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Keywords:

  • prostate carcinoma;
  • prostate specific antigen;
  • detection;
  • radical prostatectomy;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

BACKGROUND

Whether patients who are diagnosed on the basis of a single microscopic focus of prostate carcinoma with a Gleason score ≤ 7 (micro PC) have potentially life-threatening disease if they are not treated is unknown.

METHODS

Pathologic findings and prostate specific antigen (PSA) outcome after radical prostatectomy (RP) for men who were diagnosed with micro PC were determined. Of 917 patients who were managed with RP during 1989–1999 at the Brigham and Women's Hospital, 66 patients (7%) were diagnosed on the basis of micro PC. Pathologic stage, tumor grade, tumor volume, margin status, and PSA outcome were investigated and are reported. Estimates of PSA outcome were calculated using the actuarial method of Kaplan and Meier. Pairwise comparisons were made using the log rank test.

RESULTS

The finding of micro PC at biopsy was associated with macroscopic disease (involving at least half of a single lobe) in 92% of the patients in this series. Although these men had favorable pathologic findings (94% had organ confined disease, 89% had negative tumor margins, and 79% had a prostatectomy Gleason score ≤ 6), approximately 10% of the patients failed biochemically within 5 years after RP.

CONCLUSIONS

The finding of micro PC at biopsy should not be used as a surrogate for clinically insignificant disease. Cancer 2000;89:1810–7. © 2000 American Cancer Society.

A man can be diagnosed with prostate carcinoma on the basis of a single microscopic focus of adenocarcinoma found in a single core (micro PC) after a transrectal ultrasound (TRUS) needle-guided biopsy of the prostate. In this setting, the biopsy is performed because of an abnormal and/or rising prostate specific antigen (PSA) level or a palpable prostate nodule found on digital rectal examination. Patients as well as their physicians who are faced with this pathologic finding often find themselves in a dilemma regarding the management of this problem. Given the sampling error that is intrinsic to the TRUS-guided prostate biopsy,1–4 the question arises of whether the tumor burden is more significant than the biopsy would suggest. Conversely, was the pathologic finding truly incidental, recognizing that autopsy series show microscopic prostate carcinoma in men as young as age 35?5 The answer is currently unknown.

Recent data6 suggest that the percent of positive prostate biopsies adds statistically independent and clinically relevant prognostic information regarding PSA outcome after radical prostatectomy (RP) or external beam radiation therapy (RT) after controlling for the established prognostic significance of the PSA, biopsy Gleason score, and the 1992 American Joint Commission on Cancer (AJCC) clinical T classification. Therefore, one would expect a more favorable PSA outcome for a patient who is diagnosed with micro PC compared with a patient who is diagnosed with multiple positive cores after controlling for the PSA level, the biopsy Gleason score, and the AJCC clinical T stage.

The purpose of this study was to determine the pathologic stage, prostatectomy Gleason score, margin status, and PSA outcome after RP and to compare these outcomes across all patients stratified by the extent of disease in the biopsy at diagnosis. In performing these comparisons, patients were matched using the established prognostic factors of the preoperative PSA level, biopsy Gleason score, and 1992 AJCC clinical T stage to isolate the impact that the extent of disease at biopsy had on the pathologic end points and PSA outcome. Finally, an analysis of the clinical predictors and pathologic predictors of time to PSA failure after RP was performed for patients diagnosed with micro PC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

Patient Selection

Between 1988 and 1998, 917 patients with 1992 AJCC clinical T Stage IC–II prostate carcinoma were treated at the Brigham and Women's Hospital with RP and comprised the study cohort. The clinical pretreatment characteristics of these 917 patients are listed in Table 1 stratified by the extent of disease found at diagnosis, ranging from micro PC to > 50% positive biopsy cores. The median age of the study population was 62 years (range, 46–70 years).

