Prostate cancer progression after therapy of ... - Wiley Online Library

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Prostate Cancer Progression after Therapy of Primary Curative Intent A Review of Data from the Prostate-Specific Antigen Era

Mark Soloway, M.D.1 Mack Roach III, M.D.2 1

Department of Urology, University of Miami School of Medicine, Miami, Florida.

2

Department of Radiation Oncology, Medical Oncology and Urology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, California.

BACKGROUND. Radical prostatectomy and radiotherapy (RT), both radical therapies, are the standard treatments of curative intent for early prostate cancer. However, these therapies are not curative in all patients and, consequently, a substantial proportion of treated patients remain at risk of disease progression and/or cancer-related death. METHODS. This article presents contemporary data on the incidence of prostatespecific antigen (PSA) and clinical disease progression after primary therapy of curative intent in relation to commonly assessed pretreatment or pathologic disease characteristics. RESULTS. The data highlight the substantial risk of progression for certain patient groups, such as those with Gleason score 8 –10, cT3 disease, lymph node metastases, and/or pretreatment PSA levels ⬎ 20 ng/mL. CONCLUSIONS. Improved and/or additional treatment options are needed for these patient groups. Cancer 2005;104:2310 –22. © 2005 American Cancer Society. KEYWORDS: prostate cancer, disease progression, radical prostatectomy, RT, brachytherapy, prostate-specific antigen, disease stage, Gleason score.

I

Address for reprints: Mark Soloway, M.D., Department of Urology, University of Miami School of Medicine, Dominion Towers, 1400 NW 10th Avenue, Miami, FL 33136; Fax: (305) 243 4653; Email: [email protected] Received December 20, 2004; revision received April 13, 2005; accepted June 6, 2005.

n recent years, increasing numbers of patients with prostate cancer have been diagnosed while their disease is still clinically localized.1 Patients with clinically localized disease and good life expectancy are generally offered radical prostatectomy or radiotherapy (RT) (external beam and/or brachytherapy) with the intent to cure, although some elect to undergo watchful waiting. However, not all patients who select local radical therapy will be cured, with the risk of an unfavorable outcome largely dependent on the biologic potential of the tumor, as characterized by the pretreatment prostate-specific antigen (PSA) level, Gleason score (GS), disease stage, and tumor volume.2– 6 In the RT setting, the irradiation dose also influences outcome, with higher doses leading to improved disease control.7–9 For example, in a Phase III randomized trial, increasing the radiation dose from 70 to 78 Gy increased 6-year freedom from disease rates from 64% to 70%. Benefits were particularly apparent in men at intermediate to high risk of progression.8 Prostate cancer progression, either PSA or clinical, can have significant implications for patients. Despite the type of progression, patients are likely to experience considerable emotional distress should their disease progress.10,11 Clinical progression may result in complications such as urinary tract obstruction, skeletal pain, pathologic fractures, and spinal cord compression,12 necessitating further medication and/or surgery, which (depending on treatment choice)

© 2005 American Cancer Society DOI 10.1002/cncr.21441 Published online 13 October 2005 in Wiley InterScience (www.interscience.wiley.com).

Risk of Prostate Cancer Progression/Soloway and Roach

may affect quality of life (QOL). Biochemical recurrence also often leads to the initiation of secondary treatment. Both biochemical and metastatic progression lead to an increase in patient management resource and health service costs.13 In this article, we review contemporary data on the incidence of PSA and clinical disease progression after primary therapy of curative intent for prostate cancer in relation to commonly assessed disease characteristics (primarily pretreatment PSA level, GS, clinical and/or pathologic stages). These data explore the magnitude of risk of progression that faces patients with adverse prognostic factors and examine the need for improved and/or additional treatment options for these patients.

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different outcome measures used), it should be mentioned that actuarial rates can underestimate true risk if a substantial proportion of patients in the study have only a relatively short follow-up time.14,15 Study follow-up times are, therefore, provided later in this article. In addition, because PSA levels decline slowly after RT, it is important that follow-up times are sufficient to ensure that all patients treated by RT have achieved their nadir PSA level. Similarly, it is necessary to ensure that the risk of the “PSA bounce”; phenomenon has passed for those who have undergone brachytherapy (typically at about 3 yrs’ posttreatment).16 The definition of PSA progression, which varies across the studies, is also provided, as the PSA cut-off level applied will clearly influence the proportion of patients with PSA progression.

MATERIALS AND METHODS A Medline Search was undertaken to identify relevant clinical studies published in the English language up to, and including, October 2003 by using the following search terms: radical prostatectomy, external-beam RT, or brachytherapy (i.e., the type of primary therapy) and prostate cancer and progression, recurrence, relapse, outcome and failure. By reviewing Medline abstracts against criteria listed below, we identified papers for inclusion in the current study.

