original article
`
`Annals of Oncology 18: 1828–1833, 2007
`doi:10.1093/annonc/mdm332
`Published online 9 September 2007
`
`Prostate-specific antigen doubling time before onset
`of chemotherapy as a predictor of survival for
`hormone-refractory prostate cancer patients
`
`S. Oudard1, E. Banu1*, F. Scotte1, A. Banu1, J. Medioni1, P. Beuzeboc2, F. Joly3, J.-M. Ferrero4,
`F. Goldwasser5 & J.-M. Andrieu1
`1Georges Pompidou European Hospital, Paris; 2Curie Institute, Paris; 3Francxois Baclesse Centre, Caen; 4Antoine-Lacasagne Centre, Nice; 5Cochin Hospital,
`Paris, France
`
`Received 26 March 2007; revised 15 May 2007; accepted 21 May 2007
`
`Background: We evaluated the possible use of prostate-specific antigen doubling time (PSA-DT) before
`chemotherapy initiation as a surrogate marker of survival in hormone-refractory prostate cancer (HRPC) patients.
`Patients and methods: Data from 250 consecutive metastatic HRPC patients treated with chemotherapy between
`February 2000 and November 2006 were retrospectively analysed. At least three PSA assays were required within 3
`
`months before chemotherapy. PSA-DT was calculated as ln 2 divided by the slope of the log PSA line, and the
`
`difference between two log PSA levels was divided by the time interval. The primary endpoint was overall survival (OS).
`
`Survival rates according to PSA-DT were stratified on chemotherapy regimen. Multivariate Cox regression analysis was
`
`performed to isolate the impact of PSA-DT on OS, controlling for associate prognostic covariates.
`Results: Patients received docetaxel- (82%) or mitoxantrone-based chemotherapy. The median PSA-DT was 45
`days (range 4.7–1108 days). There were 174 deaths (70%). The median survival was 16.5 months (95% confidence
`
`interval [CI] = 12.5–20.5) and 26.4 months (95% CI = 20.3–32.4) for patients with a PSA-DT < 45 and ‡45 days,
`
`respectively. In the multivariate setting, the adjusted hazard ratio (HR) was 1.39 (95% CI = 1.03–1.89; P = 0.04),
`
`stratified by chemotherapy regimen.
`Conclusion: A short PSA-DT before onset of chemotherapy in HRPC patients was associated with an increased risk
`of death. This could be useful as a stratification parameter in trials with new drugs in a metastatic setting.
`Key words: chemotherapy, hormone-refractory prostate cancer, overall survival, predictive factor, prostate-specific
`antigen doubling time
`
`article
`original
`
`introduction
`
`Prostate cancer is currently the most frequent malignancy in
`men and is responsible for the second highest number of
`cancer-related deaths after lung cancer. The American Cancer
`Society estimates that 232 000 new cases of prostate cancer were
`diagnosed in the United States during 2005 and more than
`30 000 men will die of metastatic disease [1]. Around half of
`all patients are metastatic at the initial diagnosis, and nearly
`50% of those who present with an initial localized disease
`will develop subsequent metastases. Androgen deprivation
`therapy allows a response rate of 80–90% [2]. Those remissions
`last 2 or 3 years, but almost all metastatic prostate cancer
`patients evolve towards an androgen-independent state
`resulting in death due to widespread metastases [3].
`
`*Correspondence to: Dr S. Oudard, MD, Georges Pompidou European Hospital,
`Medical Oncology Department, 20 Leblanc Street, 75015 Paris, France.
`Tel: +33-1-56-09-34-34; Fax: +33-1-56-09-24-31; E-mail: stephane.oudard@egp.aphp.fr
`
`ª 2007 European Society for Medical Oncology
`
`For a long time, prostate cancer has been considered as
`a chemoresistant disease [4]. Two major randomized trials
`modified our chemotherapy procedure in hormone-refractory
`prostate cancer (HRPC) patients [5, 6]. These studies compared
`docetaxel–estramustine with or without prednisone or
`docetaxel–prednisone regimens with the previous standard
`(mitoxantrone–prednisone combination). The authors
`demonstrated a significant advantage of docetaxel-based
`regimens in terms of overall and progression-free survival.