Table 1. Prostate Specific Antigen Level, Biopsy Gleason Score, and 1992 American Joint Committee on Cancer T Stage for the 917 Study Patients Stratified by the Extent of Disease Found at Biopsya
Biopsy (%)No.PSA levelbGLAJCC T classification
≤ 44–1010–20202–678–10ICIIAIIBIIC
  • PSA: prostate specific antigen; bGL: biopsy Gleason score; AJCC: American Joint Committee on Cancer; Micro PC: a single microscopic focus of prostate carcinoma.

  • a

    Values represent the percentage of the total n number.

  • b

    This category excluded patients with a single microscopic focus of prostate carcinoma.

Micro PC6614701609730791740
< 34b4621370134791836127102
34–501561361197583575226193
> 50233740332057331037292311

Preoperative Staging

Staging evaluation included a history and physical examination, including a digital rectal exam (DRE), serum PSA, a computed tomography (CT) scan of the pelvis or an endorectal and pelvic coil magnetic resonance imaging (MRI) scan of the prostate and pelvis, bone scan, and a TRUS needle-guided biopsy of the prostate with Gleason score histologic grading.7 A sextant biopsy was performed using an 18-gauge Tru-Cut needle (Travenol Laboratories, Deerfield, IL) through a transrectal approach. The clinical stage was obtained from the DRE findings using the 1992 AJCC staging system.8 The 1992 system, rather than the 1997 AJCC system, was used because of recent data suggesting that the classification using the 1992 staging system yielded a significantly improved stratification of recurrence free survival after RP compared with the 1997 staging system.9 Radiologic and biopsy information were not used to determine clinical stage. The PSA level was obtained on an ambulatory basis prior to radiologic studies and biopsy. All PSA measurements were made using the Hybritech, Inc. (San Diego, CA), Tosoh, or Abbott Laboratories (Chicago, IL) assay.10 The limit of detection for the PSA assays used was 0.1 ng/mL.

Pathologic Processing

A referee genitourinary pathologist reviewed the diagnostic biopsy and RP specimens for all patients at the Brigham and Women's Hospital (A.A.R.). Prior to prostatectomy, all patients underwent bilateral open or laparoscopic pelvic lymph nodal sampling. If the intraoperative frozen sections of any sampled lymph node were positive for carcinoma, then the RP was aborted. Prostatectomy specimens were weighed, measured, inked over the entire surface, and fixed in 10% buffered formalin. Both the apical and basal margins were amputated to a thickness of 5 mm and sectioned parasagitally in a direction perpendicular to the initial transverse incision at 3-mm intervals. The base of the seminal vesicles and the basal cross section were submitted separately for microscopic analysis. The prostate was sectioned perpendicular to the long axis (apical-basal) of the gland along the posterior/rectal surface at 5-mm intervals, with most specimens requiring four to seven cross sections to be entirely sectioned. For each cross section, a single section each of the right and left posterior region was submitted. Finally, a single section from the midanterior prostate was submitted for microscopic evaluation. Evidence of extraprostatic disease, including seminal vesicle invasion (SVI), extracapsular extension (ECE), and/or positive surgical margins, was recorded. Disease extending into but not through the prostatic capsule was considered negative for ECE.

Follow-Up

The patients were seen 1 month postoperatively, then at 3-month intervals for 2 years, every 6 months for 5 years, and annually thereafter. The median follow-up for the 917 study patients was 55 months. At each follow-up, a serum PSA level was obtained prior to performing the DRE. All baseline PSA values were obtained within 1 month of the date of surgery. No patient was lost to follow-up. No patient received adjuvant or neoadjuvant hormonal or radiation therapy prior to PSA failure.

Statistical Analyses

Established clinical risk groups11–18 based on the preoperative PSA level, biopsy Gleason score, and 1992 AJCC T Stage were used to determine the impact that the extent of disease found at biopsy had on the pathologic stage, prostatectomy Gleason score, margin status, and PSA outcome after RP. The specific risk groups included a low risk group (PSA ≤ 10 ng/mL, biopsy Gleason score ≤ 6, and 1992 AJCC clinical T Stage IC or IIA disease), an intermediate risk group (PSA > 10–20 ng/mL, or biopsy Gleason score = 7, or 1992 AJCC clinical T Stage IIB disease), and a high risk group (PSA > 20 ng/mL, or biopsy Gleason score = 8–10, or 1992 AJCC clinical T Stage IIC disease).

