Report to the Nation on Prostate Cancer 2004
Copyright © 2004 Prostate Cancer Foundation.
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Therapeutic Strategies for Patients With a Rising PSA: A Case-Based Approach

Introduction

Despite significant ongoing debate in the scientific community regarding
the reliability of prostate-specific antigen (PSA) as a marker of
disease progression, it remains the primary means of determining whether
prostate cancer has recurred following local therapy as well as whether
androgen independence has been established following androgen
deprivation therapy (ADT). In the clinic, a rising PSA can cause
significant anxiety not only for the patient but also for the physician,
as there are few clearly defined therapeutic standards for the treatment
of a rising PSA in the absence of any other objective measures of
disease progression. Nevertheless, many physicians and patients are
frequently uncomfortable proceeding with a surveillance strategy to
determine the rate of PSA rise over time without initiating additional
treatment or changing therapeutic strategy.

PSA is a 34 kD glycoprotein found almost exclusively in normal and
neoplastic prostate cells and in seminal fluid. Since its clinical
introduction in the 1980s, the use of PSA as a marker for prostate
tissue cell proliferation, and, consequently, for prostate cancer, has
dramatically changed the epidemiology of prostate cancer, enabling
physicians to diagnose patients earlier in the course of disease and to
detect disease progression before extensive dissemination.[1]
Concurrently, however, widespread clinical use of PSA has created a new
subset of patients: men whose rising PSA levels demonstrate biochemical
failure but who have no evidence of clinical disease.

Because PSA changes can precede clinical disease progression by months
or even years,[2] the question of when and if to initiate therapy in
these patients can be challenging. For patients who underwent radical
prostatectomy (RP), a PSA threshold at which to initiate salvage
radiotherapy and/or ADT has not yet been clearly defined, but remains at
the discretion of the treating physicians and the patient. Similarly,
for those who are currently receiving ADT, there is no PSA threshold at
which one can definitively state that androgen independence has been
achieved and that chemotherapy or alternative strategies should be
initiated.

This chapter of the Report to the Nation on Prostate Cancer will explore
the complex issues associated with the management of patients with a
rising PSA and no evidence of clinical disease progression. Using a
case-based approach, key issues associated with the use and
interpretation of PSA test results in patients with biochemical failure
following RP as well as in patients with a rising PSA following ADT will
be discussed. For each setting, the clinical problem will be defined,
potential therapeutic strategies and options will be reviewed, and
suggested management strategies will be presented.

Managing the Patient With a Rising PSA Following Radical Prostatectomy

Use of PSA in Defining Recurrence and Predicting Outcomes

Each year, thousands of men in the United States develop biochemical
failure following RP.[3,4] A full 27% to 53% of all men who undergo RP
will develop PSA elevations in the 10 years following surgery,[5-7] with
approximately 77% of these recurrences occurring within the first 2
years.[8] By contrast, up to 23% of those who fail may have undetectable
PSA levels for 5 years after surgery, and as many as 4% may be 10 or
more years out from surgery before their PSA begins to rise.[7]

However, despite the widespread use of PSA, establishing a definitive
threshold for biochemical failure has proven difficult. For patients who
undergo RP, the therapeutic goal is removal of prostatic and neoplastic
tissue, resulting in an immediate drop of PSA to undetectable levels (<
0.2 ng/mL) following surgery. In patients who achieve this state,
standard practice is to define post-RP biochemical failure as a PSA
level exceeding 0.2 ng/mL on at least two successive evaluations or
exceeding 0.4 ng/mL on a single evaluation; either of these findings 1-4
years after surgery indicates a likelihood of local recurrence.[9,10] By
contrast, patients who never achieve undetectable levels and/or whose
PSA rises very rapidly following surgery likely have metastatic disease.[9]

For patients who undergo radiotherapy, PSA typically declines steadily
during the course of treatment as the prostate and neoplastic tissues
are ablated. In these patients, postradiotherapy PSA may never reach
completely undetectable levels and rather will reach a very low nadir,
typically below 1.0 ng/mL within 2 years after therapy.[11] The American
Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel
defined postradiotherapy biochemical recurrence as three consecutive
rises in PSA, measured every 3-6 months, with the midpoint between nadir
and first elevation designated as the date of failure.[12]