`These results led us to consider a docetaxel-based regimen as
`the reference treatment in the management of HRPC patients,
`and we have been using this since 2004. A phase II randomized
`study evaluated the crossover impact on survival of HRPC
`patients [7].
`The main issue with the evaluation of response to
`chemotherapy for HRPC patients is due to the predominance
`of bone metastases, which are considered to be evaluable
`but non-measurable lesions (non-target). The level of
`prostate-specific antigen (PSA) is related to tumour growth and
`
`Amerigen Exhibit 1115
`Amerigen v. Janssen IPR2016-00286
`
`

`
`Annals of Oncology
`
`has a positive correlation with tumour burden [8]. A decrease
`of more than 50% in the PSA level as compared with the
`baseline value has been proposed as a biological response
`criterion [8]. A significant relationship has been established
`between this decrease and an improvement in survival,
`justifying the use of this criterion to identify potentially
`effective drugs. Nevertheless, this cut-off did not met the
`criteria for surrogacy in a recent retrospective analysis of
`docetaxel-treated HRPC patients [9]. Reliable surrogate
`endpoints for survival are being investigated in order to reduce
`the time required to assess the efficacy of a new treatment and
`appropriate selection of patients for clinical trials. New
`biological variables such as albumin, alkaline phosphatase and
`lactate dehydrogenase have been validated and included in
`nomograms for HRPC patients [10]. For instance, the rate of
`increase in PSA has been shown to correlate with the prostate
`cancer-specific mortality following primary therapy: patients
`presenting with a rapid increase in PSA [i.e. a short PSA
`doubling time (PSA-DT)] had a higher risk of death than those
`with a slower increase [11–15]. In order to confirm these
`findings, we analysed the PSA-DT before initiation of
`chemotherapy in metastatic HRPC patients as a surrogate
`endpoint for overall survival (OS).
`
`methods
`
`study population
`We retrospectively analysed data from consecutive metastatic HRPC
`patients who had received docetaxel- or mitoxantrone-based chemotherapy
`in five French centres (Georges Pompidou European Hospital,
`Curie Institute and Cochin Hospital in Paris, Francxois Baclesse Centre,
`Caen and Antoino-Lacasagne Centre, Nice). At least three consecutive PSA
`determinations had to be available within 3 months before the start of
`chemotherapy. To be eligible for this analysis chemo-naı¨ve patients had to
`fail both androgen blockade and anti-androgen withdrawal, to present an
`Eastern Cooperative Oncology Group (ECOG) performance status (PS) £ 2
`and a castrate serum testosterone level.
`The database was declared to the appropriate French authorities
`supervising individual computerized data files (Commission Nationale
`Informatique et Liberte´).
`
`PSA doubling time evaluation
`The PSA-DT was estimated in patients with rising PSA before the onset of
`chemotherapy according to the formula: t · loge(2)/[loge(PSA2) –
`loge(PSA1)] where t is the time between two consecutive PSA
`determinations (PSA1 and PSA2) [16]. This was made possible because all
`PSA assays for each patient were performed in the same laboratory. More
`complex models able to estimate PSA-DT have been described in the
`literature [17].
`
`statistical analysis
`The primary endpoint was OS defined as the time interval between the start
`of chemotherapy and death or last follow-up for living (censored) patients.
`The OS rates according to PSA-DT categories were estimated using the
`Kaplan–Meier method and compared using a stratified log-rank test.
