Review
Prostate-specific antigen (PSA) alone is not an appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials

https://doi.org/10.1016/j.ejca.2006.02.011Get rights and content

Abstract

The prostate-specific antigen (PSA) is the most studied marker of prostate cancer. It is used for screening and as indicator of disease evolution for individual patients. PSA being a prognostic factor is however not sufficient to justify using PSA-derived endpoints as surrogate for definitive survival endpoint in phase III trials. First, we clarify the terminology and requirements for a marker to be a valid surrogate endpoint. We then review the published literature pertaining to the validation of PSA endpoints as surrogate in all disease stages. We discuss the limitations of these studies and conclude that so far, PSA is not a validated surrogate endpoint in any of the disease settings and treatment conditions considered. We give some recommendations for the planning of trials that would use PSA endpoints (in hormone refractory disease) and for the early stop of (endocrine treatment) trials on the basis of intermediate results based on PSA.

Introduction

Phase III cancer clinical trials that evaluate the clinical benefit of new treatment options often require large patient numbers and long follow-up. Recent advances in the understanding of the biological mechanisms of disease development have resulted in the emergence of a large number of potentially effective new agents. There is also increasing public pressure for promising new drugs to receive marketing approval as rapidly as possible, in particular for life threatening diseases such as cancer. For these reasons, there is an urgent need to find ways of shortening the duration of cancer clinical trials. The duration of phase III trials results from the use of long-term clinical endpoint (clinical progression, survival). Therefore, to replace this endpoint (the “true” endpoint) by another (a “surrogate” endpoint), that could be measured earlier, more conveniently or more frequently, and that would adequately reflect the benefit of new treatments on the clinical endpoint(s), seems an attractive solution. In the field of prostate cancer, prostate-specific antigen (PSA) has probably been the most studied biomarker.1 It has been investigated as a prognostic factor and as a potential surrogate endpoint across disease stages.

It is a common misconception that established prognostic factors necessarily make valid surrogate endpoints. A prognostic factor is an intermediate outcome that is correlated with the true clinical outcome (T) for an individual patient.2 Its knowledge may be useful for diagnostic or prognostic assessment of an individual patient. For a prognostic factor to be a surrogate endpoint (S), it is further required that “the effect of treatment on a surrogate endpoint must be “reasonably likely” to predict clinical benefit”.2, 3 In other words, a biomarker S will be a good surrogate for the true endpoint T if the results of a trial using outcome S can be used to infer the results of the trial if T had been observed and used as endpoint and this with sufficient precision. To demonstrate surrogacy, a high association between the treatment effects on the surrogate and on the true endpoint thus needs to be established across groups of patients treated with a new versus a standard intervention.

Fig. 1 shows a schematic of two situations: a) where post-treatment PSA level (S) is prognostic for mortality risk (T) (as shown by the diagonal orientation of the ovals representing the individual patient data in two treatment groups), but is not surrogate, as is indicated by the line linking the two group’s averages being horizontal; and b) where post-treatment PSA level (S) is weakly prognostic for mortality risk (T) (as shown by the more horizontal orientation and more circular shape of the ovals representing the individual patient data), but is a strong surrogate of the treatment difference on the mortality risk, as shown by the bar linking the group’s averages being diagonal, so that differences in average post-treatment PSA level between the treatment groups correlate with difference in average mortality risk.

To illustrate this, let us consider the recently published secondary results of the Tax-327 study.4 This study compared a weekly and a three-weekly schedule of docetaxel plus prednisone to mitoxantrone and prednisone in hormone refractory prostate cancer (HRPC). In this study, like often in this disease state, patients who achieved a PSA response had a 60% reduction in mortality risk compared with non-responders (hazard ratio (HR) = 0.40, 95% CI: 0.31–0.51). The reduction of the PSA by 50% or more from baseline value, which was defined as a PSA response, was a strong prognostic factor for survival. Now considering PSA response as an endpoint and as a putative surrogate for overall survival, we observe with the authors that the weekly docetaxel arms resulted in a response rate of 48% which was significantly different from the 32% response rate that was obtained with standard arm mitoxantrone plus prednisone (P < 0.0001). However, the median overall survival on the weekly docetaxel arm amounted 17.4 months and did not differ statistically significantly from the 16.5 months median survival achieved with the standard treatment (P = 0.362, Fig. 2). The benefit amounting less than a month was also not medically relevant, contrary to the difference in response rates. Thus in this study, PSA response although it was a strong prognostic factor for survival at the patient level, did not appear to be reliable as a surrogate for survival when comparing the weekly docetaxel treatment to mitoxantrone plus prednisone.

Section snippets

Statistical validation of surrogate endpoints

Traditionally, the “Prentice Criteria”5 were used for the purpose of demonstrating surrogacy on the basis of data from a single trial. The Prentice criteria require that four conditions be shown to be true in order to demonstrate the validity of a putative surrogate endpoint (here PSA), as a replacement endpoint for a true endpoint T (here survival):

  • (a)

    There must be a statistically significant treatment effect on the PSA endpoint (in univariate analysis)

  • (b)

    There must be a statistically significant

Published results on PSA surrogacy in prostate cancer

Although the literature concerning the association between PSA and long-term outcome with prostate cancer is extensive, there are relatively few reports of true validation studies of this endpoint. We shall critically review the published evidence assessing PSA endpoints (PSA response, time to PSA progression, PSA velocity, PSA doubling time) as potential surrogate endpoint for overall or progression-free survival, for each stage of prostate cancer.

Discussion

The literature on PSA surrogacy thus far failed to satisfactorily demonstrate the value of PSA as a surrogate endpoint in prostate cancer.

