LHRH AGONISTS: CONTEMPORARY ISSUES
`
`The Evolving Definition of
`Advanced Prostate Cancer
`
`Judd W. Moul, MD, FACS
`
`Division of Urologic Surgery and Duke Prostate Center (DPC), Duke University School of Medicine, Durham, NC
`
`Each year more patients present with prostate cancer at increasingly younger
`ages and with earlier stage disease, resulting in the potential for longer
`survival time, longer-term hormonal therapy, and a heightened risk of devel-
`oping biochemical recurrence after treatment. It seems clear that clinicians
`need to broaden the definition of “advanced” prostate cancer to include
`recent knowledge that will influence the form and timing of treatment as
`well as the monitoring of disease progression. A more contemporary
`definition should include patients with lower-grade disease and with an
`increased risk of progression and/or death from prostate cancer along with
`those with widely disseminated metastatic disease. Treatment alternatives for
`these patients should be evaluated based on a risk stratification equation
`toward a goal of the greatest efficacy and the least patient harm over time
`given that increasing numbers of these patients are entering treatment long
`before they develop widespread osteoblastic metastases.
`[Rev Urol. 2004;6(suppl 8):S10-S17]
`
`© 2004 MedReviews, LLC
`
`Key words: Advanced prostate cancer • Risk stratification • Prostate-specific antigen •
`Early hormonal therapy • Metastasis • Recurrence • Biochemical recurrence • Hormones
`
`Prostate cancer, second only to skin cancer incidence among men in the
`
`United States, will affect an estimated 230,100 men during 2004.1 It is fur-
`ther estimated that 1 in 6 US men will develop prostate cancer during his
`lifetime and that over 70% of these cases will be among men older than age 65.1,2
`Incidence rates reached a peak in the mid 1990s, following widespread use of
`prostate-specific antigen (PSA) screening programs; these rates subsequently
`declined and currently are increasing, albeit at a less rapid pace.1,3 Prostate cancer
`
`S10
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY
`
`MYLAN - EXHIBIT 1030
`
`

`
`Advanced Prostate Cancer: Evolving Definition
`
`death from prostate cancer should be
`included in the definition and that
`any patient with cancer outside the
`prostate capsule with disease stages
`as low as T3/N0/M0 clearly has
`“advanced” disease and should be
`treated accordingly.12,13
`
`Evolving Definition of
`Advanced Prostate Cancer
`Currently, younger and healthier
`men are being diagnosed with
`prostate cancer and treated with a
`variety of modalities (eg, hormonal
`therapy, brachytherapy, and external
`
`of patients and disease states.
`The definition now must be broad-
`ened to reflect younger, healthier
`men with a significant risk of disease
`progression, the potential for longer
`survival, and possibly prolonged
`treatment with hormone therapy.
`With the acceptance and prolifera-
`tion of PSA screening, there has
`clearly been a stage migration in dis-
`ease; many otherwise healthy
`patients now present with local
`lymph node metastasis or stage T3
`disease that progresses to distant
`metastasis.14 Most of these patients
`
`A contemporary definition of advanced prostate cancer should consider
`including stages C and D1.
`
`locally
`for
`radiotherapy)
`beam
`advanced disease, as well as older
`men with rising PSA levels years
`after being treated with a radical
`prostatectomy. Both scenarios define
`current advanced disease and under-
`score the necessity of modifying the
`disease definition and treatment
`plans to reflect this broader spectrum
`
`do not have any significant comor-
`bidities and very few have bone
`metastasis at diagnosis (Figure 1).
`Analysis of the Department of
`Defense Center for Prostate Disease
`Research (CPDR) database demon-
`strates this migration with decreas-
`ing proportions of patients present-
`ing with bone metastasis at the time
`
`1990
`
`1991
`
`1992
`
`1993
`
`1998
`1997
`1996
`1995
`1994
`Diagnosis Year (N=10,686)
`
`1999
`
`2000
`
`2001
`
`2002
`
`12
`
`8
`
`4
`
`0
`
`Rate of Bone Metastasis at Diagnosis (%)
`
`Figure 1. Stage migration: Decreasing rate of patients presenting with clinical metastasis (stage D1/D2) at diag-
`nosis. Data from Department of Defense Center for Prostate Disease Research.