`Reduction in the risk of death and hazard ratios (HRs) were estimated with
`a 95% confidence interval (CI) at the univariate analyses. Because patients
`were not randomly assigned to chemotherapy and treatments were
`previously shown as different in terms of survival, regression and log-rank
`analyses were stratified by chemotherapy regimen. A multivariate Cox
`proportional hazard regression analysis was used as the main statistical
`
`original article
`
`method, controlling for explanatory covariates that have been shown to be
`prognostic and therefore, could confound the core analysis [18]. These
`variables included age, PSA baseline, hormone sensitivity interval, Gleason
`score, haemoglobin, number of metastatic sites and ECOG PS. The stepwise
`backward elimination strategy was used in order to better estimate the
`impact of PSA-DT on OS as the backbone of the multivariate analysis. The
`PSA-DT was expressed in days and analysed as a binary variable (short and
`long PSA-DT) according to the median value. The hormone sensitivity
`interval was calculated as the difference between two chronological
`moments: the start of hormonal therapy and the start of chemotherapy
`(when patients were considered as hormone-refractory), expressed in days.
`The Fischer test and Student’s t-test were used to estimate differences
`between PSA-DT categories on demographic, clinical and biological
`categorical or quantitative variables, respectively. All statistical tests were
`two-sided and assessed for significance at the 0.05 level. No statistical
`adjustment was performed for the multiplicity of tests. The relational
`database was created using FileMaker Proä 8.5 (FileMaker Inc, CA, USA)
`software. The statistical analysis was performed by Eugeniu Banu using
`SPSSä 15 (SPSS Inc., Cary, NC, USA) and EpiInfo 2000 version 3.2.2
`(Centers for Disease Control, Atlanta, GA, USA).
`
`results
`
`patient characteristics
`
`Data from 250 metastatic HRPC patients who had received
`chemotherapy between February 2000 and November 2006
`were analysed. Chemotherapy consisted of docetaxel- or
`mitoxantrone-based regimens in 204 (82%) and 46 (18%) of
`patients, respectively. The median time interval between two
`consecutive PSA readings before the start of chemotherapy (for
`PSA-DT estimation) was 22 days (95% CI = 3–90 days). The
`median PSA-DT was 45 days (range 4.7–1108). Two groups of
`patients were defined: those with a short PSA-DT < 45 days
`(n = 125) and those with a long PSA-DT ‡ 45 days (n = 125).
`Patient characteristics according to PSA-DT groups are
`summarized in Table 1. There were significant differences
`between some baseline characteristics such as hormone-
`sensitivity interval, age and PSA level (P < 0.02).
`
`overall survival
`
`At the time of analysis 174 (70%) patients had died,
`of whom 88 (70%) were in the short PSA-DT group and
`86 (69%) in the long PSA-DT group. The median OS for the
`entire cohort was 20.2 months (95% CI = 16.7–23.7).
`Docetaxel-based regimens demonstrated a significant survival
`benefit over mitoxantrone: median OS of 21.3 months
`(95% CI = 17.5–25.1) and 13.8 months (95% CI = 5.9–21.6),
`respectively. As specified in the statistical design, stratified
`survival analyses were performed thereafter according PSA-DT.
