The treatment of prostate cancer has made tremendous advances over the past decade. Once a certain death sentance, improved detection and treatment modalities have given afflicted men a fighting chance to lead a relatively normal life after the diagnosis.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Stage-see American Joint Committee on Cancer TNM staging below GENERAL
Early detection of prostate cancer.
Urol Clin North Am 1989;16:635–55.
Only 30% of men diagnosed with PCa will ultimately die of their disease and at autopsy up to 71% of men between the ages of 80 and 89 harbor latent PCa
Clinical significance of minimal prostatic adenocarcinoma found on needle biopsy
Am J Clin Pathol 2000;114:896-909
Amount of tumor in the needle biopsy does not influence grading error-this error is more likely to occur as a result of sampling error and prostate cancer heterogeneity
Most common problem in needle biopsy is undergrading. NOTE, a small amount of tumor in needle biopsy is not equivalent to low-grade tumor. However, minimal high grade (Gleason score of 7 or higher) carcinoma in the needle biopsy was predictive of high grade carcinoma in the whole gland in 79% of cases
A small amount of carcinoma in the needle biopsy does not predict a small amount of cancer in the entire gland, even if 6 core biopsy specimens are obtained. These 6 biopsies only sample 0.03% of all prostate gland tissue
Perineural Invasion and MIB-1 Positivity in Addition to Gleason Score Are Significant Preoperative Predictors of Progression After Radical Retropubic Prostatectomy for Prostate Cancer.
Sebo TJ, Cheville JC, Riehle DL, Lohse CM, Pankratz VS, Myers RP, Blute ML, Zincke H.
Departments of Laboratory Medicine and Pathology (T.J.S., J.C.C., D.L.R.), Health Sciences Research (C.M.L., V.S.P.), and Urology (R.P.M., M.L.B., H.Z.), Mayo Clinic, Rochester, Minnesota, U.S.A.
Am J Surg Pathol 2002 Apr;26(4):431-9 Abstract quote
We assessed the use of clinical stage, serum prostate specific antigen, DNA ploidy, proliferation, and traditional histologic findings from the biopsy to predict prostate cancer progression after radical retropubic prostatectomy. Between 1995 and 1998, 454 consecutive patients with cancer on biopsy were treated by radical retropubic prostatectomy.
Preoperative serum prostate specific antigen, clinical stage, Gleason score, percentage of cores and surface area positive for cancer, perineural invasion, and DNA ploidy and MIB-1 immunostain quantitation by image analysis were evaluated in a multivariate Cox proportional hazards regression model to predict cancer progression. Cancer progression was defined as a postoperative serum prostate specific antigen level of >/=0.4 ng/mL, local recurrence, or systemic progression. Mean follow-up was 3.4 years (range 17 days to 5.8 years). Cancer progression was observed in 73 patients with a mean time to progression of 2.1 years (range 33 days to 5.1 years). Gleason score (p <0.001), MIB-1 cancer proliferation (p = 0.008), and perineural invasion (p = 0.008) were significantly associated with progression. Patients with cancer Gleason scores of 7 and >7 had a 2.5-fold and nearly 4-fold increased risk, respectively, of cancer progression compared with patients with cancer Gleason scores of </=6. Patients with perineural invasion at biopsy were twice as likely to progress compared with patients without perineural invasion. Each 1-unit increase in MIB-1 on the natural logarithmic scale increased the risk of cancer progression by 64%.
Cancer progression models that include serum prostate specific antigen and clinical stage may require revision to incorporate perineural invasion and MIB-1 proliferative activity in addition to Gleason score.
BIOPSY TUMOR VOLUME
Percent of cancer in the biopsy set predicts pathological findings after prostatectomy.
Grossklaus DJ, Coffey CS, Shappell SB, Jack GS, Chang SS, Cookson MS.
Department of Urologic Surgery and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
J Urol 2002 May;167(5):2032-5; discussion 2036 Abstract quote
PURPOSE: The ability to use pretreatment variables to identify patients with organ confined prostate cancer continues to challenge physicians. We examined information available preoperatively, including prostate needle biopsy, clinical stage and preoperative prostate specific antigen (PSA), and evaluated these data based on pathological variables after radical retropubic prostatectomy.
