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PSA After Radiation for Prostate Cancer

PSA After Radiation for Prostate Cancer

ABSTRACT: The introduction of prostate-specific antigen (PSA) as a reliable tumor marker for prostate cancer brought significant changes in the end points used for outcome reporting after therapy. With regard to a definition of failure after radiation, a consensus was reached in 1996 that took into account the particular issues of an intact prostate after therapy. Over the next several years, the consensus definition issued by the American Society for Therapeutic Radiology and Oncology (ASTRO) was used and studied. Concerns and criticisms were raised. The sensitivity and specificity of this definition vs other proposals has been investigated, and differences in outcome analyzed and compared. Although the ASTRO definition came from analysis of datasets on external- beam radiation and most of the work on this topic has been with this modality, failure definitions for brachytherapy must be explored as well. The concept of a universal definition of failure that might be applied to multiple modalities, including surgery, should also be investigated, at least for comparative study and research purposes.

Although we are lucky enough
to have a marker in the treatment
of prostate cancer to predict
prognosis before therapy and outcome
afterwards, it has taken over 15
years to determine how to best use it,
and recent long-term outcome studies
have raised several issues along with
options for improvement. While little
controversy surrounds the prognostic
use of this marker in choosing therapy,
we are still exploring treatment
failure definitions, their application
across unlike therapeutic modalities,
and the utility of early documentation
of recurrence and associated salvage
therapy.

History

When prostate-specific antigen
(PSA) first came into clinical use in
the mid- to late 1980s, there was great
enthusiasm for its use in screening
and in the follow-up of prostate cancer
after therapy. As studies were conducted,
PSA was also found to be a
surrogate for tumor burden and proved
its value in pretreatment prognosis and
therapeutic decision-making. A normal
postsurgery PSA level was soon
agreed upon, given that with nearly
all prostate tissue removed, it had to be
very close to zero. Such was not the
case with radiation, however, because
PSA-secreting prostate was left intact.
Thus, the dilemma and debate began.

Some of the first publications using
PSA as a measure of outcome
defined successful radiation as a posttreatment
PSA level ≤ 4 ng/mL[1]; it
was soon discovered, however, that
this level might be normal before therapy
but too high for an irradiated prostate
with a markedly changed
secretory capacity.[2-4] Much discussion
ensued as to what the appropriate
level should be.[5] We saw a rapid
transition to using this marker as an
indicator of treatment efficacy as opposed
to waiting long periods for local
or distant disease to become
clinically evident. Outcome studies
were reported with a variety of PSA
end points, however. Of note were
the differences between the clinical
outcome measures previously used-
local, regional, and distant failure-
and the PSA results that appeared to
document treatment failure earlier and
in higher proportion.[1,6]

Consensus Guidelines
In an effort to standardize study
reporting using this objective PSA
parameter, the American Society for
Therapeutic Radiology and Oncology
(ASTRO) assembled an expert panel
in 1996 and charged the members
with reaching a consensus on "the
significance of the depth of the PSA
nadir, the definition of a rising PSA,
the optimal PSA surrogate end point
for total eradication of tumor or for
relapse after irradiation, and guidelines
for using PSA end points for
reporting (publishing) success or failure
after irradiation."[7]

Data on patient outcomes with various
PSA characteristics and trends
after external-beam radiation along
with illustration of various failure definitions
were supplied by investigators
from seven institutions, who had
made significant contributions to the
literature in the PSA era. Following
presentations by these individuals and
additional information obtained from
recursive partitioning techniques, the
ASTRO panel agreed on four guidelines:

  • Biochemical failure is not justification
    per se to initiate additional
    treatment. It is not equivalent to clinical
    failure. It is, however, an appropriate
    early end point for clinical trials.
  • Three consecutive rises in PSA
    is a reasonable definition of biochemical
    failure after radiation therapy. For
    clinical trials, the date of failure should
    be the midpoint between the postirradiation
    nadir PSA and the first of the
    three consecutive rises.
  • No definition of PSA failure
    has, as yet, been shown to be a surrogate
    for clinical progression or survival;
    and
  • Nadir PSA is a strong prognostic
    factor, but no absolute level is a
    valid cutoff point for separating successful
    and unsuccessful treatments.
    Nadir PSA is similar in prognostic
    value to pretreatment prognostic
    variables.