The specific pathologic end points that were evaluated included organ-confined disease, ECE, SVI, margin status, and prostatectomy Gleason score ≤ 6, 3 + 4, and ≥ 4 + 3. The prostatectomy Gleason score was stratified using 3 + 4 versus 4 + 3 because of the importance on outcome prediction of the percent of Grade 4–5 disease in the RP specimen.19 For patients who were diagnosed on the basis of a single microscopic focus of carcinoma, < 34% of the biopsies positive and > 5% of a single core positive, 34–50% positive biopsies, or > 50% positive biopsies, the proportions of patients with these pathologic end points were calculated. The test for linear trend between the extent of disease found at biopsy and a given pathologic end point was performed using a Cochran–Armitage test.20 This evaluation was performed separately for patients in the low, intermediate, and high risk clinical groups to eliminate the confounding impact of the known prognostic factors on the pathologic end points.

A multivariate logistic regression analysis20 was used to evaluate the ability of the preoperative PSA level, the biopsy Gleason score, and the 1992 AJCC T stage to predict for ECE or for positive surgical margins. A multivariate Cox regression analysis20 was used to evaluate the ability of the same clinical factors to predict time to PSA failure. For the purpose of illustration, estimates of PSA outcome were calculated using the actuarial method of Kaplan and Meier21 and graphically displayed. Pairwise comparisons were made using the log rank test. Patients with 1992 AJCC clinical T Stage IA or IB disease were excluded, because the diagnosis of prostate carcinoma in these patients was made on the basis of a transurethral resection sample of the prostate and not through the use of multiple needle biopsy specimens.

PSA failure was defined when two consecutive, detectable PSA values (> 0.1 ng/mL) were obtained after an undetectable value. Time zero was defined as the date of surgery for all patients, and the time of PSA failure was back dated to the time of the first rise above 0.1 ng/mL. If a PSA level never became undetectable postoperatively (n = 2 patients), then PSA failure was defined at a time equal to zero. Patients who were found to have positive pelvic lymph nodes at the time of frozen section or at final pathologic section were started on androgen-suppression therapy and, thus, were excluded from this analysis.

Definitions of Clinically Significant and Insignificant Prostate Carcinoma

Clinically insignificant

One or more microscopic foci with a Gleason score ≤ 6 (no Gleason Grade 4) within the prostate gland at the time of histologic processing of the RP specimen was considered clinically insignificant. There could be no dominant macroscopic focus of any Gleason score within the prostate gland.

Clinically significant

At least a single dominant focus of macroscopic disease comprising at least half of a lobe with or without the presence of microscopic disease in the prostate gland or disease of any volume, including microscopic volume, that contained a Gleason Grade 4 component was considered clinically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

Clinical Characteristics

Table 1 shows that patients who were diagnosed on the basis of micro PC did not have a biopsy Gleason score ≥ 8 or a preoperative PSA in excess of 20 ng/mL. In addition, all of these patients had either clinical T Stage IC (79%), Stage IIA (17%), or Stage IIB (4%) disease. Therefore, there were no patients who were diagnosed with micro PC in the high risk clinical group, whereas 76% (50 of 66 patients) and 24% (16 of 66 patients) were in the low and intermediate clinical risk groups, respectively. Patients with micro PC had a significantly lower rates (P = 0.001) of PSA > 20 ng/mL (0% vs. 4%), biopsy Gleason score ≥ 7 (3% vs. 21%), and clinical T stage ≥ IIB (4% vs. 12%) compared with patients with ≤ 34% positive biopsies and > 5% of a single core positive.

