Japanese Journal of Clinical Oncology Advance Access published online on August 12, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn071
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© The Author (2008). Published by Oxford University Press. All rights reserved
Undetectable Level of Prostate Specific Antigen (PSA) Nadir Predicts PSA Biochemical Failure in Local Prostate Cancer with Delayed-combined Androgen Blockade
Division of Nephro-Urologic Surgery and Andrology, Department of Reparative and Regenerative Medicine, Institute of Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie, Japan
For reprints and all correspondence: Norihito Soga, Division of Nephro-Urologic Surgery and Andrology, Department of Reparative and Regenerative Medicine, Institute of Medical Life Science, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. E-mail: n-soga{at}clin.medic.mie-u.ac.jp
Received June 8, 2008; accepted July 14, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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Objective: To determine optimal predictors with which to select the crucial patients enrolled in delayed-combined androgen blockade (CAB) trials, based on risk factors.
Methods: From January 2001 to December 2004, 92 prostate cancer patients with T1c, T2 and T3aN0M0 were enrolled in a clinical trial. Medical castration and anti-androgen treatment were used sequentially as delayed-CAB. The prostate specific antigen (PSA) nadir was determined following medical castration only. Anti-androgen treatment was administered if a PSA progression was observed and the subsequent PSA response was evaluated. Time to PSA biochemical failure, induced by medical castration or with anti-androgen treatment, was estimated. Risk factors of PSA failure were evaluated by multivariate analysis.
Results: During luteinizing hormone–releasing hormone (LH–RH) monotherapy, a Kaplan–Meier analysis estimated that the proportion of patients without PSA progression was 64.8% at 5 years. In the multivariate analysis of the prediction of PSA progression with LH–RH monotherapy, a Gleason score over 8, initial PSA >20 ng/ml and PSA nadir >0.2 ng/ml were significant independent risk factors that affected PSA biochemical failure. The PSA progression-free rate in the lower PSA nadir group was significantly lower than that in the other. The 25 patients in the higher PSA nadir group were treated with anti-androgen therapy. Under anti-androgen therapy, the PSA progression-free rate was 62.6% at 5 years. Only PSA nadir >0.2 ng/ml was a significant independent risk factor. The PSA progression-free rate in the lower PSA nadir group was significantly lower than the other.
Conclusions: PSA nadir was the optimal predictive for low stage, non-metastatic population during delayed-CAB.
Key Words: nadir PSA • PSA biochemical failure • delayed-CAB
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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For patients newly diagnosed with localized prostate cancer (LPC), a significant choice arises regarding whether to provide conservative treatment or early active treatment (1). In previous studies, various treatments, including radiation, radical prostatectomy, expectant management including observation or primary androgen depletion therapy (ADT), were utilized for low-risk prostate cancer in the USA (2) and Japan (3). However, because observation and primary ADT were classified in the same category, differences in efficacy between observation and primary ADT were not clarified (4).
ADT was classified into two groups: the first included patients with only medical or surgical castration, and the second included patients with both anti-androgen treatment and either medical or surgical castration. The benefits of an initial combined androgen blockade (CAB), consisting of both anti-androgen treatment and either medical or surgical castration, on the survival of prostate cancer patients remain controversial. CAB appears to benefit only patients with metastases, in contrast to those with less advanced disease (5–7).
According to medical guidelines, surgical and medical castration are the recommended initial treatments for metastatic prostate cancer. However, early ADT is not strongly recommended because no overall survival benefit has been shown (8). For other early stages of prostate cancer, the role of primary ADT has not been elucidated.
Recently, in patients with LPC and locally advanced prostate cancer (LAPC), primary ADT provided the same survival of the same age group (3). Primary ADT may become the standard optional treatment for selected LPC and LAPC patients (9).