`The median and 2-year OS rates were 16.5 months (95%
`CI = 12.5–20.5) and 32% in the short PSA-DT group and
`26.4 months (95% CI = 20.3–32.4) and 55% in the long
`PSA-DT group, respectively (P = 0.04; log-rank test, P = 0.004
`Breslow–Gehan test; Table 2, Figure 1.) The unstratified and
`stratified HRs according to chemotherapy regimen were 1.40
`(95% CI = 1.04–1.89) and 1.37 (95% CI = 1.01–1.84),
`respectively, allowing a significant reduction in the risk of death
`for patients presenting with a longer PSA-DT (P = 0.04, Cox
`regression; Table 3). The median OS for patients treated with
`
`Volume 18 | No. 11 | November 2007
`
`doi:10.1093/annonc/mdm332 | 1829
`
`

`
`original article
`
`Table 1. Patient characteristics according to PSA doubling time
`
`Annals of Oncology
`
`Characteristic
`
`PSA-DT <45 days (n = 125)
`n
`%
`
`PSA-DT ‡45 days (n = 125)
`n
`%
`
`PSA-DT (days)
`Median
`Range
`Age (years)
`Median
`Range
`Baseline PSA (ng/ml)
`Median
`Range
`Haemoglobin (g/dl)
`Median
`Range
`ECOG PS
`0
`1
`2
`Gleason score
`2–4
`5–7
`8–10
`Hormone-sensitivity interval (months)
`Median
`Range
`No. of metastatic sites
`1
`‡2
`Type of metastases
`Bone
`Lymph nodes
`Visceral
`Chemotherapy regimen
`Docetaxel-based
`Mitoxantrone-based
`
`25.7
`4.7–44.5
`
`67.4
`50.7–85.5
`
`98.8
`4–3720
`
`12.6
`7.8–15.1
`
`58
`53
`14
`
`2
`56
`67
`
`87.7
`45.2–1108
`
`69.3
`49.5–90.9
`
`63
`4.1–1840
`
`12.5
`8–17
`
`46.4
`42.4
`11.2
`
`6
`44.8
`53.6
`
`33.9
`3–204.4
`
`45
`2.8–215.6
`
`77
`48
`
`117
`47
`18
`
`98
`27
`
`61.6
`38.4
`
`93.6
`37.6
`14.4
`
`78.4
`21.6
`
`73
`37
`15
`
`1
`71
`53
`
`85
`40
`
`113
`43
`9
`
`106
`19
`
`58.4
`29.6
`12
`
`0.8
`56.8
`42.4
`
`68
`32
`
`90.4
`34.4
`7.2
`
`84.8
`15.2
`
`P
`
`0.0001
`
`0.25
`
`0.002
`
`0.50
`
`0.10
`
`0.25
`
`0.03
`
`0.09
`
`0.18
`
`0.25
`
`n, number of patients; P, statistical P-value; PSA-DT, prostate-specific antigen doubling time; ECOG PS, Eastern Cooperative Oncology Group performance
`status.
`
`Table 2. Overall survival according to PSA doubling time
`
`Survival parameter
`
`PSA-DT <45 days
`(n = 125)
`
`PSA-DT ‡45 days
`(n = 125)
`
`Deaths, n (%)
`OS (months)
`Median (95% CI)
`1-year OS, % (95% CI)
`2-year OS, % (95% CI)
`3-year OS, % (95% CI)
`
`86 (69)
`
`88 (70)
`
`16.5 (12.5–20.5)
`62 (53–70)
`32 (23–41)
`22 (14–30)
`
`26.4 (20.3–32.4)
`80 (72–87)
`55 (45–64)
`33 (24–43)
`
`n, number of patients; PSA-DT,prostate-specific antigen doubling time; OS,
`overall survival; CI, confidence interval.
`
`docetaxel were 26.2 months (95% CI = 18.1-34.3) and 17.8
`months (95% CI = 12.1–23.4) for PSA-DT ‡45 days and <45
`days, respectively. The associated HR was 1.27 (95% CI, 0.90–
`1.81), P = 0.17.
`
`The univariate analyses for pre-defined variables showed that
`ECOG PS, haemoglobin, hormone sensitivity interval, baseline
`PSA and PSA-DT were significantly associated with the risk of
`death (Table 3), whereas age, number of metastatic sites and
`Gleason score were not predictive of survival. In the
`multivariate analysis by Cox regression modelling, ECOG PS,
`haemoglobin and PSA-DT remained significantly predictive of
`risk of death (Table 3, Figure 1, stratified by chemotherapy
`regimen. Despite their statistical significance, the impact on
`survival for two covariates (hormone sensitivity interval and
`baseline PSA) was negligible (associated HR = 1.00, 95%
`CI = 1.00–1.01, regression coefficient < 0.001, P-value < 0.005).