Inclusion Criteria 1. Studies enrolling ⱖ 250 patients with clinically localized or locally advanced disease representative of patients treated in normal clinical practice (i.e., not selected on the basis of particular disease characteristics, e.g., a cohort with GS 7); patients diagnosed and treated after the availability of PSA testing (i.e., within the PSA era), and who did not receive any additional therapy at the time of primary therapy of curative intent. (The minimum study size was set to ensure that results were meaningful and that risk subgroupings within each study population were of sufficient size). 2. Studies citing progression rates as actuarial (Kaplan–Meier) estimates according to one or more prognostic disease factor (e.g., GS, pretreatment PSA level) at 5 years after radical therapy or beyond. Prostate cancer has a long natural history, and we consider outcomes at 5 years and beyond to be most relevant for patients with a good life expectancy. Furthermore, assessing PSA progression at 5 years captures the majority of such events after radical local therapy. Actuarial rates allow data across studies with varying follow-up to be compared at a common time point (e.g., 5 yrs). Although the purpose here is not to critically appraise the studies reviewed (or debate the

Exclusion Criteria 1. As tumor biology and/or outcomes of primary therapy of curative intent may be improved by neoadjuvant or adjuvant hormonal therapy, studies in which some or all patients received neoadjuvant or immediate adjuvant hormonal therapy were excluded. 2. Almost all of the studies included in this review were conducted within the United States. Where more than one paper from a particular institution reporting on the same set of patients was identified, only data from the latest follow-up were included. However, we have included data from a number of centers reported in an interinstitutional report of Vicini and colleagues,17 as well as from individual institutions.18 –20 Both sets of data are included as the patient database and the definitions of progression applied differ between prime publications and the interinstitutional report and they, therefore, provide complementary information.

Radical Prostatectomy PSA progression Although patients may not necessarily be actively treated if they experience PSA progression, it is the most common (and often the only) endpoint of disease progression used in prostate cancer studies, being widely regarded as a useful indicator for subsequent clinical progression. The majority of patients who experience PSA progression after radical prostatectomy for clinically localized disease do so within 5 years;18,21–23 accordingly, the focus here is 5-year data. Actuarial 5-year PSA progression rates cited in the literature vary by ⬎ 2-fold (16 –38%),18,24 –26 but a major factor influencing this variability is the definition of PSA progression.

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CANCER December 1, 2005 / Volume 104 / Number 11

TABLE 1 Actuarial 5-Year Rates of PSA Progression after Radical Prostatectomy for Clinically Localized Disease Study center

No. patients disease characteristics

PSA progression defined as detectable / ⬎ 0.1 ng/mLb Baylor College of n ⫽ 1306 Medicine17c

Brigham and Women’s Hospital and University of Pennsylvania6

n ⫽ 2099 GS ⱖ 7: 27.1% PSA ⬎ 10: 28%

n ⫽ 265 pT3–4 or N⫹: 31% GS ⱖ 7: 86% PSA ⱖ 10: 27% PSA progression defined as ⬎ 0.2 ng/mLb CPDR hospitals22 n ⫽ 503 ECE: 55% GS ⱖ 7: 44.5% PSA ⱖ 10: 35% Johns Hopkins Medical n ⫽ 721 Institute28 pN⫹: 8% Technical University of n ⫽ 291 Munich27 pT3–4: 48% GS ⱖ 8: 15% PSA ⬎ 10: 52% University of Texas MD Anderson Cancer Center29

PSA progression defined as ⬎ 0.4 ng/mLb Baylor College of n ⫽ 986 Medicine18 pT3–4 or N⫹: 40% GS ⱖ 7: 27% PSA ⱖ 10: 25% Medical Hospital n ⫽ 688 Houston25 pT3–4 or N⫹: 43% GS ⱖ 7: 27% PSA ⱖ 10: 30%

Follow-upa mos

By pathologic stage

By PSA level

By GS

By risk group

Medians for different risk groups: 30– 66c 44

Not analyzed

Not analyzed

Not analyzed

Not analyzed

Not analyzed

Not analyzed

Minimum 48

Not analyzed

Not analyzed

Not analyzed

PSA ⱕ 20, GS ⱕ 6: 6–13% PSA ⬎ 20, GS ⱕ 6: 46% PSA ⱕ 20, GS ⱖ 7: 26–27% PSA ⬎ 20, GS ⱖ 7: 60% Lowd ⱕ 50% ⫹ve biopsies: 7% ⬎ 50% ⫹ve biopsies: 48% Mediumd ⱕ34% ⫹ve biopsies: 10–17% ⬎34–50% ⫹ve biopsies: 46% /⬎ 50% ⫹ve biopsies: 81% Highd ⱕ 50% ⫹ve biopsies: 42% /⬎ 50% ⫹ve biopsies: 88% pT2, SM-, GS ⱖ 8: 19% pT2, SM⫹, GS ⱖ 8: 23% pT3a, SM⫹-, GS ⱖ 8: 13%