New hormonal therapy strategies, including sequential usage with luteinizing hormone–releasing hormone (LH–RH) agonist (leuporolide acetate or goserelin) and the non-steroidal anti-androgen deferred CAB (10,11) or delayed-CAB (12) were discussed in papers that included cases with metastases and lymph node invasion, but not LPC or LAPC. In this study, we summarize the cases with LPC and LAPC to address the optimal parameters with which to predict chemical failure, and in delayed-CAB therapy, provide us the optimal classification to choose the cases that should be treated with delayed-CAB.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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The inclusion criteria and treatment strategy are explained in detail in a previously published report (12). From January 2001 to December 2004, we picked up 92 prostate cancer patients classified into cT1c, cT2 and cT3aN0M0 groups who were enrolled in this prospective study. All patients gave their full informed consent.
In this trial, we used androgen deprivation agents, including the sequential injection of the LH–RH agonist (leuporolide acetate or goserelin), and the non-steroidal anti-androgen (bicalutamide). We called this treatment regimen ‘delayed-CAB’ and this protocol consisted of two steps as described here.
The prostate specific antigen (PSA) level was determined during treatment with monthly LH–RH agonist alone to see whether monthly PSA levels decreased to <0.2 ng/ml. We defined the PSA nadir level as an undetectable PSA level.
If an undetectable PSA level could not be accomplished, the PSA nadir level was defined as the final PSA level during its decline (over 0.2 ng/ml) that was followed by three elevations, the PSA progression with LH–RH agonist monotherapy was decided and then we added anti-androgen therapy.
When the patient demonstrated an undetectable PSA level (<0.2 ng/ml), we continued treatment with LH–RH alone. When the patient exhibited three consecutive elevations after PSA level over 0.2 ng/ml, the PSA progression with LH–RH agonist monotherapy was defined, and we added anti-androgen therapy to the drug regimen. Thereafter, we checked the PSA level again until the occurrence of PSA biochemical failure with anti-androgen therapy based on the same definition of PSA progression. The PSA half-life was calculated according to a previously reported method (13).
Statistical Analysis
In the study, the primary end-point was PSA biochemical failure. The Kaplan–Meier method was utilized to evaluate the rate of PSA biochemical failure during each period, and statistical differences were estimated by the log-rank test. Multivariate analysis was performed using a Cox proportional hazards regression model.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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This study consisted of 92 patients; the median age of all patients was 75.4 years (range 59–91). The median observation period was 36.1 months (26–66 months). The classification based on the TNM was as follows: distribution, T1c 27, T2a 39, T2b 20, T3a 6, N0 92, N1 0, M0 92, M1a 0, M1b 0 and M1c 0. Forty-five patients had a Gleason score of <6, 26 patients had a Gleason score of 7 and 21 patients had a Gleason score of >8. The median pre-treatment PSA level was 14 ng/ml (3.68–492), and the median of PSA half-life was 2.0 months. During the observation period, five patients died from either a cancer-unrelated illness, pneumonia at 12 months, lung cancer at 23 months, arithemia at 24 months or acute myocardial infarction at 25 months (Table 1).
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During LH–RH monotherapy, a Kaplan–Meier analysis estimated that the proportion of patients without PSA progression was 88.9% after 1 year, 79.8% after 2 years and 64.8% after 5 years (Fig. 1). The flare up with LH–RH monotherapy was recognized in 6.5% cases (6 cases in 92) without the symptomatic phenomenon.
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In the multivariate analysis (Cox proportional hazards model), significant independent risk factors that affected the PSA biochemical failure were the prediction of PSA progression with LH–RH monotherapy, a Gleason score over 8 (P < 0.05), an initial PSA of >20 ng/ml (P < 0.05) and a PSA nadir of >0.2 ng/ml (P < 0.001) (Table 2). Other factors were not significantly related to PSA failure.
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A total of 55 cases reached a PSA nadir level of <0.2 ng/ml (abbreviated as the lower PSA nadir group), whereas 37 cases were assigned to the group with PSA nadir >0.2 ng/ml (abbreviated as the higher PSA nadir group). Eighty-three per cent (five out of six) of T3a cases could not achieve a PSA nadir under 0.2 ng/ml.
The PSA progression-free rate was estimated by the Kaplan–Meier method for comparisons between the lower PSA nadir group and the higher PSA nadir group. The PSA progression-free rate in the lower PSA nadir group was 86.7% at 5 years. In contrast, the progression-free rate in the higher PSA nadir group was 67.1%, which was significantly lower than that of the lower PSA nadir group (log-rank, P < 0.0001) (Fig. 2).
