chemotherapy does not appear to be a good treatment choice for newly diagnosed bone metastatic PC patients, as we found a correlation between chemotherapy and poor prognosis. Of all bone metastatic PC patients in our study, 65% (30/46) received chemotherapy because their cancer rapidly progressed to CRPC within 2 years. Overall, however, a small proportion of all study patients received chemotherapy (i.e., 17.9%), which may explain the poor correlation between chemotherapy and poor prognosis.
Previous studies demonstrated that high pretreatment PSA levels had a relatively negative effect on survival outcomes.[16],[17] While our survival analyses suggest that high pretreatment PSA levels are associated with a higher probability of survival, after controlling for other variables in the Cox proportional hazard model, there was no significant difference in the survival status. This may be explained by the small number of cases with high pretreatment PSA levels or the high number of cases with good responses to combined androgen therapy.
Prognostic factors, such as performance status, pain due to bone metastasis, Gleason score, nPSA, and the extent of bone metastasis, have been previously identified as predictors of survival.[1],[6],[7],[9],[18],[19] Patients with a good performance status are capable of tolerating alternative treatments.[5] In our study, no survival benefit was noted for various prognostic factors, such as performance status, bone pain, Gleason score, and initial serum PSA level. The nPSA after hormone therapy was the most significant prognostic predictor for survival in patients with newly diagnosed bone metastasis PC. A lower nPSA level implied that the patient was more sensitive to hormone therapy. The nPSA level, particularly when the lower limit is defined as 0.5 ng/ml, appears to be the most accurate predictor of hormone-refractory PC, and is an independent prognostic factor for survival.[7] Similar findings have been previously found in several other studies.[1],[9],[16],[20] Furthermore, in our study, it was found that setting the lower limit of the nPSA level to 0.5 ng/ml results in the optimal sensitivity and specificity for survival. Thus, the nPSA level is highly predictive of bone metastatic PC response to hormone treatment.
There are several limitations in this study. First, the retrospective nature and the relatively small size of the cohort might distort the interpretation of our results. Second, this study enrolled the patients with bone metastatic hormone-sensitive PC, who initially received only ADT. The novel hormonal agents, including abiraterone and enzalutamide, are currently the standard of care for these patients in the upfront use with the combination of ADT. The prognostic value of nPSA is needed further investigated.
ConclusionPosttreatment nadir serum PSA level was the most significant factor to influence the survival of patients with bony metastatic PC. Specifically, a lower limit of 0.5 ng/mL for the nPSA appears to be the most accurate predictor of hormone-refractory PC with the optimal sensitivity and specificity for survival. Thus, the nPSA level is highly important to predict the prognosis of patients with bone metastatic PC receiving hormone therapy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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