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S11
`
`remains the second leading cause of
`cancer deaths among US men,
`accounting for close to 30,000
`deaths annually, a total that is
`exceeded only by the number of
`deaths from lung cancer.1 Age of
`diagnosis continues to decrease with
`a concomitant increase in the num-
`ber of men diagnosed with early-
`stage or clinically localized dis-
`ease.1,4 In addition, over the past 10
`years the age-adjusted death rate
`has decreased approximately 15%,
`partly due to earlier detection and in
`part to improved treatment of both
`early stage and advanced disease.1,4-6
`As increasing numbers of men are
`living longer with prostate cancer,
`larger proportions will eventually
`present to our collective practices
`with rising PSA levels. Such PSA
`relapses, conservatively estimated to
`affect around 50,000 men each year,
`have become the most common form
`of advanced prostate cancer in the
`current PSA era.1,7-9
`
`Contemporary Prostate Cancer
`Traditionally, “advanced” prostate
`cancer was defined as disease that
`had widely metastasized beyond the
`prostate, the surrounding tissue, and
`the pelvic lymph nodes, and was
`considered incurable by most clini-
`cians and patients.9-11 The average
`patient had symptomatic stage D-2
`disease and the most common symp-
`tom was bone pain that caused
`physicians to seek therapy for this
`form of the disease.11,12 However,
`given the changing face of the dis-
`ease (ie, younger, healthier, better
`informed men with lower-grade dis-
`ease), and the fact that the patho-
`genicity of the cancer and the risk of
`its metastasis were not considered, it
`seems clear that we need to rethink
`the definition of advanced prostate
`cancer.10-12 The current evidence sug-
`gests that patients with significant
`risk of progressive disease and/or
`
`

`
`prostate cancer.13,15-19 The use of such
`a risk stratification system, particu-
`larly for younger patients, permits
`modification of the timing and
`form of the treatment prescribed.
`Currently, treatment for advanced
`prostate cancer is being modified
`to include:
`
`• Neoadjuvant/adjuvant hormonal
`therapy
`• Earlier use of hormonal therapy
`• Risk-stratified early Rx in PSA-
`recurrent disease
`• Traditional versus nontraditional
`hormonal therapy
`• Luteinizing hormone-releasing
`hormone agonists (the mainstay
`of treatment for some 50 years)
`• Antiandrogen monotherapy
`• Intermittent hormonal therapy
`(appealing because it minimizes
`potentially deleterious effects of
`long-term hormonal treatment)
`
`Clearly many contemporary men are
`better informed about health in gen-
`eral and their disease in particular
`and thus, there is much less blanket
`acceptance of traditional hormonal
`therapy with its accompanying side
`effects that could last for many
`years. Many of these men are con-
`cerned about such therapy and are
`looking to us for alternatives, partic-
`ularly given the possibility of long-
`term treatment.
`
`Risk Stratification
`As indicated previously, stratifying
`the risk of disease progression is
`important in determining the timing
`and treatment regimens for patients
`with locally advanced prostate can-
`cer.13,20 In a recently published article,
`D’Amico and colleagues13 presented
`PSA-era validation of a risk stratifi-
`cation nomogram for clinically
`localized prostate cancer. Patients
`categorized as having “high risk”
`localized disease (Table 1) have PSA
`
`Advanced Prostate Cancer: Evolving Definition continued
`
`>70
`
`65~70
`
`60~65
`55~60
`
`<55
`1991
`
`1990
`
`1992
`
`1993
`
`1994
`
`1995
`1996
`1997
`Diagnosis Year
`
`1998
`
`1999
`
`2000
`
`2001
`
`2002
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Constituent Age Ratio (%)
`
`Figure 2 Age migration: Decreasing age of patients diagnosed with prostate cancer. Data from Department of
`Defense Center for Prostate Disease Research.