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Anti-androgen treatment was initiated in the 25 patients of the higher PSA nadir group. The median age of all patients was 76.4 years (range 68–85). The classification based on the TNM was as follows: distribution, T1c 4, T2a 10, T2b 6 and T3a 5. Six patients had a Gleason score of <6, 8 patients had a Gleason score of 7 and 11 patients had a Gleason score of >8. The median pre-treatment PSA levels with LH–RH agonist and anti-androgen were 27 and 2.5 ng/ml, respectively. The median of PSA half-life with anti-androgen and LH–RH agonist were 2.0 and 1.5 months, respectively. The median observation period with LH–RH agonist monotherapy was 13.3 months, and the observation period with anti-androgen therapy was 12.6 months (Table 3).
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Following patients under anti-androgen therapy revealed a PSA progression-free rate, evaluated by the Kaplan–Meier proportion, of 80.8% at 1 year and 62.6% at 5 years (Fig. 3).
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In the multivariate analysis, the only significant independent risk factor for PSA progression that affected PSA chemical failure with anti-androgen therapy was a PSA nadir of >0.2 ng/ml with anti-androgen (P < 0.05) (Table 4).
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A total of 15 cases were classified into the lower PSA nadir group, whereas 10 cases were labelled as belonging to the higher PSA nadir group, including three T3a cases. In comparisons between the lower PSA nadir group and the higher PSA nadir group, the PSA progression-free rate in the lower PSA nadir group was 92.0% at 5 years. In contrast, in the higher PSA nadir group, the progression-free rate was 30.0%. The PSA progression rate was significantly different between the two groups (log-rank, P < 0.0001) (Fig. 4).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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In early stage prostate cancer, several treatment options are available, including radiation, radical prostatectomy, and expectant management including observation or ADT (2,3). In expectant management, watchful waiting is one option to manage LPC; however, it is important to realize that in one study, 13% of patients with untreated LPC under observation died (1). ADT is a crucial optional treatment for LPC. However, discussion of ADT has been limited to cases of advanced cancer (5–7). Optimal treatment strategies with ADT have not been established except for advanced cases of prostate cancer.
Focusing on quality of life (QOL) with ADT, CAB had a greater adverse effect on QOL in comparison with monotherapy (5,14). Many patients apply more leverage to QOL aspects when deciding on treatment methods (15). Considering this aspect of treatment and patient decision-making, if LH–RH monotherapy can contribute the same benefits as CAB, monotherapy holding anti-androgen is the preferable choice.
On the basis of these ideas, we started to evaluate delayed-CAB (12), sequential usage of medical castration and anti-androgen therapy.
According to our data, during the first 5 years of treatment, 64.8% of cases will be controlled with LH–RH monotherapy alone, and 62.6% of PSA chemical failure cases will be stabilized by additional anti-androgen treatment. On the basis of these results, if all cases are treated with initial CAB, nearly 60% of cases would be over-treated. Many of these cases would not need initial anti-androgen treatment, which has the possibility of inducing undesirable side effects. Furthermore, to design a good control plan with ADT, crucial monitoring will be needed to avoid the development of lethal conditions. Reliable predictors of chemical failure and survival are indispensable.
The PSA level is a crucial candidate as an optimal predictor of lethal steps during prostate cancer treatment. The PSA was evaluated as an independent risk factor after radical prostatectomy (16), and baseline PSA values and rates of PSA change are prognostic factors for lethal prostate cancer (1). As a predictor of treatment failure in prostate cancer with androgen deprivative therapy, the PSA should be a strong independent predictor of survival in new metastatic prostate cancer (17), Gleason sum >6 and age <70 (9), but there has been no discussion of the efficacy of PSA only for ADT in LPC or LAPC. To address these points, we first reported that PSA nadir, Gleason score and initial PSA were independent risk factors for early PSA biochemical failure with delayed-CAB in LPC.