Mean 47.1

Not analyzed

Not analyzed

Not analyzed

Lowe: 7.5% Mediume: 15.1% Highe: 37.7%

72

Not analyzed

Not analyzed

Not analyzed

Mean 63

pT2a/b: 17–19% pT2c: 38% pT3a: 21% pT3b: 35% pT3c: 50%

Not analyzed

Not analyzed

ECE, SM⫹, GS 7: 50.0% Other: 4–17% Not analyzed

Mean 53.2

OC: 5.1% ECE: 23.7% SV⫹: 63.6% N⫹: 81.5% OC: 7% ECE: 28% SV⫹: 63% N⫹: 85%

⬍ 10: 9–13% 10–⬍ 20: 31% 20–⬍ 50: 50% ⱖ 50: 71% Not analyzed

2–6: 10–16% 7: 40.1% 8–10: 51.3%

Lowd: 7.5% Mediumd: 21.7% Highd: 34.9%

Not analyzed

Not analyzed

48

ECE: extracapsular disease; FCP: focal capsular penetration; GS: Gleason score; N: lymph nodes; OC: organ-confined disease; PSA: prostate-specific antigen (quoted as ng/mL) a Median unless otherwise stated. b Unless otherwise stated, PSA progression also includes clinical progression, initiation of hormone therapy or death from prostate cancer. c Results were reported as part of an interinstitutional and interspecialty comparison of treatment outcome data. For the group as a whole, median follow-up was at least 36 months. d Low risk (cT1c–2a, GS 2–6, PSA level ⱕ 10 ng/mL); medium risk (cT2b, GS 7 or PSA level 10.1–20 ng/mL); high risk (cT2c, GS 8–10 or PSA level ⬎ 20 ng/mL). e Risk groups were based on consideration of race, preradical prostatectomy PSA level, GS and pathologic stage.

PSA progression by individual risk factors Table 1 presents rates of PSA progression at 5 years by pathologic stage and risk group (based on pathologic stage, pretreatment PSA level and GS, and in some cases percentage of positive biopsies).6,17,18,22,25,27–29 Considering pathologic stage, patients with extracapsular disease, and particularly seminal vesicle invasion and/or lymph node involvement, have a considerable

risk of PSA progression within 5 years of surgery; risks range from 17–54% for extracapsular disease (⫾ surgical margins), 48 – 68% for seminal vesicle invasion, and ⬎ 80% for patients with lymph node metastases (Table 1; Fig. 1a).18,25,27 From studies meeting our inclusion criteria, 5-year data by GS or pretreatment PSA level are more limited.18 In the series of Hull and colleagues,18 actu-


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FIGURE 1. Range of the actuarial 5-year rates of PSA progression (defined as PSA level ⬎0.2 or 0.4 ng/mL) after radical prostatectomy for clinically localized disease by risk factor: (a) pathologic disease stage (derived from data in Table 1); (b) baseline PSA level (taken from18); (c) Gleason score (taken from18); and (d) risk group (low, medium, and high, derived from data in Table 1). Abbreviations: OC: organ-confined disease; ECE: extracapsular disease; SV⫹: seminal vesicle invasion; N⫹: positive lymph nodes; PSA: prostate-specific antigen.

arial rates of PSA progression (PSA rise to ⱖ 0.4 ng/ mL) at 5 years for patients with pretreatment PSA levels of 10 –19.9, 20 – 49.9, and ⱖ 50 ng/mL were 31%, 50%, and 71%, respectively, compared with 9 –13% when PSA levels at diagnosis were ⬍ 10 ng/mL (Fig. 1b). Data from the same series stratified by GS are also presented in Figure 1c.

PSA progression by risk grouping Several investigators have evaluated the impact of a composite of disease characteristics on risk of PSA progression (Table 1; Fig. 1d). In the series from the Baylor College of Medicine (n ⫽ 986),18 approximately 35% of patients in the highest risk group (American Joint Commission on Cancer [AJCC] staging system cT2c, GS 8 –10, or pretreatment PSA level ⬎ 20 ng/mL) experienced PSA progression (PSA rise to ⱖ 0.4 ng/ mL) within 5 years. The correlation of percentage of

positive diagnostic biopsies with outcome has also been investigated. In a series of 2099 patients, the rate of PSA progression (defined as two consecutive increases ⬎0.1 ng/mL) at 5 years in the low-risk (cT1–2a, GS ⱕ 6, pretreatment PSA level ⱕ 10 ng/mL) group was 7% when ⱕ 50% of biopsies were positive for cancer but was 48% when there were ⬎ 50% positive biopsies (Table 1).6 Corresponding rates among highrisk patients (cT2c, or GS ⱖ 8, or pretreatment PSA level ⬎ 20 ng/mL) were 42% and 88%, respectively (Table 1). As shown in Table 1, rates of progression are higher in men with pathologically locally advanced disease than in those with organ-confined disease.18,25,27 However, none of these studies go beyond these analyses and break down separate data for locally advanced and localized disease by other disease characteristics.