MATERIALS AND METHODS: We reviewed results in 135 consecutive patients who underwent radical retropubic prostatectomy at a single institution. Needle biopsy information, such as the number of cores, percent of tumor per biopsy set, laterality of positive cores and Gleason sum, were compared with pathological data on the radical retropubic prostatectomy specimen, including pathological stage, Gleason sum and tumor volume. Clinical data, including biopsy information and pathological findings, were compared using univariate and multivariate models.
RESULTS: Overall total PSA, percent of tumor in the biopsy and bilateral positive cores directly correlated with tumor volume (p <0.01). Also, increasing PSA, increasing percent of tumor in the biopsy and bilateral positive cores were associated with increased risks of extracapsular extension (p <0.01).
CONCLUSIONS: From the information readily available from prostate needle biopsy these results suggest that percent of tumor in the biopsy is a useful predictor of pathological stage and tumor volume. Furthermore, including percent of tumor in the biopsy set and bilateral disease with traditional variables such as serum PSA and clinical stage may improve pretreatment tumor staging. This finding adds additional credence to the inclusion of percent of tumor in the biopsy set in models for the preoperative prediction of pathological stage and should be factored into discussions with patients on treatment options.
The Influence of Percentage of Preradiation Needle Biopsies With Adenocarcinoma and Total Radiation Dose on the Pathologic Response of Unfavorable Prostate Adenocarcinoma
Neal S. Goldstein, MD
Larry L. Kestin, MD
Frank A. Vicini, MD
and Alvaro A. Martinez, MD
Am J Clin Pathol 2002;117:927-934 Abstract quote
We studied relationships among clinicopathologic factors in 78 patients with unfavorable prostate adenocarcinoma treated in a dose-escalation radiation therapy (RT) study using pre- and 18-month protocol post-RT biopsy specimens. Pre-RT factors analyzed were serum prostate-specific antigen (PSA) level, Gleason score, and percentage of needle cores with adenocarcinoma; post-RT factors were percentage of needle cores with adenocarcinoma and amount of radiation effect on the adenocarcinoma.
Of 78 patients, 42 (54%) had residual adenocarcinoma in the post-RT biopsy specimen. Lower total RT dose and dose per implant and greater serum PSA level were associated with an increasing percentage of needle cores with residual post-RT adenocarcinoma. Lower RT dose, an increasing percentage of pre-RT needle cores with adenocarcinoma, and a greater serum PSA level were associated with an increasing percentage of post-RT needle cores with no to moderate RT effect scores in adenocarcinoma.
The mean percentage of pre-RT and post-RT needle cores with adenocarcinoma was greater in patients with post-RT biopsy specimens with no to moderate RT effect.
Down-regulation of CEACAM1 in human prostate cancer: Correlation with loss of cell polarity, increased proliferation rate, and Gleason grade 3 to 4 transition.
Busch C, Hanssen TA, Wagener C, oBrink B.
Department of Pathology, University Hospital, Tromso, Norway, Department of Clinical Chemistry, University Hospital Eppendorff, Hamburg, Germany, Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden.
Hum Pathol 2002 Mar;33(3):290-8 Abstract quote
Many cancers have altered expression of various cell adhesion molecules. One of these is CEACAM1, which has been found to be downregulated in several carcinomas, including prostate cancer.
We explored its immunohistochemical expression in a set of 64 total prostatectomy specimens and compared it with that of the epithelial cell adhesion molecule E-cadherin and occludin, a tight junction-associated molecule. The luminal surface of the epithelial cells of normal prostate glands and ducts showed a dense expression of CEACAM1. This pattern prevailed in prostate cancer of Gleason grades 1 to 3 as long as the cells maintained their polarity and formed individual glands. With "fusion" of glands (ie, in the transition to Gleason grade 4), the expression of CEACAM1 was lost in polygonal nonpolar cells and was lost or focally very weak in cells lining a lumen in the cribriform complexes. E-cadherin, which outlined the basolateral cell membranes of contacting neighboring epithelial cells was also downregulated in prostate carcinomas. However, the loss of E-cadherin expression in higher grades was gradual and not related to the Gleason 3 to >4 transition. Occludin was also lost in polygonal (ie, unpolarized) cells of Gleason grades 4 and 5, but remained expressed in all cells facing a lumen in all grades of cancer, which CEACAM1 was not.