Pathologic Outcome

Table 2 contains a complete listing of the pathologic stage, margin status, and prostatectomy Gleason score stratified by the extent of disease on biopsy and clinical risk group. It is noteworthy that there were no patients with micro PC who had SVI. However, there were significantly (P = 0.001) more patients with pathologic T Stage II disease, prostatectomy Gleason score ≤ 6, and/or margin negative disease who were diagnosed on the basis of micro PC compared with men who were diagnosed with < 34% positive biopsies and > 5% of a single core positive for both the low and intermediate clinical risk groups. Conversely, there were significantly (P = 0.001) fewer patients with pathologic T Stage IIIA disease, prostatectomy Gleason score ≥ 4 + 3, and/or margin positive disease who were diagnosed with micro PC compared with men with < 34% positive biopsies and > 5% of a single core positive.

Table 2. Pathologic Stage, Prostatectomy Gleason Score, and Tumor Margin Status for 917 Study Patients Stratified by the Clinical Risk Group and Extent of Disease at Biopsya
Biopsy (%)No.OCECESVIMargin positivepGL
2–63 + 4≥ 4 + 3
  • OC: organ confined; ECE: extracapsular extension; SVI: seminal vesicle invasion; pGL: prostatectomy Gleason score; Micro PC: a single microscopic focus of prostate carcinoma.

  • a

    Combining the low and intermediate risk groups for the 66 patients who were diagnosed with micro PC resulted in the following values: OC, 94%; ECE, 6%; SVI, 0%; margin positive, 10.5%; and pGL ≤ 6: 79%. Values represent the percentage of the total n number.

Low risk (n = 428)
 Micro PC509640686104
 < 34277871211974206
 34–5054801912265296
 > 504762281021403426
Intermediate risk (n = 352)
 Micro PC16881202556386
 < 341507919125403921
 34–50785833924313930
 > 5010844411544263638
High risk (n = 137)
 Micro PC00000000
 < 34356626829203743
 34–502454331329292546
 > 507835283750222652

The trend analyses examining the proportion of patients with a given pathologic stage, prostatectomy Gleason score, and margin status were statistically significant (P = 0.001) across all three clinical risk groups, as shown in Table 2. Specifically, patients who were diagnosed with micro PC had the most favorable profile, and patients who were diagnosed with > 50% positive biopsies had the least favorable profile, with less organ-confined disease and more extraprostatic disease, higher prostatectomy Gleason scores, and higher rates of positive surgical margins.

Most important, however, is that, of the 66 patients who were diagnosed with micro PC, only 5 (8%) had, at most, microscopic Gleason score ≤ 6 (no Grade 4) disease found at the time of pathologic evaluation of the RP specimen. Of these 5 patients, 3 had a single microscopic focus, 1 patient had 2 microscopic foci, and the other had three distinct foci in separate sextants of the prostate gland. The remaining 61 patients (92%) had prostate carcinoma involving at least half of a single lobe with (n = 58 patients) or without (n = 3 patients) microscopic disease elsewhere in the gland. Other than the 5 patients with microscopic disease, no patient had less than half of a lobe involved. Because the specimens were not wholemounted, the 8% of patients with, at most, microscopic Gleason score ≤ 6 (no Grade 4) disease is an overestimate, so that, in truth, < 8% of these men truly had only microscopic disease in the RP specimen. Moreover, no patient with > 5% of a single core positive at biopsy had only microscopic disease with Gleason score ≤ 6 (no Grade 4) prostate carcinoma found in the RP specimen.

PSA Outcome Based on Clinical and Pathologic Factors

Figures 1 and 2 show PSA outcomes for patients in the low and intermediate clinical risk groups stratified by the extent of disease found at biopsy. It is important to note that, despite the more favorable pathologic profile (Table 2) of men who were diagnosed with micro PC compared with men who were diagnosed with < 34% positive biopsies and > 5% of a single core positive, there were no significant differences in the PSA outcome between these two groups. In particular, the 5-year PSA outcomes were 97% and 97% for low risk patients and 92% and 93% for intermediate risk patients who were diagnosed on the basis of micro PC or on the basis of < 34% positive biopsies and > 5% of a single core positive, respectively.

thumbnail image

Figure 1. Prostate specific antigen failure free survival evidence of disease (bNED) for low risk patients stratified by the extent of disease at biopsy. Pairwise P values: for a single microscopic focus of prostate carcinoma with a Gleason score ≤ 7 at biopsy (micro PC) versus < 34% +bx; excluding micro PC, P = 0.56; or all other pairwise values, P < 0.0001. +bx: positive biopsies.