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TABLE 2 Actuarial Rates of Clinical Progression (Including Prostate Cancer-Related Death) After Radical Prostatectomy for Clinically Localized Disease Study center Baylor College of Medicine18

Baylor College of Medicine17b

Johns Hopkins30

Mayo Clinic31


Follow-up mos

Local or metastatic

Metastatic

Prostate cancer death

n ⫽ 986 pT3–4 or N⫹: 40% GS ⱖ 7: 27% PSA ⱖ 10: 25% n ⫽ 1306

Mean 53.2

Not analyzed

5-yr: 10.1% 10-yr: 15.8%a

5-yr: 0.9% 10-yr: 2.4%a

Medians for different risk groups: 30–66b

Not analyzed

Not analyzed

n ⫽ 1997 pT3–4 or N⫹: 54% GS ⱖ 7: 41% PSA ⱖ 10: 24% n ⫽ 4774 pT3–4 or N⫹: 39.5%

63.6 (6–180)

5-yr: PSA ⱕ 10, GS ⱕ 6: 1.4% PSA 10–20, GS ⱕ 6: 4% PSA ⬎ 20, GS ⱕ 6: 19% PSA ⱕ 10, GS ⱖ 7: 11% PSA 10–20, GS ⱖ 7: 6% PSA ⬎ 20, GS ⱖ 7: 24% Not analyzed

15-yr: 18%

10-yr: 6% 15-yr: 9%

Not analyzed

Not analyzed

5–yr: cT1: 3% cT2: 7%

GS: Gleason score; N: lymph nodes; PSA: prostate-specific antigen (quoted as ng/mL). a Rates are reported by various disease characteristics in Table 3. b These results were reported as part of an interinstitutional and interspecialty comparison of treatment outcome data. For the group as a whole, median follow-up was at least 36 months.

Clinical Progression There are relatively few studies reporting actuarial rates of clinical progression at ⱖ 5 years after radical prostatectomy (Table 2).17,18,23,30,31 The available data suggest that contemporary overall rates of clinical progression after radical prostatectomy are low (at least at leading institutions in the United States, where nearly all these studies were conducted). For example, Hull and colleagues18 report rates of metastatic progression of 10.1% at 5 years and 15.8% at 10 years after radical prostatectomy. Corresponding rates of prostate cancer-related death were 0.9% and 2.4%, respectively.

Clinical progression by risk factors Analysis of clinical progression rates by disease characteristics has rarely been undertaken in a radical prostatectomy series. However, a study from Baylor College of Medicine provides a very detailed analysis by disease characteristics of 10-year rates for metastatic progression and cancer-related death (Table 3).18 Some patient subgroups were at considerable risk of metastatic progression within this timeframe: 42.4% of patients with GS 8 –10 and 70.4% of those with positive lymph nodes developed metastases within 10 years of radical prostatectomy. Patients at greatest risk of cancer-related death were those with GS 8 –10 (18.4%). In a larger group of surgically treated patients from Baylor (n ⫽ 1306) reported as part of the inter-

institutional analysis of Vicini et al.,17 those patients with 2 adverse prognostic factors (pretreatment PSA level ⬎ 20 ng/mL and GS ⱖ 7) had a 24% risk of clinical progression within 5 years;17 the risk of death from any cause in the entire group at 5 years was 15%. Corresponding risks for patients with pretreatment PSA level ⬎ 20 ng/mL and GS ⱕ 6 were 19% and 7%, respectively.

RT (External-Beam RT/Brachytherapy) PSA progression As with radical prostatectomy, the majority of patients who experience PSA progression after RT do so within 5 years.32–34 Rates of PSA progression 5 years after conventional external-beam RT (31–72%) tend to be higher than those after radical prostatectomy, at least partly because of differences in the types of patients selected for the two types of treatment.19,32,34 – 40 In contrast, as the majority of patients treated with brachytherapy have clinically localized disease, estimates of 5-year rates of PSA progression after brachytherapy are more comparable with radical prostatectomy rates, ranging from 10 –29%.19,41,42 In these radical prostatectomy studies, the definition applied to PSA progression contributes to the variation in reported progression rates. The type of radiation (conventional external-beam irradiation, conformal, brachytherapy, etc.), as well as the irradi-

Risk of Prostate Cancer Progression/Soloway and Roach TABLE 3 Actuarial 10-Year Rates of Metastatic Progression and Cancer-Specific Death After Radical Prostatectomy for Clinically Localized Disease18

Disease characteristics GS 2–4 5–6 7 8–10 Preoperative PSA level 0–3.9 4.0–9.9 10–19.9 20–49.9 Pathologic stage Organ-confined disease Extracapsular extension alone SV invasion N⫹ Surgical margins Negative Positive

No. of patients

% Metastasis

% Prostate cancer-related deaths

111 617 229 38

11.2 41.7 42.4 5.3

2.4 0.8 18.4 0

192 461 164 68

5.3 7.7 17.6 26.1

1.2 0 5.0 3.7

593 251 81 71

2.2 15.3 43.1 70.4

0.2 2.9 5.4 10.0

857 126

11.9 34.2

1.8 5.7

GS: Gleason score; N: lymph nodes; PSA: prostate-specific antigen (quoted as ng/mL); SV: seminal vesicles.

ation field and dose, are additional factors influencing outcomes in the RT setting; higher and more targeted doses (including combined external-beam RT and brachytherapy) tend to achieve improved outcomes depending on patient risk profiles.7–9,19,41,43,44 Choice of the type of radiation to be used for a particular patient will not only take into account PSA and other outcomes but also the risk of increased side effects at higher irradiation doses, for example, with combined brachytherapy and external-beam irradiation.