In conclusion, downregulation of CEACAM1 as well as that of occludin in prostate cancer is associated with loss of cell polarity. It coincides with the formation of the complex glandular architecture of Gleason grade 4 pattern or complete loss thereof in Gleason grade 5 patterns. The proliferative activity, measured as Ki67 labeling index, showed a fourfold increase in the carcinoma cells with lost CEACAM1 expression, supporting previous observations that CEACAM1 regulates cell proliferation. Immunohistochemical analysis of CEACAM1 expression patterns may be useful in assessment of the malignant potential of prostate carcinoma.
Aneusomy of chromosomes 7, 8, and 17 and amplification of HER-2/neu and epidermal growth factor receptor in Gleason score 7 prostate carcinoma: A differential fluorescent in situ hybridization study of Gleason pattern 3 and 4 using tissue microarray
Marek Skacel, MD
Adrian H. Ormsby, MBChB
James D. Pettay
Evangelos K. Tsiftsakis, MD
Louis S. Liou, MD, PhD
Eric A. Klein, MD
Howard S. Levin, MD
Craig D. Zippe, MD
Raymond R. Tubbs, DO
Hum Pathol 32:1392-1397. Abstract quote
Recent evidence shows that the proportion of poorly differentiated prostate carcinoma (Gleason pattern [GP] 4/5) is a surrogate factor for biochemical failure after radical prostatectomy (RP). However, little is known about specific molecular and cytogenetic changes in this aggressive component of localized prostate cancer.
We constructed a tissue microarray containing areas of GP 3 and 4 from formalin-fixed radical prostatectomy specimens of 39 patients with Gleason score 7 carcinoma (50% GP 4), known pathologic staging parameters (stage < T3b), and biochemical failure data (mean follow-up, 30 months; range, 5 to 74 months). Interphase fluorescent in situ hybridization (FISH) was performed on 5-µm microarray sections using pericentromeric probes to chromosomes 7, 8, and 17 and probes for the HER-2/neu and epidermal growth factor receptor (EGFR) genes.
Low-level amplification of HER-2/neu was found in 26% of cases (3 to 5 signals per nucleus, corrected for chromosome 17 aneusomy). Aneusomy of chromosomes 7, 8, and 17 was identified in 21%, 15%, and 5% of cases, respectively. All aberrations occurred almost exclusively in GP 4 carcinoma (8 of 8 aneusomies 7, 2 of 2 trisomies 17, 9 of 10 HER-2/neu amplifications, and 5 of 6 aneusomies 8; P < .001). The presence of HER-2/neu amplification was associated with high tumor volume (>2.0 cm3, P = 0.004). Among patients with negative surgical margins, gain of chromosome 7 was associated with biochemical failure after RP (P = .004, log-rank). Amplification of the EGFR gene occurred in only 1 case (3%). Significant differences in HER-2/neu amplification and gain of chromosomes 7, 8, and 17 were detected between GP 4 prostate carcinoma and GP 3. The frequency of aberrations increased with tumor volume.
Chromosome 7 abnormalities may play an important role in cancer progression in margin-negative patients. EGFR amplification was rare, suggesting that this oncogene is not altered at the gene copy number level.
E-cadherin expression in prostate cancer: A broad survey using high-density tissue microarray technology
Mark A. Rubin, MD Neil R. Mucci, BS Jay Figurski, BS Alice Fecko, BA Kenneth J. Pienta, MD Mark L. Day, PhD
Hum Pathol 2001;32:690-697. Abstract quote
E-cadherin is a calcium 2+–dependent cell-adhesion molecule that determines epithelial development in the embryo and maintains adult differentiated epithelium and homeostasis. Aberrant or decreased expression has been reported to be associated with prostate carcinoma progression. The degree of E-cadherin expression in prostate cancer remains controversial. Some studies have reported decreased expression of E-cadherin as tumors advance and metastasize. Other studies have not demonstrated this relationship.
