Outcome of Patients with Hormone-Refractory Prostate Cancer: Prognostic Significance of Prostate-Specific Antigen-Doubling Time and Nadir Prostate-Specific Antigen
1 Department of Urology, Asahi General Hospital, Asahi, Chiba, Japan
2 Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
For reprints and all correspondence: Jun Shimazaki, Department of Urology, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba-shi 260-8670, Japan. E-mail: shimajun{at}opal.famille.ne.jp
Received August 6, 2007; accepted September 27, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: Most patients with advanced prostate cancer after prostate-specific antigen (PSA) relapse following maximum androgen blockade rapidly progress to death. The present study was aimed to predict the survival of these serious patients after PSA relapse.
Methods: Sixty-eight patients with M1b and 20 patients with T3b, who relapsed and died of cancer within a short period, were studied. PSA-doubling time (PSA-DT) at PSA relapse influenced the outcome after PSA relapse [hazard ratio (CI): 2.000 (1.283–3.226)]; thus, on the basis of the median values of PSA-DT (>2 months) and additionally nadir PSA in previous treatment (
2 ng/ml), patients were stratified into four groups. Outcome in the respective groups was examined.
Results: The patients with PSA-DT of >2 months and nadir PSA of 2 ng/ml showed the longest survival. The other patients in various classifications proceeded with the similarly worse outcomes, in which PSA-DT still influenced survival [hazard ratio (CI): 0.422 (0.203–0.878)]. In several treatments, estramustine phosphate and dexamethasone were relatively effective. A similar rate of response to these drugs was obtained in all four groups, irrespective of stratifying with PSA-DT and nadir PSA, and this may be possibly due to the intervals between relapse and treatments, in which tumor volume was increased and tumor property was altered. Patients responding to treatment showed prolonged survival.
Conclusion: Both PSA-DT and nadir PSA were predictive factors for subsequent survival at PSA relapse, and the patients with long PSA-DT and low nadir PSA may show long outcome.
Key Words: prostate cancer • hormone-refractory cancer • PSA-doubling time • nadir PSA • PSA relapse
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Incidence of prostate cancer has been increasing in Japan and will soon reach a rate similar to that in western countries. Stage migration to rather early stage of prostate cancer along with increasing the number of patients occurred and management for early stage of them was improved. Advanced stage of this cancer, however, is still a serious disease with a high mortality rate. Patients with advanced stage initially respond to hormone therapy at a rate of >90%, but then relapse into the hormone-refractory state and finally die, usually within 3 years after relapse (1). Numerous therapeutic strategies after relapse are being tried on the basis of chemotherapy or gene therapy, but at present there does not seem to be any established critical management. Patients with advanced stage in the hormone-refractory state proceed along various courses; some show rapid progression, whereas others reveal rather slow way. It is necessary to predict the courses of patients after prostate-specific antigen (PSA) relapse. For this purpose, it may be worthwhile to examine the entire course of patients with advanced prostate cancer.
Previously, we reported that the PSA-doubling time (PSA-DT) at PSA relapse was a factor influencing subsequent survival in the cases of advanced prostate cancer (2), but the stratification of patients with PSA-DT alone showed incomplete grouping for survival. The present study was aimed to stratify the patients on the basis of PSA-DT in addition to nadir PSA, with an interest in patients with rapidly progressing course who may be candidates for aggressive treatment. Effects of the second treatment were also mentioned.
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PATIENTS AND METHODS |
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Patients
To study the serious outcome, patients with advanced prostate cancer who died within a few years after relapse were studied. Sixty-eight patients with M1b cancer (UICC TNM classification, 6th edn., 2002) and 20 patients with T3b (MX without bone metastasis) cancer, who had negative bone scans and chest X-ray findings, were enrolled between 1992 and 2002. The patients, who had not received any previous treatment for prostate cancer, were treated for the entire course of disease at the Asahi General Hospital. Initially, their performance status was Grades 0–1 with no or slight lumbar pains. During this period, five patients with M1b and six patients with T3b relapsed and died of other causes (other cancers, pneumonia, etc.), and they were excluded from the present study.