PSA progression by individual risk factors RT studies that have analyzed 5-year PSA progression rates according to disease characteristics reveal that a substantial proportion of patients with clinically locally advanced disease, high GS,7–10 or high pretreatment PSA levels (⬎ 20 ng/mL), have a poor prognosis with radiation alone, with between 47–77% of such patients experiencing PSA progression within 5 years (Table 4; Figs. 2a-d).9,17,19,19,32,36 – 40,45– 48 Zagars and colleagues20,33 updated their results at 6 years in a larger cohort (n ⫽ 938) and found that data were broadly comparable to those at 5 years. The brachytherapy data of Brachman and colleagues are broadly comparable to those for a similar patient group (n ⫽ 1527) treated by external-beam RT over a similar period.19

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PSA progression by risk grouping The external-beam irradiation data of Catton and colleagues37 have also been presented according to three approximately equal-sized risk groupings (low, medium, or high) (Table 4). Of the patients in the highest risk group (cT2c, GS 8 –10, or PSA level ⬎ 20 ng/mL), nearly three-quarters experienced PSA progression (defined using the American Society for Therapeutic Radiology and Oncology [ASTRO] criteria) within 5 years of receiving external-beam RT. Similar findings (also using the ASTRO definition of PSA progression) were reported at the William Beaumont Hospital in the interinstitutional comparison of Vicini and colleagues,17 in which the group at highest risk had a pretreatment PSA level ⬎ 20 ng/mL and a GS ⱖ7. In another institution (Fox Chase) included in the interinstitutional comparison, where patients received conformal RT, 64% of the highest risk patients (pretreatment PSA level ⬎ 20 ng/mL and GS ⱖ7) progressed within 5 years.17

Clinical Progression Relatively few studies evaluating outcomes with RT have reported actuarial rates of clinical progression at 5 years or beyond. Analyses of the 5-year rates by disease characteristics in these studies, which reported various outcome measures including local, metastatic, or any clinical progression, as well as death from prostate cancer or any cause, are detailed in Table 5.17,20,36,43,47

Clinical progression after external-beam irradiation As in the surgical setting, certain patient subgroups are at high risk of clinical disease progression 5 years after RT; for example, Zagars and colleagues36 reported that 46% of patients with a baseline PSA level ⬎ 20 ng/mL experienced local progression within 5 years of external-beam RT, whereas 16% developed metastases. These results were updated to 6-year rates of local and metastatic progression according to seven risk groups based on clinical stage, PSA level, and GS in an expanded patient group (n ⫽ 938).33 Patients with T1–2 disease and an unfavorable pretreatment PSA level (⬎ 20 ng/mL) and/or GS8 –10 had 43% and 12% risk of local and metastatic recurrence, respectively, at 6 years. Corresponding risks in patients with T3– 4 disease and the same unfavorable characteristics were 42% and 24%, respectively. Overall 6-year mortality for those with unfavorable disease characteristics was 25% versus 18% for the remaining patients (P ⫽ 0.046). When the results were considered by disease stage, more than one-third of the patients with locally

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TABLE 4 Actuarial 5-Year Rates of PSA Progression After Radiotherapy (for Clinically Localized Disease [cT1-2, N0/Nx] unless otherwise stated) Study center

No. patients disease characteristics Radiation dose Gya

Follow-up mosb By disease stage By PSA level

By GS

By risk group

PSA progression defined according to ASTRO definition modified in some cases Arizona Oncology Services17c n ⫽ 574 cT1c–3

Not stated (125I or 103Pd)

54–62

Not analyzed

T1: 17% T2a: 28% T2b: 30% T2c: 43% T2 (any): 33% T1: 22% T2: 33%

Arizona Oncology Services19

n ⫽ 695 GS ⱖ 8: 3% PSA ⬎ 10: 31%

160 (125I) or 120 (103Pd)

51.3

Arizona Oncology Services19

14.4–72.0 median 66.6

41.3

Fox Chase Cancer Center9

n ⫽ 1527 GS ⱖ 8: 3% PSA ⬎ 10: 31% n ⫽ 618

3D CRT 70–78

53

Not analyzed

Fox Chase Cancer Center17c

n ⫽ 941

3D CRT 63.5–76

37–65

Not analyzed

Harvard Medical School45

n ⫽ 1310

70–72.4 median 70.2

23–30

Not analyzed

Massachusetts General Hospital40

n ⫽ 314

68.4–72

41

Not analyzed

Memorial Sloan-Kettering Cancer Center46

n ⫽ 1100

Not analyzed

Pooled analysis32

n ⫽ 1765 GS ⱖ 7: 10% PSA ⬎ 10: 50%

64.8–86.4 60 Conformal intensity modulated 63–79 49 median 69.4

Seattle Prostate Institute48

n ⫽ 403 cT1–3

145 (125I) or 115 (103Pd)