To address these variations, we undertook a study to systematically evaluate E-cadherin expression in a broad range of prostate tissue. Benign prostate, clinically localized prostate cancer, and hormone-refractory metastatic prostate cancer were analyzed under uniform conditions using high-density tissue microarrays (TMA).
Formalin-fixed, paraffin-embedded prostate carcinoma from men with clinically localized prostate carcinoma and autopsy material from men who died of widely metastatic, hormone-refractory prostate carcinoma were arrayed into 6 high-density TMA blocks. Benign and atrophic prostate tissue and high-grade prostatic intraepithelial neoplasia (PIN) were also included from the clinically localized cases. Immunohistochemistry was performed using the immunoglobulin G1 mouse monoclonal antibody (HECD-1; Zymed, San Francisco, CA). Membranous staining was recorded as low (aberrant) or high (normal). E-cadherin expression was considered aberrant if less than 70% of the cells had strong membranous staining. A total of 1,220 prostate TMA samples were analyzed. High (normal) E-cadherin expression was seen in 87% of 757 benign, 80% of 41 high-grade PIN, 82% of 325 prostate carcinoma and 90% of 97 hormone-refractory prostate carcinoma TMA samples. Mean E-cadherin expression was determined for each of the 128 clinically localized prostate cancer cases. Aberrant E-cadherin expression showed a statistical trend toward an association with positive surgical margins (P = .012), higher Gleason score (P = .18), and prostate-specific antigen (PSA) failure (Kaplan-Meier analysis, log-rank P = .09). There was a statistically significant association between aberrant E-cadherin expression and larger tumor size (P = .01). No significant associations were seen with extraprostatic extension and seminal vesicle invasion.
The current study shows a broad-spectrum approach to evaluating E-cadherin protein expression in prostate carcinoma. Clinically localized prostate tumors, treated with surgery alone, show a high level of E-cadherin expression. Aberrant expression was identified in tumors with positive surgical margins, higher Gleason score, and a higher rate of PSA failure. However, these trends were not statistically significant. A statically significant association between aberrant E-cadherin expression and larger tumor size was identified. In the metastatic hormone-refractory prostate tumors, E-cadherin expression was vastly expressed, and only rare cases had aberrant expression. Therefore, the findings of this study are most consistent with a transient down-regulation of E-cadherin in localized prostate cancer. Metastatic prostate cancer shows strong E-cadherin expression as determined by anti-E-cadherin antibody HECD-1.
Prostate carcinoma expression of estrogen receptor-beta as detected by PPG5/10 antibody has positive association with primary Gleason grade and Gleason score.
Torlakovic E, Lilleby W, Torlakovic G, Fossa SD, Chibbar R.
Departments of Pathology and Oncology, Norwegian Radium Hospital, Oslo, Norway, and the Department of Pathology, Royal University Hospital, Saskatoon, Canada.
Hum Pathol 2002 Jun;33(6):646-51 Abstract quote
The objective of this study was to study the expression of estrogen receptor-beta (ER-beta) in prostatic adenocarcinoma and correlate it with Gleason grade and clinical outcome. Immunohistochemical evaluation was performed on prostate needle biopsies from 53 patients (T1-T3pN0M0).
ER-beta and ER-alpha transcripts were also studied by semiquantitative reverse transcriptase polymerase chain reaction in PC-3 and LNCaP prostate carcinoma cell lines. ERbeta was expressed in 93% of adenocarcinomas and was positively associated with primary Gleason grade (P = 0.028 for percentage of positive cells and P = 0.046 using a semiquantitative scale) and Gleason score (P = 0.010 for percentage of positive cells and P = 0.014 using a semiquantitative scale). ER-beta expression in the benign epithelium of prostates with adenocarinoma was detected in 92% of cases and in the stroma in 47% of cases. A trend for longer time to treatment failure was noted for cases with low ER-beta expression after curatively intended radiotherapy (P = 0.082). PC-3, an aggressive prostate cancer cell line with invasive properties in nude mice, expressed higher levels of ER-beta than LNCaP, a nonmetastasizing cell line, whereas no difference for ER-alpha transcripts could be observed.