According to our data, the cases with pre-treatment parameters that include a Gleason score of 8 or an initial PSA of >20 ng/ml should not be enrolled for delayed-CAB, because these cases have high-risk back gland with early PSA chemical failure associated with a PSA nadir of over 0.2 ng/ml. The cases with a Gleason score over 8 or an initial PSA of >20 ng/ml may be classified as high risk in D'Amico's classification (18), and high-risk cases should not be treated with delayed-CAB therapy.
The other parameter, PSA half life, reflected the declining trend of PSA with initial hormonal therapy. However, this variable's relation to PSA biological failure or survival may be still be controversial (13,19). Our latest report with advanced cases (12) showed that PSA half life might be a crucial parameter to predict PSA trends, but this was not confirmed in the present report. There are several reasons why we could not demonstrate the same result. The first may depend on the longer surveillance period. We could find several cases that took over 3 years to reach PSA nadir with a longer PSA half-life, which were associated with good PSA control (data not shown). Another variable is the static reflection induced by advanced cases. In advanced cases, alteration of PSA changed drastically, but PSA half life is longer than 3.6 months. The PSA half life could not be selected as an independent significant risk factor for PSA biological failure in this report without advanced cases. Finally, the determination of the PSA nadir to be the optimal parameter, compared with the PSA half life, agreed with previous reports (13,19).
Of cases with T3a (n = 6), 83% (5 of 6) of cases could not reach an undetectable level of PSA nadir with LH–RH monotherapy. In addition, 60% (3 of 5) of T3a cases could not reach undetectable PSA nadir levels induced by anti-androgen treatment. Since this study did not enrol enough cases with T3a, >T3 was not listed as a significant risk factor. In other published reports, LPC and LAPC were often discussed as the same category (3,20). In the future, we must elucidate the effects of delayed-CAB in LPC and LAPC separately.
Of the relationships between the PSA nadir level and survival or PSA progression during ADT, cases with a PSA nadir of 0.2 ng/ml or less had significantly better survival than the other group (17). A PSA nadir level >0.2 ng/ml was significantly associated with PSA progression (9). On the basis of our data, we suggest that a PSA nadir >0.2 ng/ml is a risk factor for PSA biochemical progression during whole delayed-CAB that consists of a LH–RH agonist monotherapy step and associated with delayed anti-androgen. However, it is indispensable to evaluate the significant association between PSA biochemical failure and survival with further observations.
During the management of prostate cancer both survival benefit and QOL maintenance should be evaluated.
In terms of effectiveness, short-term or intermittent primary ADT cannot be recommended because incomplete androgen ablation may cause progression of cancer (21). Delayed-CAB therapy should be classified in the category of incomplete androgen ablation. To refine the benefit of delayed-CAB, there should be no survival disadvantage of delayed-CAB compared with initial-CAB. However, in elderly prostate cancer cases, being watchful and waiting may be an optional strategy (2). Randomized trials between ADT and being watchful and waiting, focusing on survival difference, should be initiated to establish the management algorithm to avoid over treatment with ADT.
Focusing on QOL, although LH–RH agonist monotherapy had a lower adverse effect on QOL compared with initial CAB (5,14), ADT itself has a possibility to decrease the QOL. Higano reported that the suppression of testosterone induced many adverse effects, including sexual dysfunction, mood changes and hot flashes. Also, since bone mineral density loss is rapid during the 5 years of ADT, cases with ADT have demonstrated a 21–37% increase in fracture risk. (22) Since bone fractures have the potential to decrease QOL, this side effect induced by ablation of testosterone cannot be ignored. Unfortunately, the evaluation of QOL was not addressed in this study. Future studies should be designed to reveal not only survival benefits but also QOL resulting from any therapy for local and LAPC, with a longer observation period.
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CONCLUSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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We first report the efficacy of delayed-CAB in LPC, and that PSA level is a useful predictor during whole delayed-CAB steps. A randomized trial will be established in the near future to compare delayed-CAB and other treatments, including initial-CAB, radiation, radical prostatectomy and observation in LPC or LAPC.
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Funding |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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This study was financially supported by the Mie J-cap association.
Conflict of interest statement None declared.
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Acknowledgements |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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We would like to sincerely thank the members belonging to the Mie J-cap association for updating the Prostate cancer survey.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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