`
`of diagnosis (Figure 1). In 1990,
`almost 12% of these men were diag-
`nosed with advanced disease (D1/
`D2); 12 years later, less than 5% of
`the newly diagnosed patients had
`metastatic prostate cancer. Thus, a
`contemporary definition of advanced
`prostate cancer should consider
`including stages C and D1.4,12 In addi-
`tion to the stage migration, CPDR
`data also documented a clear age
`migration of the disease (Figure 2).15
`In the early 1990s, prostate cancer
`
`vival as well as long-term hormonal
`therapy.
`
`Evolving Treatment for
`Advanced Prostate Cancer
`Concomitant with the changing def-
`inition of advanced prostate cancer
`is the continuing evolution of treat-
`ment regimens for the disease. Now,
`more than ever, it is important to
`balance the risk of treatment with
`the benefits derived because of the
`likelihood of longer survival and the
`
`We are seeing younger and younger patients being diagnosed with
`localized advanced prostate cancer, all with the potential of long-term
`survival as well as long-term hormonal therapy.
`
`was mainly a diagnosis of men over
`age 70. Over the years, as we have
`moved through the PSA era (1991-
`present), the proportion of men diag-
`nosed under age 55 more than dou-
`bled to almost 15% of all cases.4
`Thus, we are seeing younger and
`younger patients being diagnosed
`with localized prostate cancer, all
`with the potential of long-term sur-
`
`probability of disease progression
`with increasing symptoms, resulting
`in a decreased quality of life over an
`extended period of time. In addition,
`there is growing acknowledgment
`that prognostic markers such as age,
`PSA levels, Gleason scores, and
`tumor stage can help identify those
`patients most likely to experience
`disease progression and death from
`
`S12
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY
`
`

`
`Advanced Prostate Cancer: Evolving Definition
`
`Table 1
`Risk Stratification in Clinically Localized Disease
`
`Low Risk
`
`PSA < 10 ng/mL and Gleason biopsy ≤ 6 and
`1992 AJCC T1c, 2a
`
`Intermediate Risk
`
`PSA 10 – 20 ng/mL or Gleason biopsy 7 or
`1992 AJCC T2b
`
`High Risk
`
`PSA > 20 ng/mL or Gleason biopsy ≥ 8 or
`1992 AJCC ≥ T2c
`
`PSA, prostate-specific antigen; AJCC, American Joint Committee on Cancer; T, tumor.
`Adapted from D’Amico AV et al.13
`
`the men who were treated with
`external beam radiation, mortality
`from prostate cancer was quite high
`among those in the high-risk catego-
`ry (Figure 4). These data demonstrate
`that there is obvious room for
`improvement in multimodality ther-
`apy, underscoring the premise that
`high risk patients, receiving either
`surgery or radiotherapy, could be
`considered to have contemporarily
`advanced disease.
`
`Biochemical Recurrence
`Rising PSA levels after initial/radical
`therapy is frustrating and disap-
`pointing for both urologists and
`patients, particularly the younger
`patients who are generally relatively
`healthy otherwise. Since approxi-
`mately 40% of men who originally
`receive
`localized treatment will
`
`levels above 20 ng/mL or a Gleason
`score ≥ 8, or the 1992 American Joint
`Committee on Cancer tumor stage
`T2c or T3. These patients, particular-
`ly the younger men, could now be
`defined as advanced prostate cancer
`patients because of their increased
`risk for death from the disease, even
`though it is detected at a localized
`stage. The study included data from
`2 multi-institutional databases of
`more than 6000 patients treated with
`either radical prostatectomy or radi-
`ation therapy. The data were com-
`
`bined and stratified according to pre-
`treatment risk (low, intermediate,
`and high) and age at initial therapy.