Our findings suggest that ER-beta, as detected by PPG5/10 antibody, may have a role in the process of dedifferentiation of prostate adenocarcinomas, with higher levels present in less differentiated tumors.
The Prognostic Significance of Tertiary Gleason Patterns of Higher Grade in Radical Prostatectomy Specimens A Proposal to Modify the Gleason Grading System
Chin-Chen Pan, M.D.; Steven R. Potter, M.D.; Alan W. Partin, M.D., Ph.D.; Jonathan I. Epstein, M.D.
From the Departments of Urology (S.R.P., A.W.P., J.I.E.) and Pathology (C.-C.P., J.I.E.), The Johns Hopkins University School of Medicine, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, MD, U.S.A. .
Am J Surg Pathol 2000;24:563-569 Abstract quote
The Gleason grading system of prostatic adenocarcinoma does not account for the existence of a tertiary (third most prevalent) pattern, and there are no studies concerning the latter's prognostic influence.
The authors analyzed 114 radical prostatectomies with small tertiary components, which mostly occupied less than 5% of whole tumors. These specimens were compared with a prostatectomy database comprised of 2,276 cases without a tertiary component.
The pathologic stages of ``typical'' Gleason score 5 to 6 tumors (Gleason scores 2 + 3 = 5, 3 + 2 = 5, 3 + 3 = 6), which contained tertiary patterns 4 or 5, were significantly higher than those of ``typical'' Gleason score 5 to 6 tumors without pattern 4 (p = 0.018) but lower than those of ``typical'' Gleason score 7 tumors (p = 0.021; Gleason scores, 3 + 4 = 7, 4 + 3 = 7). Typical Gleason score 7 tumors with a tertiary pattern 5 showed significantly worse pathologic stages than typical Gleason score 7 tumors (p = 0.008) without pattern 5 and were not different statistically from typical Gleason score 8 (Gleason score, 4 + 4 = 8) tumors. Both typical Gleason score 5 to 6 and 7 tumors with tertiary components revealed significantly higher progression rates than typical Gleason score 5 to 6 tumors (p <0.0001) and Gleason score 7 tumors (p = 0.003) without tertiary components, and progressed like typical Gleason score 7 and 8 tumors respectively.
Tertiary high-grade components have an adverse impact on biologic behavior. The authors propose that the Gleason system for radical prostatectomy specimens be modified to take into account small volumes of patterns 4 and 5, which are important prognostically.
Primary Gleason Pattern as a Predictor of Disease Progression in Gleason Score 7 Prostate Cancer A Multivariate Analysis of 823 Men Treated With Radical Prostatectomy
C. M. Herman, etal.
Am J Surg Pathol 2001;25:657-660 Abstract quote
Gleason score (GS) is a powerful predictor of disease progression in men with prostate cancer (PCa). The majority of clinically localized prostate cancers, however, are moderately (GS5/6) or moderate to poorly (GS7) differentiated tumors with indeterminate prognosis. Differences in disease progression between patients with GS5/6 and GS7 tumors suggest the presence of any component of high-grade tumor (Gleason pattern [GP] 4/5) worsens prognosis markedly. Indeed, McNeal et al. have shown that quantification of GP4/5 provides prognostic information beyond the standard GS. Few investigators have analyzed whether primary and secondary GPs are important prognostically within GS7 PCa.
All 823 whole-mount radical prostatectomy specimens with GS7 from a single surgeon (P.T.S.) were analyzed. Tumors were either 3+4 or 4+3, and primary GP was assigned by the same pathologist (T.M.W.). A total of 643 patients with 3+4 tumors and 180 patients with 4+3 tumors were studied.