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thumbnail image

Figure 2. Prostate specific antigen failure free survival (bNED) for intermediate risk patients stratified by the extent of disease at biopsy. Pairwise P values: a single microscopic focus of prostate carcinoma with a Gleason score ≤ 7 at biopsy (micro PC) versus < 34% +bx; excluding micro PC, P = 0.48; for all other pairwise values, P < 0.0001. +bx: positive biopsies.

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Figures 3–5 depict the PSA outcomes stratified by pathologic T stage (Stage II vs. Stage IIIA), prostatectomy Gleason score (≤ 6 vs. ≥ 7), and margin status (positive vs. negative) for the 66 patients who were diagnosed with micro PC, respectively. Statistically significant differences in the estimates of 5-year PSA outcome were noted for patients with organ-confined disease versus extracapsular disease (97% vs. 75%; P = 0.04) or margin negative disease versus margin positive disease (100% vs. 60%; P = 0.002). Therefore, despite the overall more favorable pathologic characteristics in men who were diagnosed with micro PC, some men still failed biochemically despite aggressive local therapy.

thumbnail image

Figure 3. Prostate specific antigen failure free survival (bNED) for the 66 patients with a single microscopic focus of prostate carcinoma with a Gleason score ≤ 7 at biopsy (micro PC) stratified by pathologic T stage (pT) (P = 0.04).

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thumbnail image

Figure 4. Prostate specific antigen failure free survival (bNED) for the 66 patients with a single microscopic focus of prostate carcinoma with a Gleason score ≤ 7 at biopsy (micro PC) stratified by pathologic margin status (P = 0.002). +: positive; −: negative.

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thumbnail image

Figure 5. Prostate specific antigen failure free survival (bNED) for the 66 patients with a single microscopic focus of prostate carcinoma with a Gleason score ≤ 7 at biopsy (micro PC) stratified by prostatectomy Gleason score (pGl) (P = 0.67).

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Clinical Predictors of Adverse Pathologic Factors and PSA Outcome

Preoperative PSA level, biopsy Gleason score, and 1992 AJCC clinical stage were not significant predictors of time to postoperative PSA failure, positive surgical margins, extracapsular extension, or prostatectomy Gleason score ≥ 7 in men diagnosed with micro PC. Therefore, the standard clinical predictors were unable to identify men who were diagnosed based on micro PC who had unfavorable pathologic findings or who were likely to sustain PSA failure after RP. The pathologic findings of ECE (P = 0.03) or positive surgical margins (P = 0.003) were significant predictors of time to PSA failure for men who were diagnosed on the basis of micro PC.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

Whether patients who are diagnosed on the basis of a single microscopic focus of Gleason score ≤ 7 prostate carcinoma have potentially life-threatening disease if they are not treated is unknown. Investigators have attempted to identify clinically insignificant prostate carcinoma on the basis of tumor volume and Gleason grade as measure in the RP specimen.22 Others have made attempts to identify these patients on the basis of the information from the needle biopsy specimen and the serum free and total PSA levels.23 However, no consensus exists about whether an individual prostate tumor is clinically significant because of our current inability, due to inadequate follow-up, to test for a correlation between the biopsy, RP, and serum findings collected during the PSA era and disease specific mortality.

This study was performed to define the pathologic characteristics of the RP specimen and PSA outcome after RP in men who were diagnosed on the basis of micro PC. Of 917 patients who were managed with RP during a 10-year period at a single institution, 66 men (7%) were diagnosed and treated on the basis of micro PC found at biopsy. The main finding of this study was that men who were diagnosed with micro PC had more favorable pathologic characteristics than men who were found to have < 34% positive biopsies and > 5% of a single core positive but had analogous 5-year PSA outcomes. Moreover, whereas the outcomes were excellent, with at least 93% control at 5 years, some men did fail biochemically. Specifically, men who were diagnosed with micro PC were at a higher risk of sustaining PSA failure if they had either prostatectomy T Stage III disease (Fig. 3) or positive surgical margins (Fig. 4). Therefore, men who were diagnosed on the basis of a single microscopic focus of Gleason score ≤ 7 prostate carcinoma have a small but real chance of PSA failure despite aggressive local therapy, suggesting that some of these tumors may be clinically significant and potentially life threatening if observed.