`As shown in Figure 3, surgery is
`effective during the first 10 years,
`
`Surgery is effective during the first 10 years, but prostate cancer-specific
`mortality remains significant for high risk younger men.
`
`but prostate cancer-specific mortali-
`ty remains significant, particularly
`for the men at high risk. Similarly for
`
`eventually experience PSA-only
`recurrence, PSA relapse has become
`the most common form of advanced
`
`<60
`
`Age (Years) When Treated
`<60 – 64
`<65 – 69
`
`70+
`
`Low Risk
`
`Intermediate Risk
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Percent of Patients Alive
`
`<60
`
`Age (Years) When Treated
`<60 – 64
`<65 – 69
`
`70+
`
`Low Risk
`
`Intermediate Risk
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Percent of Patients Alive
`
`
`
`00
`
`0
`
`5
`
`100
`
`0
`
`0
`5
`100
`5
`100
`Years Following Surgery
`
`0
`
`5
`100
`High Risk
`
`
`
`00
`
`0
`
`5
`
`100
`
`0
`
`5
`100
`5
`0
`100
`Years Following Surgery
`
`0
`
`5
`100
`High Risk
`
`Figure 3. Mortality (prostate cancer- and non-prostate cancer-specific) after radical
`prostatectomy stratified by age at time of initial therapy and pretreatment risk group.
`Blue, prostate cancer-specific mortality; red, non-prostate cancer-specific mortality.
`Reproduced with permission from D’Amico AV et al.13
`
`Figure 4. Mortality (prostate cancer- and non-prostate cancer-specific) after radia-
`tion therapy stratified by age at time of initial therapy and the pretreatment risk
`group. Blue, prostate cancer-specific mortality; red, non-prostate cancer-specific
`mortality. Reproduced with permission from D’Amico AV et al.13
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S13
`
`

`
`Advanced Prostate Cancer: Evolving Definition continued
`
`prostate cancer in the current PSA
`era.4,7,9 Rising PSA levels usually rep-
`resent the earliest sign of advanced
`disease and/or an indication of resid-
`ual tumor with an implicit negative
`impact on the patient’s natural life
`span and his quality of life.21,22 Both
`the urologist and the patient face
`challenging treatment decisions.7
`
`Early Hormone Therapy
`One of the dilemmas faced by clini-
`cians treating a young patient with
`PSA relapse is whether to initiate
`hormone
`therapy early
`in
`the
`course of the secondary treatment.
`Arguments favoring early hormonal
`therapy include the fact that the clin-
`ical situation is fairly easy to define
`and monitor, and the increasing evi-
`dence demonstrates clear survival
`advantages associated with early
`hormone therapy for high risk malig-
`nancies.23,24 In addition, as Dr. Brawer
`points out in this supplement,25
`in
`both the adjuvant and neoadjuvant
`setting, early hormonal therapy may
`increase the cure rates of conven-
`tional therapies. Another powerful
`argument for initiating hormone
`treatment early in biochemical recur-
`rence is that “watchful waiting” is no
`longer an acceptable option for most
`men. Many contemporary men and
`their families are increasingly better
`informed than their counterparts a
`decade or so ago. Thus, many men
`faced with rising PSA levels consider
`metastatic disease to be an inevitable
`consequence of treatment delay and
`understandably are concerned.