Statistical analysis using the log-rank test showed a significant difference in recurrence-free survival between patients with primary GP4 and those with GP3 (p <0.0001). However, in multivariate analysis with preoperative prostate-specific antigen, total tumor volume, surgical margin status, and the presence or absence of seminal vesicle involvement, extraprostatic extension, and lymph node metastasis, the primary GP did not retain independent significance (p = 0.0557). GS7 PCa is a heterogeneous group of tumors.
In this cohort of men with GS7 tumors treated by radical retropubic prostatectomy, primary GP showed a significant correlation with other histologic and clinical predictors of disease progression; however, it was not independently predictive of disease progression in multivariate analysis (p = 0.76).
Incidence, Location, and Significance of Periprostatic and Periseminal Vesicle Lymph Nodes in Prostate Cancer
Pulin S. Kothari, M.D. ; Peter T. Scardino, M.D. ; Makoto Ohori, M.D. ; Michael W. Kattan, Ph.D. ; Thomas M. Wheeler, M.D.
From the Department of Pathology (P.S.K., T.M.W.), Baylor College of Medicine, Houston, Texas; and the Department of Urology (P.T.S., M.O., M.W.K.), Memorial Sloan Kettering Cancer Center, New York, NY, U.S.A.
Am J Surg Pathol 2001;25:1429-1432 Abstract quote
Pelvic lymph node metastases in prostate cancer (PCa) carry an ominous prognosis. Periprostatic/periseminal vesicle (PP/PSV) lymph nodes are present in some individuals, but their incidence and involvement by metastases are unknown.
A total of 832 of 1233 (67.5%) patients who underwent radical retropubic prostatectomy for clinically localized PCa at the Methodist Hospital from 1983 to 1998 by one surgeon (P.T.S.) had whole-mount slides available for review. Of these, 92 (11.1%) had received preoperative therapy (radiation in 48 [5.8%], hormonal in 44 [5.3%]). Slides were examined with the naked eye by placing them on a white illuminated background, and any area suggestive of a lymph node in PP/PSV fat was confirmed microscopically and assessed for the presence of metastases.
Thirty-seven of 832 patients (4.4%) had 39 PP/PSV lymph nodes—one bilateral, one with two ipsilateral lymph nodes, and the rest solitary. Sizes ranged from 0.7 to 4.5 mm (mean 1.8 mm). Distribution was 2 of 39 (5.1%) apical, 3 of 39 (7.7%) mid, 17 of 39 (43.6%) base, and 17 of 39 (43.6%) seminal vesicle. Five patients (0.6%) had metastatic PCa to the PP/PSV lymph nodes. All five patients were of advanced pathologic T stage [one pT3a (extraprostatic extension) and four pT3b (seminal vesicle invasion)]. Only two of those five (40%) had metastases (all ipsilateral) to pelvic lymph nodes. In three of five (60%) the metastases were isolated to the PP/PSV lymph nodes. Metastases were to the lymph nodes in the periseminal vesicle fat in four of five (80%) of the cases and in the fat surrounding the base of the prostate in one of five (20%). Four of five (80%) patients recurred. Histologic grade (Gleason score), tumor volume, and failure (recurrence) rates were significantly different between the five patients with metastases and the 32 patients without metastases to the PP/PSV lymph nodes (p <0.0001, p <0.0001, and p = 0.005, respectively). However, there was no evidence that an individual patient's probability of having a PP/PSV lymph node increased with resection of the neurovascular bundle (p = 0.7698).
PP/PSV lymph nodes are uncommon, but based upon these limited data, it appears that patients with metastases limited to PP/PSV lymph nodes have a poor prognosis (similar to pelvic lymph node metastases) and should be included in the American Joint Committee on Cancer (AJCC) Staging Manual to indicate “N1” if positive for metastases.
Loss of p53 and c-myc Overrepresentation in Stage T2-3N1-3M0 Prostate Cancer are Potential Markers for Cancer Progression
Junqi Qian, M.D., Kiyoshi Hirasawa, M.D., David G. Bostwick, M.D., Erik J. Bergstralh, M.S., Jeff M. Slezak, M.S., Kari L. Anderl, B.S., Thomas J. Borell, B.S., Michael M. Lieber, M.D. and Robert B. Jenkins, M.D., Ph.D.