Biochemical recurrence can generally be predicted by Gleason score,
pathologic stage, PSA, clinical T stage, and pathologic organ
confinement.[13-15] According to one study of post-RP patients, 304 of
1997 patients (15%) developed biochemical failure within 5 years of
surgery, of whom 34% ultimately developed metastatic disease. The median
actuarial time from PSA elevation to metastatic disease was 8 years, and
the median time to death after the development of metastases was
slightly less than 5 years. Gleason score, time to PSA recurrence, and
PSA doubling time significantly influenced outcomes.[6] Using a slightly
broader set of measures, Kattan and colleagues found a probability
biochemical failure of 25% at 5 years, 27% at 7 years, and 29% at 7
years for 996 patients with stage T1a-T3c prostate cancer who underwent
RP by a single surgeon.[16] In this study, serum PSA, degree of capsular
invasion, Gleason score, surgical margin status, seminal vesicle
invasion, and lymph node status all influenced outcomes.

In addition to the controversy surrounding the definition of biochemical
recurrence, questions have been raised as to whether PSA is always a
reliable marker of disease activity, or if it is useful only in select
populations. Partin and colleagues found that PSA rise is most reliable
in patients at higher risk,[17] but D'Amico and colleagues showed that
it might be useful in additional populations as well; specifically, PSA
levels in those treated with salvage ADT were useful reliable
intermediate end points for prostate-specific cancer mortality.[18]

Stratification of risk groups is somewhat controversial as well. Two
groups have developed predictive models that stratify patients into
high-risk and low-risk groups for clinical relapse,[19,20] both of which
were independently validated.[21,22] Combining these two models, general
predictive factors in patients at high risk of recurrence include:
positive seminal vesicles; Gleason score 6 and pretreatment PSA > 18;
Gleason score 7 and PSA > 14; and Gleason score 8-10 and any PSA level.
By contrast, low-risk patients are those with pretreatment PSA levels <
10 ng/mL; stage T1c or T2a disease; and Gleason grade 1-3 disease.[2]

The indicators of PSA dynamics, such as PSA velocity and PSA doubling
time, have recently been found to be significant predictors of outcomes
after surgery. As an update to their earlier work,[7] Partin and
colleagues found that a PSA doubling time of </= 10 months was a
predictor of distant metastases and prostate-cancer specific mortality
in all patients following RP, regardless of tumor grade, and that PSA
doubling time is a more important measure in predicting outcomes than
are time to PSA recurrence or Gleason score.[23,24] Of note, D'Amico and
colleagues found that a PSA doubling time < 3 months and the specific
value of the PSA doubling time in patients with a doubling time of >/= 3
months were reliable predictors of prostate cancer-specific mortality
after RP[11] and that preoperative PSA velocity greater than 2.0 ng/mL
during the year before prostate cancer diagnosis correlates with a
relatively high risk of disease-specific mortality despite RP.[25] These
data suggest that patients with a very short (ie, < 3 months) PSA
doubling time who have a so-called "lethal phenotype" are the highest
risk for disease progression and death, and should be considered for
entry onto a clinical trial or given the opportunity to start ADT.

Imaging studies have a low yield in asymptomatic patients with
biochemical failure: the probability of a positive bone scan, for
example, is less than 5% until the PSA reaches levels of greater than 40
ng/mL.[26,27] Thus, in the absence of symptoms, the predictive factors
described above remain the primary strategies for determining whether
there has been a cancer recurrence.

Based upon currently available data, monitoring of serum PSA levels and
digital rectal examinations should be performed every 3 months in the
first year following surgery, every 6 months in the second year, and
annually thereafter. If the accepted thresholds are reached (ie, one
instance of PSA > 0.4 ng/mL, two consecutive increases > 0.2 ng/mL, or a
PSA doubling time < 10 months), and if lab error can be ruled out,
follow-up therapy should be considered.
Treatment Strategies

Surveillance alone remains a viable option for post-RP patients who want
supportive care only, for men with stable PSA levels that remain lower
than 0.4 ng/mL, or for patients with very slowly rising PSA levels (ie,
doubling time > 10 months). However, many patients and their physicians
may find a surveillance strategy to be untenable in the face of the
knowledge of a cancer recurrence, regardless of whether it is likely to
metastasize.