`Arguments for early hormonal
`therapy are countered, however, by a
`number of factors, including:
`• The long natural history for most
`men of rising PSA levels before
`clinical metastases and death
`• No randomized controlled clinical
`trials to confirm the survival
`advantage or to document the
`long-term effects of such therapy
`
`S14
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY
`
`100
`
`80
`
`60
`
`40
`
`20
`
`P = .004
`
`Early HT
`
`Late HT
`
`0
`
`0
`
`2
`
`4
`
`6
`8
`10
`Time (Years)
`Time zero is from PSAR (PSA after surgery >0.2 ng/mL)
`
`12
`
`14
`
`16
`
`Clinical Metastasis–free Survival (%)
`
`Figure 5. Early hormonal therapy (HT) administered at PSA 5 ng/mL or less affects clinical metastasis survival
`in patients with pathological Gleason sum greater than 7 or PSA-DT 12 months or less. Time zero is from PSAR
`time. PSA, prostate-specific antigen; PSA-DT, PSA doubling time; PSAR, PSA relapse only. Reproduced with per-
`mission from Moul JW et al.9
`
`• The side effects of hormone
`therapy, particularly for younger
`men
`• Costs of hormone treatment,
`particularly if over a long period
`of time
`The classic study by Pound and
`associates26 reported an average of 8
`years between PSA relapse after a rad-
`ical prostatectomy and clinical mani-
`festation of metastatic disease. Once
`hormone therapy was initiated, the
`patients lived, on average, for anoth-
`er 5 years. In total, there was an
`
`biochemical recurrence when deter-
`mining the appropriate therapy to be
`recommended and pursued.
`
`Early Versus Delayed Therapy
`In our recently published article in
`the Journal of Urology,9 we reported
`results of early versus delayed hor-
`monal treatment for PSA-only recur-
`ring prostate cancer after a radical
`prostatectomy among 1352 patients
`in the CPDR database. Differences in
`outcome and time to the develop-
`ment of clinical metastasis were
`
`In both the adjuvant and neoadjuvant setting, early hormonal therapy
`may increase the cure rates of conventional therapies.
`
`average of 13 years separating bio-
`chemical recurrence and death for
`these surgically treated men: a rela-
`tively long period of time for the
`older patients, but not very reassur-
`ing or acceptable for the younger
`patients. Once again, the key is to
`take a risk-stratified approach to
`
`measured, stratified by risk status
`(high risk PSA recurrence versus
`lower risk PSA relapse) and time of
`hormone therapy initiation (ie, early
`[after PSA only relapse but before
`clinical metastasis] or late [therapy at
`time of clinical metastasis or none
`received by follow-up]). The median
`
`

`
`Advanced Prostate Cancer: Evolving Definition
`
`high risk PSA relapse. The high risk
`PSA-only recurrence was defined as
`those patients who developed a ris-
`ing PSA doubling time that was ≤ 1
`year or had a Gleason score of 8, 9,
`or 10 in their radical prostatectomy
`specimen. Results indicated that the
`high risk individuals with biochemi-
`cal recurrence who received early
`hormonal therapy experienced a
`delayed time to the development of
`bony metastasis. Thus, the natural
`history of bone metastasis in this
`group of men was changed. And
`similarly, high risk men who received
`early hormone therapy with PSA
`levels ≤ 10 ng/mL also experienced
`delayed clinical metastasis (Figure 6).
`However, when data for the entire
`cohort were analyzed, there was no
`such delay in the development of
`clinical metastasis with early hor-
`monal therapy (Figure 7). The reason
`for this apparent discrepancy is that
`risk of progression was not taken
`into account in this analysis. The
`total sample
`included all men
`with a biochemical recurrence (PSA
`> 0.2 ng/mL), regardless of risk strat-
`ification. Nonetheless, this study was
`the first to demonstrate a clinical
`disease-free survival benefit for early
`hormonal therapy and PSA-only
`relapse. It also emphasizes the critical
`importance of risk stratification as we
`demonstrated a benefit for high risk
`individuals, patients with rapid PSA
`doubling time, and patients with
`high-grade disease. For such patients,
`it seems reasonable to use early hor-
`monal therapy.
