Clinical investigation
Prostate
Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference

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In 1996 the American Society for Therapeutic Radiology and Oncology (ASTRO) sponsored a Consensus Conference to establish a definition of biochemical failure after external beam radiotherapy (EBRT). The ASTRO definition defined prostate specific antigen (PSA) failure as occurring after three consecutive PSA rises after a nadir with the date of failure as the point halfway between the nadir date and the first rise or any rise great enough to provoke initiation of therapy. This definition was not linked to clinical progression or survival; it performed poorly in patients undergoing hormonal therapy (HT), and backdating biased the Kaplan-Meier estimates of event-free survival. A second Consensus Conference was sponsored by ASTRO and the Radiation Therapy Oncology Group in Phoenix, Arizona, on January 21, 2005, to revise the ASTRO definition. The panel recommended: (1) a rise by 2 ng/mL or more above the nadir PSA be considered the standard definition for biochemical failure after EBRT with or without HT; (2) the date of failure be determined “at call” (not backdated). They recommended that investigators be allowed to use the ASTRO Consensus Definition after EBRT alone (no hormonal therapy) with strict adherence to guidelines as to “adequate follow-up.” To avoid the artifacts resulting from short follow-up, the reported date of control should be listed as 2 years short of the median follow-up. For example, if the median follow-up is 5 years, control rates at 3 years should be cited. Retaining a strict version of the ASTRO definition would allow comparisons with a large existing body of literature.

Introduction

The serum marker called PSA (prostate specific antigen) is widely used for screening, diagnosing, determining prognosis, and selecting the appropriate treatment for men with clinically localized prostate cancer (1, 2, 3, 4, 5, 6, 7). After treatment, PSA is used to determine the effectiveness of treatment. Reports early in the PSA era (early 1990s) tended to emphasize the need for normal values (<4.0 ng/mL) or other threshold values (such as 2 or 1 ng/mL) (8). This lack of standardization made it impossible to compare the results from different institutions.

In 1994 the Board of the American Society for Therapeutic Radiology and Oncology (ASTRO) formed a committee to develop a standard definition for PSA failure after external beam radiotherapy (EBRT). To this end, in 1996 ASTRO sponsored a Consensus Conference to establish a working definition of biochemical failure after EBRT (9). A panel of experts including radiation oncologists, urologists, statisticians, and medical oncologists used the best available evidence at the time and the ASTRO consensus definition was born. This definition provided a standard definition that allowed radiotherapy series from different institutions to be compared.

Stated simply, the ASTRO Consensus Definition (as it came to be called) defined PSA failure as occurring after three consecutive PSA rises after a nadir with the date of failure defined as the point halfway between the nadir date and the first rise or any rise great enough to provoke initiation of salvage therapy. The Consensus Panel also went on to say that “it is recommended that series be presented for publication with a minimum period of observation of 24 months” and that “… PSA determinations be obtained at 3 to 4 month intervals during the first 2 years after the completion of radiation therapy, and every 6 months thereafter.” Unfortunately, many investigators ignored this last portion of the recommendation. Consequently, there have been many studies published that include patients with inadequate follow-up (as will be discussed in more detail later), leading to inaccurate estimates of long-term outcomes and compromising the robustness of this definition.

Three additional important conclusions were also reached during the first ASTRO Consensus Conference including:

  • 1

    “Biochemical failure is not justification per se to initiate additional treatment. It is not equivalent to clinical failure.”

  • 2

    “It is however, an appropriate early endpoint for clinical trials.”

  • 3

    “No definition off PSA failure has, as yet, been shown to be a surrogate for clinical progression or survival.”

These conclusions reflected the desire for recommendations about therapeutic interventions to be evidence based. They also left open the possibility that “PSA failure” might in some cases be a clinically irrelevant endpoint.