How many of these tumors may have been clinically significant? The pathologic evaluation of the RP specimen would suggest > 90%. Specifically, of the 66 patients who were diagnosed with micro PC, only 5 (8%) had, at most, microscopic Gleason score ≤ 6 (no Grade 4) disease found at the time of pathologic evaluation of the RP specimen. The remaining 61 patients (92%) had macroscopic prostate carcinoma involving at least half of a single lobe. Moreover, no patient with > 5% of a single core positive at biopsy had only microscopic disease with Gleason score ≤ 6 (no Grade 4) prostate carcinoma found in the RP specimen. Because the specimens were not whole mounted, the 8% of patients who, at most, had microscopic Gleason score ≤ 6 disease is an overestimate, so that, in truth, < 8% of these men had only microscopic disease found in the RP specimen. In that minority (8%), the disease is not likely to be clinically significant given that this type of finding is seen commonly at autopsy in men at age 62 years, the median age of the men in this study.

The most likely explanation why, in some cases, a single microscopic focus of prostate carcinoma on the biopsy may underrepresent the true volume of disease is the known sampling error associated with a TRUS-guided prostate biopsy. The basis of the sampling error is that an 18-gauge biopsy core samples a 1-mm diameter of tissue over the prostatic rectal interface with a surface area of ≈30 mm × 30 mm in the case of a normal sized gland (prostate gland volume, 25–30 cm3). Therefore, despite taking six samples, only a 2 mm × 3 mm region of the entire surface area is sampled. In addition, the core length typically is 1.0–1.5 cm, which, at best, samples 50% of the anterior to posterior extent of the tumor-bearing region of the prostate gland (i.e., the peripheral zone). The clinical support for this sampling error has been provided by many investigators who have found that 20–30% of patients who undergo a second biopsy after a negative sextant sampling will be diagnosed with prostate carcinoma.1, 4 More important, however, is the observation that a significant minority (10–35%) of these prostate carcinomas diagnosed at a second or later attempt are high grade tumors (Gleason score ≥ 7)1–4 and, thus, potentially lethal.

Can we identify patients on the basis of the PSA level, biopsy Gleason score, and/or 1992 AJCC T stage who, at most, have microscopic disease in the prostate gland? No: The logistic regression and Cox regression multivariable analyses were unsuccessful in identifying pretreatment clinical factors that predicted for unfavorable pathologic findings or subsequent PSA failure. Therefore, new pretreatment clinical factors are needed to identify men with micro PC at biopsy who truly have only microscopic disease in the prostate gland.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