`It must be cautioned, however,
`that these data are from a database,
`not a randomized clinical trial, and
`thus the outcomes may change with
`additional years of follow-up and as
`more patients are treated with hor-
`mone therapy for PSA relapsing dis-
`ease. In addition, an overall survival
`benefit could not be determined
`given the relatively short follow-up
`
`Early HT
`
`Late HT
`
`P = .004
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Bone Metastasis–free Survival (%)
`
`Time (Years)
`Time zero is from PSAR (PSA after surgery >0.2 ng/mL)
`
`Figure 6. Early hormonal therapy (HT) administered at PSA ≤10 ng/mL affects clinical metastasis-free survival
`in patients with pathological Gleason sum greater than 7 or PSA-DT 12 months or less. Time zero is from PSAR
`time. PSA, prostate-specific antigen; PSA-DT, PSA doubling time; PSAR, PSA relapse only. Reproduced with per-
`mission from Moul JW et al.9
`
`Late HT
`
`Early HT
`
`P = .004
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Bone Metastasis–free Survival (%)
`
`Time (Years)
`Time zero is from PSAR (PSA after surgery >0.2 ng/mL)
`
`Figure 7. Early hormonal therapy (HT) administered at PSA 5 ng/mL or less did not affect clinical metastasis-
`free survival in the overall cohort of 1,352 patients with PSAR at current followup. Time zero is from PSAR time.
`PSA, prostate-specific antigen; PSAR, PSA relapse only. Reproduced with permission from Moul JW et al.9
`
`follow-up period was 5.5 years after
`PSA relapse.
`We found a benefit for early hor-
`monal therapy when it was adminis-
`
`tered at PSA ≤ 5 ng/mL versus those
`who started therapy with a PSA > 5
`ng/mL (Figure 5). However, this ben-
`efit was limited to patients who had
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S15
`
`

`
`Advanced Prostate Cancer: Evolving Definition continued
`
`period (5.5 years), although we were
`able to demonstrate delayed bone
`metastasis among high risk patients.
`Doubling time. With regard to
`PSA recurrence, PSA doubling time
`is critically important.27,28 As previ-
`
`1980s, the face of advanced prostate
`cancer has been changing, and this
`change is profound. Years ago,
`advanced prostate cancer patients
`typically were men with bone metas-
`tasis. Nowadays, we are increasingly
`
`This study was the first to demonstrate a clinical disease-free survival
`benefit for early hormonal therapy in the settng of PSA-only relapse.
`
`based on more contemporary data.
`Observational data, however, seem to
`indicate that high-risk individuals (ie,
`those with high-grade disease and
`with PSA doubling time less than 12
`months) benefit from early hormone
`therapy. The long-term consequences
`of such
`therapy, however, are
`unknown and may be potentially
`deleterious.29,30
`The final question concerning the
`efficacy of early versus late hormone
`therapy for PSA relapse remains
`unanswered because of the need for
`longer follow-up in order to assess
`overall and improved survival for
`
`ously indicated, a doubling time of
`less than 1 year clearly identified
`high risk individuals—individuals
`who had delayed bone metastasis
`when hormone therapy was started
`early. With D’Amico and colleagues28
`we studied PSA doubling time
`< 3 months and found a direct corre-
`lation between this short doubling
`time and death from prostate cancer.
`Thus it seems clear that PSA dou-
`bling time is a very important prog-
`nostic factor in biochemical recur-
`rence and that early hormone therapy
`should be considered in efforts to delay
`metastatic disease when the doubling
`time is less than 3 to 12 months.
`
`Conclusion
`Since the introduction and wide-
`spread use of PSA testing in the late
`
`seeing younger patients, patients
`with biochemical recurrence, and
`patients with
`locally advanced
`prostate cancer. These men all have
`
`Although PSA relapse is becoming so much more common, there are still
`no randomized controlled clinical trials to help us make informed
`clinical decisions based on more contemporary data.
`
`potentially advanced prostate cancer
`with its attendant poor prognosis.
`Currently, high risk localized dis-
`ease and PSA recurrence are the most
`common presentations of advanced
`prostate cancer. Although PSA
`relapse is becoming so much more
`common, there are still no random-
`ized controlled clinical trials to help
`us make informed clinical decisions
`
`men with advanced prostate cancer.