Salvage radiotherapy is an effective method for achieving PSA response
and improving progression-free survival in post-RP patients with a
rising PSA,[28,29] but is most useful in select patient populations. Two
large retrospective studies found that patients with Gleason score 8-10,
preradiotherapy PSA < 2.0 ng/mL, negative surgical margins, PSA doubling
time </= 10 months, and seminal vesicle invasion independently predicted
disease progression.[30,31] Nevertheless, early salvage radiotherapy
(ie, upon detection of PSA </= 2.0 ng/mL) enabled patients with Gleason
8-10 and positive surgical margins to achieve a 4-year progression-free
probability of 81% when the PSA doubling time was > 10 months and a 37%
probability when the PSA doubling time was </= 10 months.[31] Thus, even
for patients with other adverse features, patients with PSA doubling
time > 10 months can show durable responses to early salvage
radiotherapy, whereas those with PSA doubling time </= 10 months are
more likely to show poorer response and should therefore be considered
for more aggressive therapy.

The use of ADT in this patient population is somewhat questionable
because the optimal timing of therapy initiation remains unclear. Data
from Messing and colleagues indicate that earlier initiation of ADT
following RP may be beneficial,[32] but the study was conducted in
patients with node-positive disease, a population that is less likely to
exist in the era of widespread PSA testing. In addition, 80% of patients
had undetectable PSA levels at ADT initiation, so extrapolating the data
to a patient with a rising PSA is difficult.[33] Further complicating
this issue, patients with biochemical failure are usually asymptomatic,
but they might be at greater risk for the progressive complications of
ADT, such as decreasing bone mineral density and fracture.[34]

Given the lack of definitive data on the merits of ADT in patients with
evidence of biochemical-only recurrence, a complete assessment of the
risk profile of each individual patient by all members of the care team
is warranted before any treatment option is selected. Patients should be
assessed for symptoms, and long-term disease course, risk, and patterns
of recurrence should be projected as best possible.

Once these have been ascertained, several treatment options can be
considered. Patients with a less favorable risk profile -- PSA doubling
time </= 10 months, negative surgical margins, Gleason score 8-10 -- are
at greatest risk for progressive disease and are unlikely to achieve
durable benefit from salvage radiotherapy.[31] As the use of systemic
ADT in this population remains unknown, these patients should be
considered for clinical trials evaluating more aggressive therapies. By
contrast, patients with a more favorable risk profile -- stage T1c-T2a,
Gleason 2-7, PSA doubling time > 10 months -- can achieve durable
benefit from salvage radiotherapy. In addition, although it remains
unproven whether initiation of ADT in these patients might help delay
the onset of distant metastases, strategies that maximize benefit but
minimize toxicity of ADT can be considered, such as intermittent ADT[35]
or antiandrogen monotherapy.[36] Upon further progression beyond these
options, more aggressive systemic therapies with ADT and/or chemotherapy
should be considered, and enrollment onto a clinical trial should be
encouraged.

The algorithm in Figure 1 suggests an approach that can be taken when
deciding how to manage patients with rising PSA after RP.

Of note, several clinical trials are currently underway in this patient
population. Some are examining chemotherapy with and without ADT, and
others are utilizing newer agents directed at molecular mechanisms of
oncogenesis. Motivated and appropriate patients should be encouraged to
participate in these trials.

Figure 1 [FIGURE UNAVAILABLE]

    Figure 1. Suggested algorithm for approaching the patient with a
rising PSA after RP.

Approach to the Patient With a Rising PSA Following Radical Prostatectomy

Case 1

A 62-year-old man undergoes RP for T1c, Gleason 3+4 prostate cancer.
There is no evidence of prostatic capsular invasion and surgical margins
are free of tumor. Following surgery, serum PSA falls to undetectable
levels. Twenty months later, the PSA rises to 0.4 ng/mL, and then to 0.6
ng/mL 6 months after that. Another 6 months later, the PSA level is 0.8
ng/mL. Computed tomography (CT) and bone scans are without evidence of
metastases. Rectal examinations are unremarkable.

This patient has several favorable factors: a relatively low clinical
stage, a well-differentiated tumor, negative surgical margins with no
evidence of capsular invasion, a PSA that fell to undetectable levels
following surgery, and a PSA doubling time of 12 months. A less
favorable factor in this patient's case is the relatively short time of
< 2 years to biochemical recurrence. Overall, he appears to be at low
risk for disease progression and distant metastases. Salvage
radiotherapy should therefore be initiated before systemic therapy is
considered.