58

Not analyzed

Seattle Prostate Institute17c

n ⫽ 729

BT not stated

63–80

Not analyzed

Staten Island University Hospital42

n ⫽ 348

120 (125I)/90 (103Pd) ⫹ 45 Gy (EBRT)

44

Not analyzed

60–78

31

T1–2: 30% T3–4: 56%

52–67

51.6

Not analyzed

University of Texas MD n ⫽ 707 Anderson Cancer Center36 cT1–4 University of Toronto37

n ⫽ 706 GS ⱖ 8: 11% PSA ⬎ 10: 48%

T1: 25% T2: 35%

Not analyzed Not analyzed PSA ⱕ 10, GS ⱕ 6: 15% PSA 10–20, GS ⱕ 6: 42% PSA ⬎ 20, GS ⱕ 6: 41% PSA ⱕ 10, GS ⱖ 7: 37% PSA 10–20, GS ⱖ 7: 67% 0–4: 13% 2–4: 22% Not analyzed ⬎ 4–10: 24 5–6: 26% ⬎ 10–20: 47 7: 51% ⬎ 20: 51 8–10: 72% Not analyzed Not analyzed Not analyzed

Not analyzed Not analyzed Unfavorabled plus: PSA ⬍ 10/⬍ 76 Gy: 30% PSA ⬍ 10/ⱖ 76 Gy: 8% PSA 10–19.9/⬍ 76 Gy: 49% PSA 10–19.9/ⱖ 76 Gy: 18% PSA ⱖ 20/⬍ 76 Gy: 71% PSA ⱖ 20/ⱖ 76 Gy: 74% Not analyzed Not analyzed PSA ⱕ 10, GS ⱕ 6: 17% PSA 10–20, GS ⱕ 6: 27% PSA ⬎ 20, GS ⱕ 6: 68% PSA ⱕ 10, GS ⱖ 7: 25% PSA 10–20, GS ⱖ 7: 38% PSA ⬎ 20, GS ⱖ 7: 64% Not analyzed Not analyzed Low: 16% Medium: 38% High: 57% ⬍ 4: 11% Not analyzed Not analyzed 4–10: 27% ⬎ 10: 55% Not analyzed Not analyzed Low:e 15% Medium:e 42% High:e 62% ⬍ 10: 19% 2–4: 25% Group 1:f 19% Group 2:f 31% 10–⬍ 20: 5–6: 27% Group 3:f 50% 32% 7–10: 47% Group 4:f 71% 20–⬍ 30: 49% ⱖ 30: 69% Not analyzed Not analyzed Low:g 6% Medium:g 16% High:g 46% Not analyzed Not analyzed PSA ⱕ 10, GS ⱕ 6: 12% PSA 10–20, GS ⱕ 6: 17% PSA ⬎ 20, GS ⱕ 6: 25% PSA ⱕ 10, GS ⱖ 7: 20% PSA 10–20, GS ⱖ 7: 25% Not analyzed Not analyzed Low:h 12% Medium:h 25% High:h 49% ⱕ 4: 11% 2–6: 33% Not analyzed 4–20: 44% 7–10: 66% ⬎ 20: 77% Not analyzed Not analyzed Low:e 27% Medium:e 54% High:e 73% (continued)


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TABLE 4 (continued) Study center


Radiation dose Gya

Follow-up mosb

By disease stage

By PSA level

By GS

By risk group

PSA progression defined according to ASTRO definition modified in some cases William Beaumont Hospital17c

n ⫽ 933

PSA progression defined as > 0.5 ng/mLi Cleveland Clinic n ⫽ 628 Foundation39 GS ⱖ 8: 10% PSA ⬎ 10: 42% PSA progression defined as > 1.0 ng/mLi William Beaumont n ⫽ 480 Hospital38 cT1–3 GS ⱖ 8: 13% PSA ⬎ 10: 48% cT3: 14% PSA progression defined as > 1.5 ng/mLi Fox Chase Cancer n ⫽ 500 Center20 cT1–4 GS ⱖ 8: 6% PSA ⬎ 10: 52% Pooled analysis47 n ⫽ 391 cT3–4: 26%

median 66

49–72

Not analyzed

Not analyzed

Not analyzed

PSA ⱕ 10, GS ⱕ 6: 29% PSA 10–20, GS ⱕ 6: 41% PSA ⬎ 20, GS ⱕ 6: 76% PSA ⱕ 10, GS ⱖ 7: 39% PSA 10–20, GS ⱖ 7: 75% PSA ⬎ 20, GS ⱖ 7: 75%