`We await with great anticipation
`results from additional research and
`directed clinical trials.
`
`References
`1.
`Jemal A, Tiwari RC, Murray T, et al. Cancer sta-
`tistics, 2004. CA Cancer J Clin. 2004;54:8-29.
`2. Wilt TJ. Prostate cancer: epidemiology and
`screening. Rev Urol. 2003;5(suppl 6):S3-S9.
`Stephenson RA. Population-based prostate can-
`cer trends in the PSA era: data from the
`
`3.
`
`Main Points
`• There is a profound change in the face of advanced prostate cancer. High-risk localized and prostate-specific antigen (PSA) recur-
`rence are the most common forms of “advanced” prostate cancer. More men diagnosed with advanced prostate cancer enter treat-
`ment long before they develop distant metastases.
`• Because many patients with T3 disease or local lymph node metastases progress to distant metastases, the concept of advanced
`prostate cancer should also include stages C and D1 (T3, T4, and any T N1).
`• Many men treated for clinically localized disease will progress rapidly and, depending on their age, general health, and selected
`prognostic markers, should be included in the advanced-disease category.
`• There are no randomized controlled clinical trials to guide clinicians in treatment decisions for men with PSA recurrent disease.
`Current observational studies, however, indicate the utility of taking a risk stratified approach to PSA relapse patients and the form
`and content of their treatment.
`• Men with high grade disease (Gleason score above 7) and those with short PSA doubling time (under 12 months) have delayed
`clinical metastasis if they receive early hormonal therapy. It is unknown if early hormonal therapy for PSA recurrent disease will
`improve prostate cancer-specific or overall survival.
`
`S16
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY
`
`

`
`5.
`
`6.
`
`Surveillance, Epidemiology, and End Results
`(SEER) Program. Monogr Urol. 1998;19:3-19.
`4. Moul JW, Wu H, Sun L, et al. Epidemiology of
`radical prostatectomy for localized prostate
`cancer in the era of prostate-specific antigen:
`an overview of the Department of Defense
`Center for Prostate Disease Research national
`database. Surgery. 2002;132:213-219.
`Catalona WJ, Smith DS, Radiff TL, et al.
`Detection of organ-confined prostate cancer is
`increased through prostate-specific antigen-
`based screening. JAMA. 1993;270:948-954.
`Newcomer LM, Stanford JL, Blumenstein BA,
`Brawer MK. Temporal trends in rates of prostate
`cancer: declining incidence in advanced stage
`disease, 1974 to 1994. J Urol. 1997;158:1427-
`1430.
`7. Moul JW. Prostate specific antigen only pro-
`gression of prostate cancer. J. Urol. 2000;163:
`1632-1642.
`Djavan B, Moul JW, Zlotta A, et al. PSA pro-
`gression following radical prostatectomy and
`radiation therapy: new standards in the new
`millennium. Eur Urol. 2003;21:483-488.
`9. Moul JW, Wu H, Sun L, et al. Early versus
`delayed hormonal therapy for prostate specific
`antigen only recurrence of prostate cancer after
`radical prostatectomy. J Urol. 2004;171:1141-
`1147.
`10. Crawford ED. Changing concepts in the man-
`agement of advanced prostate cancer. Urology.
`1994;44:67-74.
`11. Moul JW. A better definition of advanced
`prostate cancer for today’s patients. Contemp
`Urol. 1997;9:15-31.
`12. Moul JW. Treatment of metastatic prostate can-
`cer. Braz J Urol. 2000;26:132-145.
`13. D’Amico AV, Moul J, Sun L, et al. Cancer-spe-
`cific mortality after surgery or radiation for
`
`8.
`
`Advanced Prostate Cancer: Evolving Definition
`
`patients with clinically localized prostate can-
`cer managed during the prostate-specific anti-
`gen era. J Clin Oncol. 2003;21:2163-2171.