`Including the hormone sensitivity interval and baseline PSA in
`the multivariate analysis (with haemoglobin, ECOG PS and
`PSA-DT as covariates), as expected, has no impact on the
`results, but this degraded the overall goodness-of-fit of the
`model. The interaction term between PSA-DT categories and
`ECOG PS was found to be statistically significant in the
`multivariate setting. As demonstrated, the risk of death was
`
`1830 | Oudard et al.
`
`Volume 18 | No. 11 | November 2007
`
`

`
`Annals of Oncology
`
`original article
`
`Figure 1. Survival distribution according to PSA-DT, multivariate Cox regression model.
`
`Table 3. Univariate and multivariate survival analyses stratified for chemotherapy regimen
`
`Covariate
`
`PSA-DT
`Haemoglobin
`ECOG PS
`Gleason score
`Age
`PSA baseline
`Number of metastatic sites
`Hormone sensitivity interval
`
`Univariate analysis
`HR
`95% CI
`
`1.37
`0.80
`2.17
`1.08
`1.01
`1.00
`1.19
`1.00
`
`1.01–1.84
`0.72–0.90
`1.74–2.72
`0.95–1.23
`0.99–1.03
`1.00–1.00
`0.92–1.55
`1.00–1.00
`
`P
`
`0.04
`0.0001
`0.0001
`0.25
`0.45
`0.0001
`0.19
`0.005
`
`Multivariate analysis
`HR
`95% CI
`
`1.39
`0.85
`2.02
`
`1.03–1.89
`0.76–0.95
`1.61–2.54
`
`P
`
`0.03
`0.004
`0.0001
`
`HR, hazard ratio; CI, confidence interval; PSA-DT, prostate-specific antigen doubling time; ECOG PS, Eastern Cooperative Oncology Group performance
`status; PSA, prostate-specific antigen.
`
`significantly higher for patients having an ECOG PS of 1 or 2
`and a PSA-DT < 45 days. The interaction term between
`chemotherapy regimen and PSA-DT categories was not
`statistically significant.
`
`discussion
`
`Data presented here represent a retrospective review of
`250 metastatic HRPC patients who received docetaxel- or
`mitoxantrone-based chemotherapy. The analysis showed
`that patients with a short PSA-DT (<45 days) before
`the onset of chemotherapy were at a higher risk of death,
`
`regardless of the chemotherapy regimen. To our knowledge,
`this is one of the first reports to investigate the role of
`PSA-DT as a predictive factor of survival in metastatic HRPC.
`PSA levels present great variability among patients; this is
`explained by different PSA expression by prostate cancer cells
`and tumour cell heterogeneity [19]. The interpretation of PSA
`values is further complicated by the fact that some patients who
`demonstrate increased values after initial treatment will not
`evolve towards clinical relapse and also that PSA-DT may
`change between disease states over time [20, 21]. One study
`showed that PSA-DT may be a useful tool in the management
`of untreated prostate cancer patients with a good prognosis,
`
`Volume 18 | No. 11 | November 2007
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`doi:10.1093/annonc/mdm332 | 1831
`
`

`
`original article
`
`and that PSA-DT varied widely, ranging from less than 2 years
`(14%) to more than 10 years (33%) [22]. Results from several
`studies have highlighted the interest in PSA-DT for the
`monitoring of prostate cancer at each step of the disease.
`Recently, a relationship between PSA-DT and survival was
`demonstrated by multivariate analysis for patients treated with
`radical prostatectomy and adjuvant hormonal therapy [23].