68–78

51

Not analyzed

Not analyzed

Not analyzed

Unfavorablej ⱖ 72 Gy: 32% ⬍ 72 Gy: 66%

58–70.4 median 66.6

48

T1a: 26% T1b: 44% T1c: 20% T2a: 58% T2b–c: 71% T3: 76%

⬍ 4: 16% 4–10: 55% 10–15: 72% 15–20: 76% ⬎ 20: 95%

2–4: 54% 5–6: 62% 7: 82% 8–10: 78%

Not analyzed

69–79

20

Not analyzed

Not analyzed

Not analyzed

median 66

68

T1: 38% T2: 47% T3: 66% T4: 100% T1: 44% T2: 48% T3–4: 64%

⬍ 10: 33% 10–⬍ 20: 59% ⱖ 20: 67% ⬍ 4: 10% 4–10: 46% ⬎10–15: 69– 86%

Not analyzed

Not analyzed

2–4: 37% 5–6: 55% 7–10: 71–76%

Not analyzed

William Beaumont Hospital38

n ⫽ 480 GS ⱖ 8: 13% PSA ⬎ 10: 48% cT3: 14%

58–70.4 median 66.6

48

William Beaumont Hospital38

n ⫽ 480 GS ⱖ 8: 13% PSA ⬎ 10: 48% cT3: 14%

58–70.4 median 66.6

48

T1a: 12% T1b: 42% T1c: 20% T2a: 44% ⱖ T2b: 65–74% T1a: 0% T1b–2a: 20–28% T2b–c: 49% T3: 53%

⬍ 4: 9% 4–10: 26% 10–15: 37% 15–20: 50% ⬎ 20: 85%

2–4: 27% 5–6: 37% 7: 44% 8–10: 70%

ASTRO: American Society of Therapeutic Radiology and Oncology; BT: brachytherapy; CRT: conformal radiotherapy; GS: Gleason score; N: lymph nodes; PSA: prostate-specific antigen (quoted as ng/mL). a Conventional external-beam radiotherapy unless otherwise stated. b Median unless otherwise stated. c These results were reported as part of an interinstitutional and interspecialty comparison of treatment outcome data. For the group as a whole, median follow-up was at least 36 months. d Unfavorable (cT2b, GS 7–10 or perineural invasion). e Low risk (cT1c–2a, GS 2–6, PSA level ⱕ 10 ng/mL); medium risk (cT2b, GS 7 or PSA level 10.1–20 ng/mL); high risk (cT2c, GS 8–10 or PSA level ⬎ 20 ng/mL). f Group 1 (PSA level ⬍ 9.2 ng/mL); Group 2 (PSA level 9.2–19.7 ng/mL); Group 3 (PSA level ⱖ 19.7 ng/mL and GS 2–6); Group 4 (PSA level ⱖ 19.7 ng/mL and GS 7–10). g Low risk (cT1c–2, GS 2–6, PSA level ⱕ10 ng/mL); medium risk (one of: cT3, GS ⱖ 7 or PSA level ⬎ 10 ng/mL); high risk (two of: cT3, GS ⱖ 7 or PSA level ⬎ 10 ng/mL). h Low risk (ⱕ T2b, PSA level ⬍ 20 ng/mL and GS ⱕ 6); medium risk (one of: ⱖ T2c or GS ⱖ 7 or PSA level ⱖ 20 ng/mL); high risk (presenting with 2 risk factors listed under medium risk). i Unless otherwise stated, PSA progression also includes clinical progression, initiation of hormone therapy, or death from prostate cancer. j Unfavorable ( cT2a, GS 7–10 or PSA level ⬎ 10 ng/mL).

advanced disease experienced clinical failure within 5 years.20,36 Roach and colleagues49 recently demonstrated the impact of pretreatment PSA level on overall survival among patients treated with external-beam RT (ⱖ 60 Gy) for clinically localized disease, with 7-year overall

mortality increases from 21% for patients with a pretreatment PSA level ⬍ 10 ng/mL to 36% for those with a PSA level ⱖ 20 ng/mL (P ⫽ 0.001). The investigators also reported overall and disease-specific survival data for these patients according to four risk groupings based on clinical stage and GS (Table 6);50 in the

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FIGURE 2. Range of the actuarial 5-year rates of PSA progression (ASTRO definition as in Table 4) after radiotherapy by risk factor: (a) clinical disease stage; (b) baseline PSA level; (c) Gleason score; and (d) risk group (low, medium, and high, derived from data in Table 4). Abbreviations: OC: organ-confined disease; ECE: extracapsular disease; SV⫹: seminal vesicle invasion; N⫹: positive lymph nodes; PSA: prostate-specific antigen.

highest risk group, 58% of patients died from prostate cancer within 8 years of receiving RT alone.

Clinical progression after brachytherapy Only one study reports clinical progression data after brachytherapy for clinically localized disease.19,41,44 Very low rates of clinical progression were reported (0.7% local failure and 2.6% distant failure at 13 years), and these were not analyzed by risk factor.