Treatment
The patients were treated with luteinizing hormone-releasing hormone (LHRH) agonist or surgical castration accompanied with an antiandrogen (maximum androgen blockade, MAB). As antiandrogens, chlormadinone acetate, flutamide or bicalutamide was used initially. The PSA (as total PSA) was assayed serially every 3 months and more frequently when progression was evident. All patients showed an increase in PSA (PSA relapse) after an initial decrease, and PSA relapse was determined by exponentially increasing PSA at three or more points, the date of which was recorded on the first increasing day. PSA relapse did not refer to changes in other subjective or objective signs. After PSA relapse, patients continued with the same LHRH agonist for more than a few months. The following treatments were serially performed: checking for antiandrogen withdrawal syndrome during 1–3 months, the second-line antiandrogen treatment with other antiandrogens, estramustine phosphate (daily dose of 560–420 mg) with/without etoposide (daily dose of 50–25 mg for 3 weeks/4–5 weeks) and dexamethasone (daily dose of 1.5–0.5 mg) in turn. One treatment was performed for 1–3 months and was changed to another when it failed. The evaluation of response as effective was a decrease in PSA by 
50% from baseline level continuing for 1 month. Duration of the response was defined as the time between the dates of response and increase in PSA from the responded level (3).
Measurement of PSA and PSA-DT
Kits used for assaying PSA were IMAX PA (before 1994, Abbot, Tokyo, Japan), AxSYM PA Dainapack (1994–98) and AxSYM PSA Dainapack (after 1999). A correlation between PSA values obtained with different kits was confirmed. To measure PSA-DT, a slope was obtained by the least square test with the values of ln PSA's from three or more points, and DT was calculated from ln 2/slope (2). PSA-DT (relapse PSA-DT) was defined as the value at PSA relapse.
Statistical Analysis
Cause-specific survival was calculated with the Kaplan–Meier method and the Cox proportional hazard model. Significance was determined by log-rank test. Mann–Whitney U test, Student's t-test and 
2 test were used, and P 0.05 was considered to be significant. All calculations were performed with the StatView program.
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RESULTS |
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Patients Characteristics
Initial PSA in patients with M1b was higher than that in patients with T3b (Table 1). Following treatment with MAB, PSA in all patients decreased to some extent and the lowest values during treatment (nadir PSA) were higher in patients with M1b than in those with T3b. After a while, all patients eventually experienced PSA relapse, and the duration between the start of treatment and the relapse was shorter in patients with M1b than in those with T3b. Duration from PSA relapse to death, however, was the same between the two groups (Fig. 1), and relapse PSA-DT was not different from each other. Therefore, patients with T3b and M1b were combined and their outcome after PSA relapse was investigated.
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Stratification of Patients at PSA Relapse Defined with PSA-DT and Nadir PSA
Factors influencing the survival after PSA relapse were examined (Table 2). Initial PSA did not influence the survival and did not correlate with nadir PSA. Nadir PSA during initial hormone therapy, duration between the start of treatment and the PSA relapse and PSA-DT associated with subsequent outcome on univariate analysis; but on multivariate analysis, PSA-DT alone correlated with survival. Duration between the start of treatment and the PSA relapse and that between the start of treatment and the time at nadir PSA had a slight correlation (R = 0.38).
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To examine the outcome of the patients after PSA relapse, factors for stratification were chosen with PSA-DT and, additionally, nadir PSA. Using the median values of PSA-DT (2 months) and nadir PSA (2 ng/ml), the patients were stratified into four groups (Table 3). The patients in Group I showed longer times from both the start of treatment to PSA relapse and PSA relapse to death than those in the other three groups. PSA-DT was similar in Groups I and III, but nadir PSA was different, so subsequent outcomes of these two groups were separated. Between Groups I and II, nadir PSA was similar but their outcomes were differently divided with PSA-DT. Survivals among Groups II–IV were similar to each other, but that of Group I was different. The Kaplan–Meier survival curve showed these trends (Fig. 2). After combining with Groups II–IV, the predictive factors were examined and PSA-DT still influenced the subsequent survival [hazard ratio (CI): 0.422 (0.203–0.878)]. From these results, together PSA relapse and nadir PSA were predictive factors for subsequent survival after PSA relapse, and patients with long PSA-DT (>2 months) and low nadir PSA (
2 ng/ml) may experience prolonged survival.