Case 2

A 64-year-old man undergoes RP for T1c, Gleason 4+4 prostate cancer.
There is no evidence of prostatic capsular invasion and surgical margins
are free of tumor. Following surgery, serum PSA falls to undetectable
levels. Fourteen months later, the PSA rises to 0.5 ng/mL. Metastatic
work-up is negative, and the patient undergoes salvage radiotherapy. His
PSA falls to undetectable levels after treatment. Eight months later,
his PSA rises to 0.3 ng/mL, and then to 0.7 ng/mL 6 months after that.
Another 6 months later, the PSA level is 2.0 ng/mL. CT and bone scans
are without evidence of metastases.

This patient initially had several favorable factors: a relatively low
clinical stage, negative surgical margins with no evidence of capsular
invasion, and a PSA that fell to undetectable levels following surgery.
His less favorable tumor grade, the relatively short time to biochemical
recurrence, and a single PSA measurement above the cutpoint of 0.4 ng/mL
made him a candidate for salvage radiotherapy. Unfortunately, the
treatment was not effective.

Using Stephenson's model, the combination of a PSA doubling time < 10
months, Gleason score 8, and negative surgical margins puts him in the
highest risk category for disease progression following salvage
radiotherapy, with a 4-year progression-free probability of only
37%.[31] However, the lack of clinical evidence of disease on both CT
and bone scans makes management of this patient challenging. Initiation
of ADT would likely delay onset of metastases, but if the patient is
motivated, enrollment on a clinical trial evaluating more aggressive or
novel treatment strategies should be considered.

Managing the Patient With a Rising PSA Following ADT

Although prostate cancer is initially responsive to hormone
manipulation, the responsiveness of tumor cells to ADT in patients with
metastatic disease begins to wane rather quickly, with a median time to
disease progression of less than 2 years,[37,38] and a median survival
of 12-16 months from the time that androgen independence is established.[38]

Unfortunately, the natural history of these patients is poorly
understood. Numerous factors such as the lactate dehydrogenase, alkaline
phosphatase, hemoglobin, and Eastern Cooperative Oncology Group or
Karnofsky performance status have been used to predict prognosis,[39,40]
while others have suggested that a detailed PSA history alone may be
enough to stratify risk and predict prognosis.[41] Because the velocity
of PSA changes may be different before and after ADT, reflecting changes
in tumor kinetics after treatment, intermediate end points based on the
ratio of the post- to pre-ADT slope are being considered in clinical
trials as an end point for comparing systemic therapy in patients with
the "lethal phenotype" (ie, PSA doubling time < 3 months).

Nevertheless, until PSA doubling time and/or calculated pre- and
post-ADT PSA velocities as predictors of survival in patients are widely
accepted, a 50% decline in PSA is typically considered the benchmark for
response to ADT, while PSA increases of a minimum of 5 ng/mL with two
consecutive increases of 25% after ADT indicate clinical disease
progression.[2,38,42]

Treatment Strategies

Castrate patients with a rising PSA present unique and complex
challenges for the treating physician. Frequently, ADT continues to be
employed while additional therapeutic strategies are explored. At this
stage of disease, the establishment of a true multidisciplinary care
team is essential, including the coordinated involvement of a urologist,
an oncologist, and a radiologic imaging specialist.

Before any additional therapeutic regimens can be considered,
maintenance of castrate levels of testosterone (< 50 ng/mL) should be
confirmed, as the presence of a rising PSA may in fact indicate that ADT
is not sufficiently suppressing testosterone production and/or action
and that additional androgen suppression therapy is warranted.[2]

Even if androgen independence is established despite castrate levels of
testosterone and the rising PSA levels indicate biochemical failure, the
tumor might respond to secondary hormonal manipulation.