`14. Epstein BE, Hanks GE. Prostate cancer: evalua-
`tion and radiotherapeutic management. CA
`Cancer J Clin 1992;42:223-240.
`15. Partin AW, Piantadosi S, Sanda MG, et al.
`Selection of men at high risk for disease recur-
`rence for experimental adjuvant therapy fol-
`lowing radical prostatectomy. Urology. 1995;
`45:831-838.
`16. Kattan MW, Eastham JA, Stapleton AM, et al. A
`preoperative nomogram for disease recurrence
`following radical prostatectomy for prostate
`cancer. J Natl Cancer Inst. 1998;90:766-771.
`17. Kattan MW, Wheeler TM, Scardino PT.
`Postoperative nomogram for disease recurrence
`after radical prostatectomy for prostate cancer.
`J Clin Oncol. 1999;17:1499-1507.
`18. D’Amico AV. Combined-modality staging for
`localized adenocarcinoma of the prostate.
`Oncology. 2001;15:1049-1059.
`19. Moul JW, Connelly RR, Lubeck DP, et al.
`Predicting risk of prostate specific antigen
`recurrence after radical prostatectomy with the
`Center for Prostate Disease Research and
`Cancer of the Prostate Strategic Urologic
`Research Endeavor databases. J Urol. 2001;
`166:1322-1327.
`20. D’Amico AV, Cote K, Loffredo M, et al.
`Determinants of prostate-specific survival after
`radiation therapy for patients with clinically
`localized prostate cancer. J Clin Oncol. 2002;
`20:4567-4573.
`21. Yu H, Diamandis EP, Presigiacomo AF, Stamey
`TA. Ultrasensitive assay of prostate-specific
`antigen used for early detection of prostate
`cancer relapse and estimation of tumor-dou-
`bling time after radical prostatectomy. Clin
`
`Chem. 1995;41:430-434.
`22. Pound CR, Partin AW, Epstein JI, Walsh PC.
`Prostate specific antigen after anatomical radi-
`cal retropubic prostatectomy. Patterns of recur-
`rence and cancer control. Urol Clin North Am.
`1997;24:395-406.
`23. Kirk D. Immediate vs. delayed hormone treat-
`ment for prostate cancer: how safe is androgen
`deprivation? Brit J Uro Int. 2000;86(suppl):220.
`Abstract MP6.1.07.
`24. Messing EM, Monola J, Sarodsy M, et al.
`Immediate hormonal therapy compared with
`observation following radical prostatectomy
`and pelvic lymphadenectomy in men with
`node-positive prostate cancer. N Engl J Med.
`1999;341:1781-1788.
`25. Brawer MK. Androgen deprivation therapy. A
`cornerstone in the treatment of advanced
`prostate cancer. Rev Urol. 2004;6(suppl 8):S3-
`S9.
`26. Pound CR, Partin AW, Eisenberger MA, et al.
`Natural history of progression after PSA eleva-
`tion following radical prostatectomy. JAMA.
`1999;281:1591-1597.
`27. D’Amico AV, Chen MH, Roehl KA, Catalona WJ.
`Preoperative PSA velocity and the risk of death
`from prostate cancer after radical prostatecto-
`my. N Engl J Med. 2004;351:125-135.
`28. D’Amico AV, Moul JW, Carroll PR, et al.
`Surrogate end points for prostate cancer-specif-
`ic mortality after radical prostatectomy or radi-
`ation therapy. J Natl Cancer Inst. 2003;95:
`1376-1383.
`29. Daniell HW. Osteoporosis after orchiectomy for
`prostate cancer. J Urol. 1997;157:439-444.
`30. Preston DM, Torrens JI, Duncan WE, McLeod
`DG. Evaluation of bone mineral density in men
`receiving total androgen blockage therapy for
`prostate cancer: preliminary results. J Urol.
`1977;157(suppl):335. Abstract 1310.
`
`VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S17