`After primary treatment consisting of radical surgery or
`radiotherapy, a PSA-DT below 3 months was significantly
`associated with cancer-specific survival in non-metastatic
`patients, whereas the treatment received was not correlated
`[24]. Thereafter, the use of PSA-DT has been proposed as
`a means of estimating the aggressiveness of the disease and
`differentiating between the local (pelvic) and metastatic risk of
`disease progression [25]. Several reports have demonstrated the
`usefulness of PSA-DT as a predictor of biochemical recurrence
`[26, 27]. In a study of 249 patients, a significant decrease in
`PSA-DT was observed when patients went through hormone-
`naı¨ve to hormone-refractory status, identifying several stages of
`the HRPC period [17]. When PSA-DT was compared between
`untreated hormone-naı¨ve and HRPC patients, values were
`approximately 10 times greater in untreated patients [12]. This
`comparison showed a wide difference in terms of PSA-DT,
`allowing an estimation of the tumour growth rate. The
`definition of a threshold value for PSA-DT is actually a major
`concern and needs to be considered differently according to the
`stage of the disease in establishing nomograms. In HRPC
`patients, PSA-DT was shorter in patients who showed bone
`progression rather than in patients with local relapse and/or
`lymph node metastases. Patients showing a longer DT (>80
`days) had a better overall prognosis than those with shorter
`DTs [12]. The value of PSA-DT has been correlated with the
`objective response to chemotherapy in metastatic HRPC
`patients: the median PSA-DT was 238, 224 and 113 days in
`patients presenting with a partial response, stable and
`progressive disease, respectively (Wilcoxon test, P = 0.002)
`[15]. More recently, a PSA-DT of 70 days has been found to be
`the cut-off value associated with significant survival differences
`between identified strata (11 vs 19 months, HR = 1.79) [28].
`In this report, the PSA-DT cut-off was identified by multiple
`chi-square tests according to minimal P-value. In our study,
`the cut-off of 45 days was the median PSA-DT value. The
`relative increase in the risk of death was slightly lower for our
`patients (HR = 1.39). In the Semeniuk et al. study [28] the
`multivariate survival analysis was not adjusted for ECOG PS,
`a well-known prognostic variable in large phase III studies.
`A higher PSA-DT cut-off was previously described in a small
`cohort of patients [11].
`Moreover, HRPC patients with a short PSA-DT had a poorer
`life expectancy [12]. Our study demonstrated that PSA-DT was
`a valuable tool capable of selecting high-risk patients after
`failure of endocrine therapy and before initiation of
`chemotherapy. The potential usefulness of PSA-DT is to
`provide reliable data at successive steps of the disease. It could
`be used to guide therapeutic strategy in patients managed
`conservatively with watchful observation, to select high-risk
`patients after primary therapy or after failure of endocrine
`therapy, to assess prognosis after relapse and to evaluate the
`efficacy of cytotoxic drugs in HRPC patients.
`
`Annals of Oncology
`
`Could we define a true surrogate endpoint in prostate
`cancer using PSA-DT? According to the Prentice criteria,
`a surrogate endpoint has to be a prognostic factor, and when
`a patient achieves a surrogate endpoint the time to prostate
`cancer-specific mortality has to be independent of the
`treatment received [29].
`
`conclusions
`
`This retrospective analysis shows that a short PSA-DT before
`chemotherapy initiation in HRPC patients is associated with an
`increased risk of death. Our results were statistically significant
`using a multivariate regression model, and showed that patient-
`related predictive factors such as ECOG PS or haemoglobin
`remained crucial. The sole disease-related covariate associated
`with OS was the PSA-DT. It directly interacted with ECOG PS,
`as demonstrated by a borderline relationship at interaction
`terms.
`We identified a high-risk subset of patients with an aggressive
`disease. PSA-DT could be used to stratify HRPC patients in
`order to avoid some potential imbalances between baseline
`covariates in the design of future clinical trials.
`
`acknowledgements
`
`Isabelle Chapelle-Marcillac provided editorial assistance in the
`preparation of the manuscript.
`
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`Annals of Oncology
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`Volume 18 | No. 11 | November 2007
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`doi:10.1093/annonc/mdm332 | 1833