From this review, one can broadly conclude that for the comparison of primary treatments, PSA is until now not proven to be a suitable replacement for a final survival endpoint. The association between PSA changes after initial treatment and survival is likely to diminish in the future, as second and third line treatments may become increasingly efficacious.

Conflict of interest statement

The authors have no conflict of interest to declare.

References (30)

  • E.J. Small et al.

    Prostate-specific antigen in prostate cancer: a case study in the development of a tumour marker to monitor recurrence and assess response

    Semin Oncol

    (2002)
  • Biomarkers Definitions Working Group

    Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework

    Clin Pharmacol Ther

    (2001)
  • J.R. Johnson et al.

    Endpoints and United States Food and Drugs Administration Approval of Oncology Drugs

    J Clin Oncol

    (2003)
  • M. Roessner et al.

    Prostate-specific antigen (PSA) response as surrogate endpoint for overall survival (OS): Analysis of the TAX 327 Study comparing decetaxel plus prednisone to mitoxantrone plus prednisone in advanced prostate cancer

    J Clin Oncol

    (2005)
  • R.L. Prentice

    Surrogate endpoints in clinical trials: definitions and operational criteria

    Stat Med

    (1989)
  • D.G. Altman et al.

    Absence of evidence is not evidence of absence

    Br Med J

    (1995)
  • M. Buyse et al.

    Criteria for the validation of surrogate end-points in randomized experiments

    Biometrics

    (1998)
  • M.J. Daniels et al.

    Meta-analysis for the evaluation of potential surrogate markers

    Stat Med

    (1997)
  • M. Buyse et al.

    The validation of surrogate endpoints in meta-analyses of randomized experiments

    Biostatistics

    (2000)
  • T. Burzykowski et al.

    Validation of surrogate endpoints in multiple randomized clinical trials with failure-time endpoints

    J R Stat Soc Ser C Appl Stat

    (2001)
  • A.V. D’Amico et al.

    Surrogate end point for prostate cancer specific mortality after radical prostatectomy or radiation therapy

    J Natl Canc Inst

    (2003)
  • H.M. Sandler et al.

    Can biochemical failure (ASTRO definition) be used as a surrogate endpoint for prostate cancer survival in phase III localized prostate cancer clinical trials? Analysis of RTOG protocol 92–02

    J Clin Oncol

    (2003)
  • R. Valicenti et al.

    Surrogate endpoint for prostate cancer-specific survival: Validation from an analysis of the Radiation Therapy Group Protocol 92-02

    J Clin Oncol

    (2005)
  • D. Newling et al.

    Is prostate-specific antigen progression a surrogate for objective clinical progression in early prostate cancer?

    J Clin Oncol

    (2004)
  • M.A. Eisenberger et al.

    Bilateral orchiectomy with or without Flutamide for metastatic prostate cancer

    N Engl J Med

    (1998)
  • Cited by (68)

    • An Updated Analysis of the Survival Endpoints of ASCENDE-RT

      2023, International Journal of Radiation Oncology Biology Physics
    • Consensus on molecular imaging and theranostics in prostate cancer

      2018, The Lancet Oncology
      Citation Excerpt :

      Several imaging methods for the evaluation of prostate cancer have been suggested, and these include methods that have been available for decades (eg, CT, bone scintigraphy, and transrectal ultrasound), as well as those that were introduced more recently (eg, whole-body MRI [WB-MRI], multiparametric MRI, and PET). However, there has been little consensus about the usefulness of these approaches.8–11 Promotion of the use of the most appropriate diagnostic and therapeutic interventions in clinical practice, guidelines, and consensus statements, are of paramount importance for the medical community, although they cannot replace scientific evidence.

    • The third line of treatment for metastatic prostate cancer patients: Option or strategy?

      2015, Critical Reviews in Oncology/Hematology
      Citation Excerpt :

      In addition, differences in the use of tumour imaging methods are evident; while some patients received bone and/or CT scans multiple times during treatment, others did not receive a CT scan at all, and most decisions were based on the rise of PSA. However, this marker has its limitations [29], although, it has been shown that patients who do not achieve a ≥50% reduction in PSA levels within the first treatment month may have primary resistance to AA or E [30]. Other retrospective analyses were conducted to evaluate the optimal sequence of Cbz and AA after D.

    • Comparative effectiveness of external-beam radiation approaches for prostate cancer

      2014, European Urology
      Citation Excerpt :

      In addition to assessing complications, we examined the use of salvage therapy with ADT as a measure of cancer control. Due in part to prostate cancer's protracted clinical course, biochemical recurrence has generally been used as a proxy for cancer control [6,8], although such definitions of recurrence vary, and some believe they lack precision [23]. In our study, the lower proportion of men receiving concurrent ADT with IMRT is congruent with the observation that more of these patients had lower stage disease.

    • Interval to biochemical failure predicts clinical outcomes in patients with high-risk prostate cancer treated by combined-modality radiation therapy

      2013, International Journal of Radiation Oncology Biology Physics
      Citation Excerpt :

      A partial explanation for the discrepancy between univariate analysis and MVA is that the CMRT cohort of patients was enriched for patients with unfavorable GS 8-10 (79% [33 of 42] in CMRT vs 62% [82 of 133] in EBRT, P=.02, χ2 test). Additionally, when patients were compared by GS categories (2-10), there was no difference in the make-up of Gleason score between RT regimens for IBF ≤18 months (P=.56, χ2), although among those with IBF >18 months, the EBRT group had a trend toward lower GS (P=.079, χ2). As a time-dependent variable IBF is prone to an immortality time bias, because to be classified as having a time-defined outcome (ie, IBF >18 months), each individual must survive and be disease-free for at least 18 months.

    View all citing articles on Scopus
    View full text