In patients who had been treated with an antiandrogen, withdrawal of the
agent while maintaining castrate levels of testosterone has been
associated with PSA responses, as well as with symptomatic and objective
responses, in about 25% of patients. The duration of response is
typically 3-4 months, but some cases have lasted for several years.[2]
This response has been noted with flutamide, bicalutamide, and
nilutamide[43] and may result from mutations of androgen receptors.[44]
Thus, a trial of antiandrogen withdrawal may be reasonable for certain
patients, particularly before initiating more toxic therapy. Although it
is unclear whether the same antiandrogen would still be effective if
reintroduced at a later point, cross-reactivity generally does not exist
among the antiandrogens: both bicalutamide and nilutamide have shown
some activity as secondary antiandrogens following resistance to
flutamide.[45-47]

Adrenal androgen inhibitors, most commonly ketoconazole, also have a
role as second-line hormonal agents. Approximately 10% of circulating
androgens derive from the adrenal glands, and a higher proportion of
adrenal androgens may be in prostate cancer cells.[2] Ketoconazole has
been shown to decrease serum PSA by 50% with high doses[48] and low
doses,[49] but the duration of response is short, with one study finding
a median PSA response duration of only 3.5 months.

Similarly, glucocorticoids have also shown some effect in patients with
AIPC. In several trials comparing hydrocortisone alone with
hydrocortisone and a study treatment, disease response was seen in the
hydrocortisone-alone arms.[50-53] However, as with ketoconazole, the
duration of response tends to be rather short and further progression of
disease is rapidly seen.

A more promising approach has been seen with chemotherapeutic agents.
Chemotherapy with cytotoxic agents historically has had a minor role in
the treatment of prostate cancer. In 1985, Eisenberger and colleagues
reviewed 17 randomized clinical trials and found complete and partial
response rates in only 4.5% of patients.[54] In 1993, in another large
review, the overall response rate with chemotherapy was 8.7%.[55]
Switching tactics, researchers began to measure quality-of-life
parameters in this population, and the use of mitoxantrone showed
significant palliative benefits,[51] which led to its approval by FDA
for use in patients with AIPC. Unfortunately, aside from its palliative
benefits, it has shown only modest activity in measurable disease and
lacks the ability to confer a significant survival advantage in patients
with AIPC.[52]

By contrast, two phase 3 trials with docetaxel, one pairing with
prednisone and the other pairing with estramustine, showed significant
improvement in both survival and palliation in patients with AIPC when
compared with the standard mitoxantrone/prednisone regimen.[56,57] These
trials led to the recent approval by FDA of docetaxel in combination
with prednisone every 3 weeks in patients with AIPC.

Newer agents targeting apoptosis, growth factors, angiogenesis,
tumor-associated antigens, and protein degradation pathways are also
being studied, many in combination with various chemotherapeutic
regimens. The ability of docetaxel and, potentially, other agents to
slow disease progression and improve survival in patients with AIPC
indicates that the natural history of prostate cancer can be altered
even in late stages of disease.

Unfortunately, these data also indicate that there is no clear standard
of care for the large number of men who will develop a rising PSA while
on ADT. Those patients who are symptomatic should undergo radiographic
studies to assess for metastatic disease, and a full evaluation of known
prognostic factors can give insight into a patient's future clinical
course. Most importantly, patients should be evaluated for inclusion
into a clinical trial, as there remains much to learn about the optimal
treatment of patients with AIPC. The algorithm in Figure 2 suggests an
approach that can be taken when deciding how to manage patients with
rising PSA despite ADT.

Figure 2 [FIGURE UNAVAILABLE]

    Figure 2. Suggested algorithm for approaching the patient with a
rising PSA despite ADT.

Approach to the Patient With a Rising PSA Following ADT

Case 3

A 66-year-old man with T3bNxMx Gleason 5+4 prostate cancer was treated
with a combination of ADT and external beam radiotherapy. His PSA
initially declined to < 0.1 ng/mL but is now beginning to rise with a
doubling time of < 3 months. Other than the side effects of ADT, he is
asymptomatic. His serum testosterone is below castrate levels. Bone and
CT scans are negative, and his physical exam shows no evidence of disease.

The patient described above has several unfavorable factors: T3 disease,
a biochemical relapse in less than 1 year, and a PSA doubling time < 3
months. Although his work-up is unremarkable for metastatic disease or
symptoms, he has several poor prognostic factors that increase his
chance of aggressive recurrent disease. This patient is therefore likely
to become symptomatic and develop radiographic evidence of metastases.