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Effect of Treatment after PSA Relapse
In general, the patients received various treatments in turn (Table 4). Antiandrogen withdrawal syndrome and second-line antiandrogen treatment showed rather small responses in number. Most patients were administered estramustine phosphate except patients with adverse events such as stomatitis. Estramustine phosphate was most effective at a response rate of 43%. Overall, there were no differences in the response rate among the four groups. Combination with etoposide increased the effectiveness (12/18 = 67%). Initial PSA, nadir PSA, duration between PSA relapse and treatment with estramustine phosphate (7.3 ± 7.1 versus 7.8 ± 6.6 months for 50% decrease in PSA or not from baseline PSA), PSA at the start of estramustine phosphate (124.1 ± 209.8 versus 115.5 ± 153.3 ng/ml, for response or not) or PSA-DT (3.0 ± 2.3 versus 2.6 ± 2.1 months for response or not) did not correlate with response of estramustine phosphate; moreover, no other predictive factors were found. When estramustine phosphate showed the effect, survival of the patients was extended after treatment (25.8 ± 13.6 versus 13.0 ± 6.8 months for response or not, P < 0.0001, Fig. 3).
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Dexamethasone was another effective drug. The response rate was similar over the four groups. The effect of estramustine phosphate was not related to that of dexamethasone. Survival after dexamethasone treatment did not correlate with the time between the PSA relapse and the start of dexamethasone treatment (17.2 ± 9.5 versus 16.7 ± 11.6 months for response or not). Similar to estramustine phosphate, predictive factors for the effect of dexamethasone were not found. When dexamethasone showed the effect, survival of the patients was prolonged after treatment (14.9 ± 12.5 versus 6.8 ± 5.7 months for response or not, P < 0.046).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Survival after PSA relapse in patients with advanced prostate cancer treated with MAB was similar between the patients with T3b and those with M1b (Fig. 1). This may be partly explained by the fact that patients with rapidly progressing advanced T3b showed bone metastatic disease at the hormone-refractory stage, and average survival after PSA relapse was about 2 years. In fact, the bone scans showed metastatic fields after PSA relapse in patients with T3b, and autopsy confirmed metastasis. Conversely, Oefelein et al. (4) reported that the median survival after hormone-refractory prostate cancer was 68 and 40 months for patients initially staged with M0 and M1b, respectively. The difference in survival of T3b between the present study and the report of Oefelein et al. may be due to tumor characteristics. Pre-treatment PSA in the present cases was higher than that in the report of Oefelein et al. Many literatures report approximately 2–3 years on survival of patients with metastatic hormone-refractory prostate cancer, such as T3b and M1b in the present study (5,6).
Associations between survival after PSA relapse of patients with advanced prostate cancer and lactate dehydrogenase, alkaline phosphatase, performance state, hemoglobin, erythrocyte sedimentation rate, body weight and serum albumin have been reported (7–9). Some of these factors correlate with general conditions, such as weakness, malnutrition and complications. Patient's age was a risk factor, and survival of patients >80 years of age was shorter than that of younger patients (10).
There have been numerous reports regarding the relationship between survival of patients with advanced prostate cancer and changes in PSA following treatment. Pre-treatment PSA is not correlated with survival, but a rate of decrease in PSA after initial treatment influences subsequent survival (11–14). Time to reach nadir PSA and duration of PSA response associates with survival (15,16). Nadir PSA during initial treatment influences the subsequent outcome (1,17,18). These literatures notice that the trend of PSA during initial treatment is one of the crucial factors for survival (19), and this study also confirms that nadir PSA and duration between the start of treatment and relapse relate to survival.
Cut-off values of nadir PSA for presumption regarding subsequent outcome after relapse are not uniform, since patients initially received different treatments such as prostatectomy, radiation or hormone therapy. With radiotherapy, 2 ng/ml of nadir PSA was stated as predicting forthcoming metastasis and death (20). In this study, using 2 ng/ml of nadir PSA can roughly divide the patients into long-term and short-term survival groups, but more definite stratification for predicting outcome may be needed (Table 3, Fig. 2).