Department of Laboratory Medicine and Pathology (JQ, DGB, TJB, KLA, RBJ), Department of Urology (KH, MML), and Section of Biostatistics (EJB, JMS), Mayo Clinic, Rochester, Minnesota.
Mod Pathol 2002;15:35-44 Abstract quote
To determine whether genetic changes are markers of cancer progression and patient survival in Stage T2–3N1–3M0 prostatic carcinoma, we compared 26 patients who died of tumor relapse after prostatectomy and lymphadenectomy (case group) with 26 matched patients who were alive at the time of the matched case’s death (control group).
Nine unmatched cases were also included in this study. In 37 cases, paired primary tumors (119 foci) and lymph node metastases (114 foci) were available for study. Fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 7, 8, and 17 and region-specific probes for D7S486 (7q31), c-myc (8q24), LPL (8p22), and p53 (17p13) was performed on available primary carcinomas and lymph node metastases. In primary tumor foci, +7q31, -8p22, +c-myc, substantial additional increases of myc (AI-c-myc), and -p53 were observed in 65%, 74%, 43%, 29%, and 31% of foci, respectively. AI-c-myc was strongly associated with higher cancer Gleason score (P = .003). Heterogeneity of genetic changes was frequently observed among multiple cancer foci. Lymph node metastases of prostate cancer usually shared genetic changes with paired primary tumors. In addition, the genetic change pattern with -8p, +c-myc or AI-c-myc, +7q, and +p53 was slightly higher in lymph node metastases (22%) than in primary tumors (6%) (P = .08). In matched case and control patients, simultaneous gain of 7q31 (+7q31) and CEP7 (+CEP7) was identified in 59% and 68% of specimens for case and control groups, respectively (P = .48). Loss of 8p22 (-8p22) was identified in 77% and 69% of specimens for case and control groups, respectively (P = 1.0). Simultaneous gain of c-myc (+c-myc) and CEP8 (+CEP8) without overt additional increase of c-myc copy number relative to CEP8 copy number, was identified in 38% and 54% of specimens for case and control groups, respectively (P = .27). AI-c-myc was identified in 54% and 23% of specimens for case and control groups, respectively (odds ratio = 3.0, P = .06). Loss of p53 (-p53) was identified in 46% and 15% of specimens for case and control groups, respectively (odds ratio = 4.0, P = .04).
Our results indicate that FISH anomalies are very common in both primary tumors and lymph node metastases of Stage T2–3N1–3M0 prostate cancer; that AI-c-myc is associated with higher cancer Gleason score; that AI-c-myc and -p53 are associated with prostate cancer progression and are potential markers of survival in Stage T2–3N1–3M0 prostate cancer; and that lymph node metastases usually have similar or additional genetic changes compared with primary tumors, and multiple lymph node metastases usually have similar genetic changes.
Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate.
Keetch DW, Humphrey P, Stahl D, Smith DS, Catalona WJ.
Division of Urologic Surgery, Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.
J Urol 1995 Aug;154(2 Pt 1):347-51 Abstract quote
PURPOSE: We evaluate the significance of grade and extent of isolated prostatic intraepithelial neoplasia in prostate needle biopsies as a predictor of cancer on repeat biopsy.
MATERIALS AND METHODS: We reviewed our experience with 58 men 50 years or older who had isolated prostatic intraepithelial neoplasia on initial prostate needle biopsy during a prostate specific antigen (PSA) based screening trial for prostate cancer. All 58 men underwent repeat biopsy to follow the initial findings of prostatic intraepithelial neoplasia. We assessed the relationship of patient age, digital rectal examination, serum PSA concentration, PSA density, prostatic intraepithelial neoplasia grade, number of foci of neoplasia and linear extent of prostatic intraepithelial neoplasia in the initial biopsy specimen to the finding of cancer on the repeat biopsy. We also compared the cancer detection rate in the 58 men with and 427 without prostatic intraepithelial neoplasia in the same screening trial.