In addition, the following guidelines
were suggested for studies submitted
for publication: (1) series
should have a minimum observation
period of 24 months; (2) PSA determinations
should be obtained at 3- or
4-month intervals during the first
2 years after the completion of radiation
therapy, and every 6 months
thereafter; and (3) patients reported
in a series who have had one or two
consecutive rises in PSA but not the
three consecutive rises necessary for
failure should be reported separately
in the results.[7]

In the 6 years following the consensus
conference, the ASTRO definition
has been the most frequently
used PSA definition of failure after
radiotherapy, providing a consistent
standard by which studies can be evaluated
and compared. Shortly after the
conference, six of the participating
investigators pooled data on stage T1/2
prostate cancer patients who had a
pretreatment PSA and received external-
beam radiation at least 2 years
prior to analysis. They reported outcome
for 1,765 patients with a median
follow-up of 4.1 years using the
ASTRO definition of failure.[8] The
efficacy and durability of irradiation
were established and prognostic factors
confirmed. Subsequently, singleinstitution
studies added to the body
of outcome data using a consistent
end point for reporting.

Deficiencies in the
ASTRO Definition

As is not uncommon in any situation
where attention is focused on one
primary recommendation, the less salient,
seemingly minor points that
arose from the consensus conference,
such as requiring a minimum of
24 months follow-up before reporting
a study and in some way indicating
patients who had two but not three
rises in PSA, were largely overlooked.
Additionally, as frequently occurs in
piloting a new procedure, more experience
with the proposed definition
and mature follow-up in the PSA era
led to the emergence of deficiencies
and interpretative issues.

Major criticisms of the ASTRO
definition included the lack of consideration
of laboratory variation and
standard error, the extensive period
of time (which was follow-up interval-
dependent) required to document
three PSA rises, the bias associated
with backdating the failure date, the
potential for greater sensitivity and
specificity of other definitions in predicting
clinical failure, and the substantial
difference between this and
surgical definitions of failure.

Several methods have been proposed
to deal with the areas of concern.
To accommodate the variation
in laboratory testing of PSA levels, to
reduce the problems associated with
PSA values near the lower limit of
detection appearing to change by large
percentages when increases occurred,
and to discount minor fluctuations in
PSA production in normal prostate
tissue, a definition that quantified the
minimum amount of each rise in PSA
was proposed-for example, three
PSA rises of at least 0.5 ng/mL
each.[9]

Another method recommended as
a way to compensate for small but
consecutive increases in PSA level,
which also reportedly enhanced the
predictive power of the ASTRO definition,
was to stipulate a required minimum
total PSA level (eg, 1.5 ng/mL)
in addition to the requirement of three
consecutive rises in PSA.[10] Proposals
to decrease the amount of time
necessary to document three PSA rises,
especially with follow-up intervals
of 6 months or more, included
defining failure as fewer rises, such
as two but of a certain value each, or
any elevation above an absolute nadir
value, such as 0.2 ng/mL.[9,11]

Some authors suggested that the
bias introduced by backdating could
be remedied by allowing for adequate
length of follow-up, perhaps an additional
3 years beyond the point chosen
for analysis.[12] The bias stems
from reporting failure at the backdated
date, when it actually takes considerably
longer (ie, time for three PSA
rises) to declare a treatment failure. If
there is not enough follow-up time
available to allow for three rises in
PSA, the failure rate may be significantly
underestimated at the backdated
date. This bias could also be dealt
with by moving the reported failure
date to the date when the failure was
actually determined-in the case of
the ASTRO definition, to the date of
the third PSA rise.[13] This, of course,
would remove the backdating aspect
of the definition.