DISCUSSION Data presented in this article, summarized below, highlight the substantial risk of progression after therapy of curative intent for certain patient groups, such as those with GS 8 –10, cT3 disease, lymph node metastases, and/or pretreatment PSA levels ⬎ 20 ng/mL (Tables 1-6, Figs. 1–2). Most of the evidence suggests that these patients have metastases at the time of treatment. Patients with lymph node metastases are

obviously at high risk of progression and prostate cancer-related death, but the most important factor appears to be the GS, which clearly correlates to the tumor biology, i.e., the aggressiveness of the tumor. The PSA level at diagnosis appears to have less impact on survival, as it correlates to the volume of prostatic tissue and is, therefore, confounded by the presence of benign hyperplasia, although is certainly an important factor for PSA progression. To our knowledge, there are no randomized studies comparing different radical therapies. It is, therefore, not possible to compare patient outcomes among these therapies at this time, as patient selection and other factors in these different studies may have influenced their reported outcomes. Considering each individual radical therapy, differences in findings of the studies included in this review with respect to PSA progression are apparent (Figs. 1–2); likewise, there are differences in rates of clinical progression


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TABLE 5 Actuarial 5-Year Rates of Clinical Progression After Radiotherapy (for Clinically Localized Disease [cT1–2, N0/Nx] unless otherwise stated) Actuarial 5-year rate of clinical progression

Study center Fox Chase Cancer Center43

Radiation dose, Gy (technique)

No. patients disease Follow-upa characteristics mos

Definition of progression

By disease stage

⬍ 74 (3D CRT)

n ⫽ 653

Not stated

Metastatic

n ⫽ 500 GS ⱖ 8: 6% PSA ⬎ 10: 52% n ⫽ 391 cT3–4: 26%

20

Death from prostate cancer Clinical

T1/2ab: 7% T2c/3: 25% T1/2ab: 2% T2c/3: 13%

5.7 yrs

Death

n ⫽ 707 cT1–4

6.5 yrs

Local

Fox Chase Cancer Center20

69–79

Pooled analysis47

Not stated

University of Texas MD Anderson Cancer Center36

60–78

William Beaumont Hospital17b

Median 66

n ⫽ 933

49–72

T1: 19% T2: 26% T3: 45% T4: 100% T1: 21% T2: 19% T3: 37% T1–2: 27% T3/4: 35%

Metastatic

T1–2: 1% T3/4: 44%

Clinical failure

Not analyzed

By PSA level

By GS

By risk group

Not analyzed

2–6: 10% 7–10: 18% 2–6: 4% 7–10: 11%

Not analyzed

Not analyzed

Not analyzed

Not analyzed

Not analyzed

Not analyzed

Not analyzed

⬍ 4: 6% ⬎ 4–20: 38% ⬎ 20: 46% ⬍ 4: 2% ⬎ 4–20: 5% ⬎ 20: 16% Not analyzed

2–6: 26% 7–10: 44%

Not analyzed

2–6: 5% 7–10: 9%

Not analyzed

Not analyzed

PSA ⱕ 10, GS ⱕ 6: 7% PSA 10–20, GS ⱕ 6: 10% PSA ⬎ 20, GS ⱕ 6: 22% PSA ⱕ 10, GS ⱖ 7: 15% PSA 10–20, GS ⱖ 7: 20% PSA ⬎ 20, GS ⱖ 7: 28%

Not analyzed

Not analyzed

CRT: conformal radiotherapy; GS: Gleason score; N: lymph nodes; PSA: prostate-specific antigen (quoted as ng/mL). a Median unless otherwise stated. b These results were reported as part of an interinstitutional and interspecialty comparison of treatment outcome data. For the group as a whole, median follow-up was at least 36 months.

TABLE 6 Disease-Specific and Overall Mortality at 5 and 8 Years by Risk Grouping in the RTOG Metaanalysis50 % Disease-specific survival

% Overall survival

Risk group

5 yrs

8 yrs

5 yrs

8 yrs

T3Nx, GS 2–6; N⫹, GS 2–6; T1–2, Nx, GS 7 T3Nx, GS 7; N⫹, GS 7; T1–2Nx, GS 8–10 T3Nx, GS 8–10; N⫹, G S8–10

6 17 36

17 30 58

18 32 48

39 55 72

GS: Gleason score; N: lymph nodes; RTOG: Radiation Therapy Oncology Group.

cited. There are several potential explanations for variability from study to study, as well as why some studies may have found that a particular disease characteristic influenced patient outcome, whereas others did not. These include the statistical power of the studies in question, the length of follow-up in the risk group in question, differences in other disease and patient characteristics among the studies, differences in definitions of outcomes concerned (e.g., for PSA progression), as well as chance. Certain subgroups of patients undergoing therapy

of primary curative intent require additional treatment options and may be considered candidates for adjuvant or other therapy. Current data support the use of immediate adjuvant hormonal therapy in patients with locally advanced disease.51–55 The choice of appropriate adjuvant therapy should be based on efficacy, QOL, and tolerability criteria. Many patients treated with curative intent within the PSA era remain at risk of PSA progression, although a much smaller proportion of these patients are at risk of prostate cancer-related death, particu-

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5.

6.

7.

8.

9.

10.

11.

FIGURE 3. Summary of the current study findings.

12. 13.

larly after radical prostatectomy. This may reflect the initiation of effective hormonal therapy and/or the natural history of the disease and competing causes of death. The analyses presented in this review identify the types of patient most at risk of progression, with the majority of data related to PSA progression. A summary appears in Figure 3. Future studies will help refine our ability to define which patients are at risk of death.

14.

15.

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