Since the growth rate of prostate cancer tissues partly correlates with an increase in PSA, PSA-DT has recently been attracted as a predictive factor of clinical course (21,22). Various methods for calculating PSA-DT have been reported, but calculation requires a careful methodology (23,24). The least square test to obtain a slope is an accurate method to estimate DT, and we used it in this study.
PSA-DT has widely been reported for predicting outcome at the start of treatment and after PSA relapse for any stage of prostate cancer. As an indication of watchful waiting for patients with early stage of prostate cancer, PSA-DT of >12 months was discussed (25,26). PSA-DT in patients with T1b–T2b and Gleason score of <7 was 3–6 years (27). At PSA relapse after radical prostatectomy or radiation therapy, PSA-DT of >12 months may be indicative of local relapse, but PSA-DT of <6 months indicates to show distant metastases later (28,29). At relapse after prostatectomy, patients with PSA-DT of <3 months proceed to death due to prostate cancer (30). In surgical cases, nadir PSA may be in a similar range, so survival was separated with PSA-DT alone into short and long terms. In cases of advanced cancer, nadir PSA was distributed over a wide range, due to various tumor burdens at relapse, so other additional factor was needed for separating outcome. This study chose nadir PSA as another predictive factor.
PSA-DT after PSA relapse in patients with advanced stage is much shorter than that in localized cancer. Some reports noticed PSA-DT of approximately 2–3 months for patients with advanced stage in the hormone-refractory state (31,32). Patients with hormone-refractory prostate cancer after castration were classified by PSA-DT, nadir PSA and time to PSA recurrence, and cancer-specific survival of the high-risk group (PSA-DT of 6 months, nadir PSA of >0.5 ng/ml, with/without time to PSA recurrence of 7 months) was 14 months, which was shorter than that of the intermediate and low-risk groups (33). Patients with hormone-refractory prostate cancer with PSA-DT of 70 days showed survival of 11 months, when compared with that of 19 months for patients with PSA-DT of >70 days (34). Gleason score was not apparently correlated with PSA-DT in advanced prostate cancer. Similar to PSA-DT, PSA velocity correlates with the growth rate of cancer tissue and associates with the survival of cases with hormone-refractory prostate cancer (35). Together with the literatures and the present study, it is shown that patients with long PSA-DT and low nadir PSA proceed on prolonged survival in general.
Antiandrogen withdrawal syndrome was observed in 15–20% (36,37), and the effect of second-line antiandrogen treatment was 20–30% (37–39). The effective rates for these managements in this study were lower than those reported by others. This may be partly due to the use of bicalutamide in many cases such as MAB, since bicalutamide used first may produce a low effective rate of both antiandrogen withdrawal syndrome and second-line antiandrogen treatment when compared first with the other antiandrogens.
Estramustine phosphate monothereapy is a relatively effective treatment for hormone-refractory prostate cancer (40,41), and the addition of etoposide to estramustine phosphate intensifies the effect (42–44). Monotherapy with dexamethasone for hormone-refractory prostate cancer is reported to provide a response rate of around 50% (45,46). Slightly lower response rates for these two drugs were obtained in this study.
The response rates for estramustine phosphate and dexamethasone did not differ among the four groups stratified with PSA-DT and nadir PSA. The lack of difference is perhaps explained by the interval between the PSA relapse and the start of estramustine phosphate (and dexamethasone), being approximately half year or more. Although both PSA-DT and nadir PSA influence survivals and stratification with them is meaningful at PSA relapse, during this term PSA-DT may vary (2) and PSA is elevated from that at nadir. Therefore, tumor volume was increased and tumor property was altered when compared with those at relapse. Factors influencing outcome might be changed long after PSA relapse and one of the factors is response to treatment. Patients with response exhibited long survival, and thus factors influencing response to next treatment remain to be studied. The information may be beneficial to the management of patients after PSA relapse.
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ACKNOWLEDGMENT |
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This work was approved by the Ethical Committee of the Asahi General Hospital.
Conflict of interest statement
None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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