Finally, the backdating bias could
be handled by a more complicated
option that would involve backdating
the censor date for patients with one
or two PSA rises for whom no additional
information was available.[14]
To address the lack of uniformity between
the definitions of failure used
for differing treatment modalities, a
single, surgically oriented definition
using a solitary cutoff point was proposed.[
11,15] As might be expected,
without appropriate sensitivity and
specificity testing, enthusiasm was
decidedly lacking.

Comparing Failure DefinitionsExternal-Beam Irradiation
To expand the work of Shipley et
al and the first multi-institutional outcome
study,[8] nine institutions recently
contributed 4,839 T1/2 prostate
cancer patients to a single, combined
database.[16] All patients were treated
in the PSA era and, therefore, had
both pretreatment and a series of posttreatment
PSA measurements. These
men were treated with definitive external-
beam irradiation alone no more
recently than 1995, to provide potential
follow-up of at least 5 years. Median
follow-up was calculated at
6.3 years with 2,049 patients still
available for analysis at 5 years, 616
at 8 years, and 179 at 10 years posttreatment.
Not only did this database
provide the most robust outcome report
on external-beam radiation to
date, but it also provided a valuable
resource with which to test and compare
definitions of failure. Although
multiple failure definitions have been
suggested for various reasons, this
large body of data provided a sound
basis for the testing and objective comparison
of definitions.

  • Sensitivity and Specificity-After
    examining the work on this subject,
    Thames et al tested 101 definitions of
    PSA failure with regard to their sensitivity
    and specificity in predicting clinical
    failure using the 4,839 patient
    multi-institution database.[17] A selection
    of these findings is listed in
    Table 1. The investigators defined
    current nadir as the lowest PSA measurement
    prior to the current measurement.
    Thus, current nadir will
    change during follow-up. Absolute
    nadir is the lowest PSA value during
    the entire follow-up period as assessed
    retrospectively. (The absolute nadir
    is the minimum of all the current nadirs
    measured during follow-up.) Failure
    definitions based on two, three, or
    four PSA rises are dated either at the
    time of the last rise ("call date"), or
    are "backdated" to the date halfway
    between the first PSA rise and the
    previous PSA. Clinical failure was
    defined as local disease recurrence,
    distant metastasis, PSA > 25 ng/mL,
    or the administration of hormone therapy.
    Although the last two of these
    factors are subject to debate, this definition
    took into account reasonable
    criterion and opinion to date.

    The last issue-the administration
    of hormone therapy before clinical
    failure-is especially problematic.
    While the reality of the situation found
    in any dataset is that hormone therapy
    is at times administered prior to clinical
    failure, altering the natural progression
    of disease, it is not certain
    that these patients would indeed have
    developed clinical failure if treatment
    had not been administered. One must
    assume, however, that they would be
    the very ones with the most suspicion
    of failure such that this circumstance
    cannot be ignored and the patients
    simply censored. Therefore, each of
    these four criteria was included in the
    definition of clinical failure.

    To calculate the sensitivity and
    specificity of each definition of failure,
    each patient was scored as either
    true-negative (no biochemical failure
    and no clinical failure), true-positive
    (biochemical failure followed by clinical
    failure), false-negative (clinical
    failure without a preceding biochemical failure or biochemical
    failure occurring after clinical failure), or falsepositive
    (biochemical failure not followed by clinical
    failure). Then:

    Sensitivity = true-positive/
    true-positive + false-negative

    Specificity = true-negative/
    true-negative + false-positive

    Thus, the sensitivity of a definition is the proportion
    of patients with a clinical recurrence who have had a
    prior biochemical failure, and the specificity is the proportion
    of patients without clinical failure who have not
    had a biochemical failure. As seen in Table 1, only four
    definitions of biochemical failure were both more sensitive
    and specific than the ASTRO definition. In retrospect,
    the ASTRO definition appears to have been a
    remarkably good choice.

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