While androgen withdrawal might be considered, the relatively aggressive
pace of his recurrence probably would leave little time to fully assess
response. The recommendation would therefore be to consider secondary
hormonal manipulation, with the caveat that if there is no immediate
response or if metastatic disease becomes evident on surveillance
studies, he should proceed immediately to chemotherapy and/or be
considered for inclusion in a clinical trial.

Conclusions

While the clinical use of PSA has contributed greatly to improvements in
the diagnosis of prostate cancer and in the detection of disease
progression, it has also created a new group of patients with
biochemical-only evidence of disease and no clear avenue for management.
In patients who are initially treated with RP, a rising PSA may forebode
local recurrence or aggressive metastatic disease, but the disease may
not become clinically evident for months or even years, placing patients
in a quandary about when and whether to initiate salvage radiotherapy or
systemic ADT.

Unfortunately, for those who do initiate ADT, resistance to therapy
occurs as disease continues to progress. Rising PSA levels are assumed
to be predictive of recurrent disease, but it remains unclear whether
they are always reliable in all patients. These and other key management
issues are presented in Table 1. A short list of crucial research
efforts yet to be completed in this area is presented in Table 2.

Given the complexity of these issues, it is essential that a
multidisciplinary approach be used in the management of patients with a
rising PSA. By involving urologists, medical oncologists, and radiation
oncologists in care decisions, the risks and benefits of options rooted
in different specialties can be judiciously assessed in the context of
the individual patient's needs. In this way, physicians and patients can
be assured of taking a rational approach in managing the patient with a
rising PSA.

Table 1. Therapeutic Strategies for Patients With a Rising PSA: Summary
1    Because PSA changes can precede clinical disease progression by months
or even years, the question of when and if to initiate therapy in
patients with a rising PSA and no evidence of clinical disease can be
challenging.
2    Salvage radiotherapy is most likely to delay disease progression in
patients with a rising PSA following RP and "unfavorable" risk factors:
PSA doubling time >/= 10 months, Gleason 2-7, and positive surgical
margins; ADT can be considered in other patients.
3    ADT should be initiated in patients with a rising PSA following RP
despite salvage RT; enrollment on a clinical trial evaluating more
aggressive or novel therapies would be appropriate.
4    Secondary hormonal manipulation in patients with a rising PSA despite
ADT can be effective; chemotherapy is warranted in patients who continue
to progress and in patients with unfavorable risk factors.

Table 2. Future Research and Practice Opportunities: Calls to Action
1    Determine the optimal time to initiate ADT in the hormone-naive
patient with a rising PSA.
2    Define meaningful end points other than overall survival for clinical
trials at all stages of disease.
3    Publish a white paper defining the optimal way to calculate PSA
doubling time as a standard for future trials and research studies.

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Authors

    Anthony V. D'Amico, MD, PhD
    Chief of Genitourinary Radiation Oncology, Brigham and Women's
Hospital and Dana-Farber Cancer Institute; Professor of Radiation
Oncology, Harvard Medical School, Boston, Massachusetts

    Disclosure: Anthony V. D'Amico, MD, PhD, has no significant
financial interests or relationships to disclose. Dr. D?Amico may
discuss investigational or unlabeled uses of commercial products in this
activity.

    Mario Eisenberger, MD
    R. Dale Hughes Professor of Oncology and Urology, Johns Hopkins
Medical Institutions, Baltimore, Maryland

    Disclosure: Mario Eisenberger, MD, has disclosed that he has
received grants for clinical research and educational activities from,
and has served as a consultant and is on the speaker's bureau for,
Aventis. Dr. Eisenberger may discuss investigational or unlabeled uses
of commercial products in this activity.

    Alan Partin, MD, PhD
    Professor of Urology, Oncology, and Pathology, Johns Hopkins
Medical Institutions, Baltimore, Maryland

    Disclosure: Alan Partin, MD, PhD, has no significant financial
interests or relationships to disclose. Dr. Partin may discuss
investigational or unlabeled uses of commercial products in this activity.

    Kenneth J. Pienta, MD
    Professor, Internal Medicine and Urology; Director, Michigan
Urology Center, University of Michigan, Ann Arbor, Michigan

    Disclosure: Kenneth J. Pienta, MD, has no significant financial
interests or relationships to disclose. Dr. Pienta may discuss
investigational or unlabeled uses of commercial products in this activity.