The finding of a single microscopic focus of Gleason score ≤ 7 prostate carcinoma at biopsy was associated with macroscopic disease (involving at least half of a single lobe) in 92% of the patients in this series. Although these men had favorable pathologic findings—94% with organ confined disease, 89% with margin negative disease, and 79% with a prostatectomy Gleason score ≤ 6–approximately 10% of patients failed biochemically within 5 years after RP. Therefore, the finding of micro PC at biopsy should not be used a surrogate for clinically insignificant disease.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES
  • 1
    Keetch DW, Catalona J, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol 1994; 151: 15715.
  • 2
    Borboroglu PG, Comer SW, Riffenburgh RH, Amling CL. Extensive repeat transrectal ultrasound guided prostate biopsy in patients with previous benign sextant biopsies. J Urol 2000; 163: 15862.
  • 3
    Epstein JI, Walsh PC, Sauvageot J. Use of repeat sextant and transition zone biopsies for assessing extent of prostate cancer. J Urol 1997; 158: 188692.
  • 4
    Stroumbakis N, Cookson MS, Reuter VE. Clinical significance of repeat sextant biopsies in prostate cancer patients. Urology 1997; 49(Suppl): 1138.
  • 5
    Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate cancer. JAMA 1992: 267; 22159.
  • 6
    D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Fondurulia J, Chen M, et al. The clinical utility of the percent of positive prostate biopsies in defining biochemical outcome following radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 2000; 18: 116472.
  • 7
    Gleason DF and the Veterans Administration Cooperative Urological Research Group. Histologic grading and staging of prostatic carcinoma. In: TannenbaumM, editor. Urologic pathology. Philadelphia: Lea & Febiger, 1977: 17187.
  • 8
    Beahrs OH, Henson DE, Hutter RVP. American Joint Committee on Cancer manual for staging cancer, 4th ed. Philadelphia: JP Lippincott, 1997.
  • 9
    Han M, Walsh PC, Partin AW, Rodriguez R. Ability of the 1992 and 1997 American Joint Committee on Cancer staging for prostate cancer to predict progression-free survival after radical prostatectomy for stage T2 disease. J Urol 2000; 164: 8992.
  • 10
    Oesterling JE, Jacobsen SJ, Klee GG, Pettersson K, Pironen T, Abrahamsson P, et al. Free, complexed and total serum prostate specific antigen: the establishment of appropriate reference ranges for their concentrations and ratios. J Urol 1995; 154: 10905.
  • 11
    Kupelian P, Katcher J, Levin HS, Klein EA. Stage T1–2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997; 37: 104352.
  • 12
    D'Amico AV, Whittington R, Kaplan I, Beard C, Jiruotek M, Malkowicz SB, et al. Equivalent biochemical failure free survival after external beam radiation therapy or radical prostatectomy in patients with a pretreatment prostate specific antigen of >4–20 ng/mL. Int J Radiat Oncol Biol Phys 1997; 37: 10538.
  • 13
    Zagars GK, Pollack A, Kavadi VS, von Eschenbach AC. Prostate specific antigen and radiation therapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1995; 32: 293306.
  • 14
    Pisansky TM, Kahn MJ, Rasp GM, Cha SS, Haddock MG, Bostwick DG. A multiple prognostic index predictive of disease outcome after irradiation for clinically localized prostate cancer. Cancer 1997; 79: 33744.
  • 15
    Lee WR, Hanks GE, Schultheiss TE, Corn BW, Hunt MA. Localized prostate cancer treated by external beam radiotherapy alone: serum prostate specific antigen driven outcome analysis. J Clin Oncol 1995; 13: 4649.
  • 16
    Pisansky TM, Cha SS, Earle JD, Durr ED, Kozelsky TF, Wie HS. Prostate specific antigen as a pretherapy prognostic factor in patients treated with radiation therapy for clinically localized prostate cancer. J Clin Oncol 1993; 11: 215866.
  • 17
    Zietman AL, Edelstein RA, Coen JJ, Babayan RK, Krane RJ. Radical prostatectomy for adenocarcinoma of the prostate. The influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology 1994; 43: 82833.
  • 18
    D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Tomaszewski JE, Wein A. PSA failure despite pathologically organ confined and margin negative disease: the basis for an adjuvant therapy trial. J Clin Oncol 1997; 15: 14659.
  • 19
    Stamey TA, McNeal JE, Yemento CM, Sigal BM, Johnstone IM. Biological determinants of cancer progression in men with prostate cancer. JAMA 1999; 281: 1395400.
  • 20
    Simultaneous inferences and other topics in regression analysis-1. In: NeterJ, WassermanW, KutnerM, editors. Applied linear regression models, 1st ed. Homewood, IL: Richard D. Irwin, Inc., 1983: 1503.
  • 21
    Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457500.
  • 22
    Stamey TA, Freiha FS, McNeal JE, Redwine EA, Whittermore AS, Schmid HP. Localized prostate cancer: relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993; 71: 9338.
  • 23
    Epstein JI, Chan DW, Sokoll LJ, Walsh PC, Cox JL, Rittenhouse H, et al. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings. J Urol 1998; 160: 240711.