Although creation of the ASTRO Consensus Definition must be viewed as a tremendous success, it became clear with additional data that it was far from an ideal definition. First, backdating seriously biases the Kaplan-Meier estimates of event-free survival and, in a way, that depends on length of follow-up (the bias is worse, the shorter the follow-up) such that reports with different follow-up cannot be compared (10, 11). Second, from the outset it was made explicitly clear that this definition was not linked to clinical progression, survival, or therapeutic interventions. Furthermore, despite the fact that the ASTRO definition was not developed using data from series using hormonal therapy (HT) or brachytherapy (BT), this definition came to be applied in both of these settings as well (12, 13, 14). The ASTRO definition of PSA failure also came to be applied to patients treated with nonradiation-based approaches such as radical prostatectomy and cryosurgery (15, 16, 17).

To address the shortcomings of the ASTRO Consensus definition, a second Consensus Conference was held on January 2005 in Phoenix, Arizona to formally consider replacing or revising the ASTRO Consensus definition. This conference was jointly sponsored by ASTRO and the Radiation Therapy Oncology Group (RTOG). This report summarizes the data presented, the issues discussed, and the major conclusions reached by the presenters and the panel. It is very important for the readers to note that the definitions proposed are to define success or failure in the context of a population, not an individual. Defining PSA/biochemical success for an individual vs. a population are separate questions with the former being guided by clinical judgment. The definitions chosen for the latter must be such that a computer program can be written to calculate automatically the disease-free status for a large number of patients. They should be used to compare results after EBRT treatment techniques with or without short-term androgen deprivation, but they should not be used for surgically-treated patients, patients undergoing salvage radiotherapy, or patients undergoing cryosurgery.

Section snippets

Summary of presentations: PSA failure after radiotherapy: Material and methods (format for data presented)

The scientific presentations were organized and moderated by the meeting Chair, Dr. Howard Sandler. The program was preceded by a number of phone conferences to clarify the purpose and goals of the meeting, and to select the expert panel and the most appropriate speakers. The speakers were selected because they were recognized experts who had large databases detailing the outcomes after EBRT with sufficient follow-up and patient numbers to justify evidence-based conclusions.

The Panel consisted

Predictions of disease progression based on the slope of the PSA

Jeremy Taylor, Ph.D., presented data that emphasized the merits of a definition of biochemical failure that was linked to PSA kinetics (19). He presented data that demonstrated that the slope of the PSA when combined with other clinical features (such as the pretreatment PSA, T stage, and radiation dose) could be used to monitor disease progression. Although this approach was seen as elegant, it was perceived as complicated and was based only on patients treated with EBRT, and thus did not

Biochemical failure and adjuvant androgen deprivation therapy

Dr. Tom Pickles (British Columbia Cancer Agency, Vancouver) discussed the combined use of radiation and ADT including: (1) the impact of testosterone recovery on PSA bounces; (2) when to set “time 0”; and (3) the predictive ability of various PSA failure definitions. He based many of his conclusions on earlier work and an analysis of unpublished data from 1,885 men treated with EBRT (46% with ADT) and 483 men treated with PPI (70% with ADT), with a minimum follow-up of 3 years. He first

Recommendations

We recommend that a rise by 2 ng/mL or more above the nadir PSA (defined as the lowest PSA achieved) be considered as the current standard definition for biochemical failure after radiotherapy with or without short-term hormonal therapy. We recommend that the date of failure be determined “at call” and not backdated. However, confirmed laboratory errors or patients with acute prostatitis effectively treated with antibiotics should not be declared as biochemical failures. Patients not meeting

Rationale for recommendations and precautionary notes

The shortcomings of the ASTRO Consensus definition as noted above includes: (1) the fact that it is very sensitive to the length of follow-up; (2) it was developed to address the issue of EBRT monotherapy; (3) there is a backdating censoring artifact; (4) there is a potential for false positives secondary to “benign PSA bounces” associated particularly with the use of ADT and PPI; (5) it does not meet proportional hazard assumptions (a basic tenant of multivariate analysis); and (6) there was a

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