RESULTS: Of 21 men with low grade and 37 with high grade prostatic intraepithelial neoplasia 4 (19%) and 19 (51%), respectively, had cancer on repeat biopsy (p < 0.02), compared to 82 of 427 (19%) without cancer or prostatic intraepithelial neoplasia on the initial biopsy. High grade prostatic intraepithelial neoplasia was a significant predictor of malignancy on repeat biopsy (p < 0.05). The number of foci of neoplasia and the linear extent of prostatic intraepithelial neoplasia on initial biopsy were not predictive of cancer on repeat biopsy.
CONCLUSIONS: Our results demonstrate that the presence of high grade prostatic intraepithelial neoplasia is a strong predictor of prostate cancer in men with elevated serum PSA concentrations and they should be followed with repeat biopsy.
Repeat biopsy strategy in patients with atypical small acinar proliferation or high grade prostatic intraepithelial neoplasia on initial prostate needle biopsy.
Borboroglu PG, Sur RL, Roberts JL, Amling CL.
Department of Urology, Naval Medical Center-San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134-1005, USA.
J Urol 2001 Sep;166(3):866-70 Abstract quote
PURPOSE: Isolated high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation on prostate biopsy increases the risk of identifying cancer on repeat biopsy. We report the results of repeat prostate biopsy for high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation, and propose an optimal repeat biopsy strategy.
MATERIALS AND METHODS: Of 1,391 men who underwent standard systematic sextant biopsy of the prostate 137 (9.8%) had isolated high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation, including 100 who underwent repeat prostate biopsy within 12 months of the initial biopsy.
RESULTS: Adenocarcinoma was detected in 47 of the 100 patients who underwent repeat biopsy. The initial biopsy site of high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation matched the sextant location of cancer on repeat biopsy in 22 cases (47%). Repeat biopsy directed only to the high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation site on initial biopsy would have missed 53% of cancer cases. In 12 of the 47 men (26%) cancer was limited to the side of the prostate contralateral to the side of high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation. Of the 31 patients with cancer in whom the transition zone was sampled cancer was limited to the transition zone in 4 (13%) and evident at other biopsy sites in 13 (42%). The only significant predictor of positive repeat biopsy was mean prostate specific antigen velocity plus or minus standard error (1.37 +/- 1.4 versus 0.52 +/- 0.8 ng./ml. per year, p <0.001).
CONCLUSIONS: Patients with isolated high grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation on prostate biopsy are at 47% risk for cancer on repeat biopsy. The optimal repeat biopsy strategy in this setting should include bilateral biopsies of the standard sextant locations. We also strongly recommend that transition zone sampling should be considered.
RADIATION RESISTANT FOCI OF CANCER
The histology of radiation therapy effect on prostate adenocarcinoma as assessed by needle biopsy after brachytherapy boost. Correlation with biochemical failure.
Goldstein NS, Martinez A, Vicini F, Stromberg J.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Am J Clin Pathol 1998 Dec;110(6):765-75 Abstract quote
Brachytherapy boost with external radiation therapy (RT) allows safer delivery to the prostate than conventional techniques.
We measured the degree of radiation effect of adenocarcinoma cells in post-RT biopsy specimens and the association with biochemical failure.
Forty-six patients with T2b-3c adenocarcinomas underwent 18-month post-RT biopsies, of whom 22 had adenocarcinoma. All biopsy specimens without obvious adenocarcinoma were stained with antibodies to prostate-specific antigen and keratins AE1/AE3 and 34 beta E12. The RT effect to adenocarcinoma cells was scored by adding the scores of the nuclear and cytoplasmic changes. Each adenocarcinoma was assigned 2 scores; the most-common and the least-amount RT effect. Treatment for 7 of the 46 patients failed; 6 of these had residual adenocarcinoma on the post-RT biopsy specimen. Sixteen of 22 patients with adenocarcinoma on the post-RT biopsy specimen did not experience biochemical failure. The presence of adenocarcinoma on the post-RT biopsy specimen was significantly associated with failure. The mean most-common RT-effect score for the 16 patients without failure was 5.2 compared with 4.2 for the 6 patients with failure. The mean least-amount RT-effect score in patients without failure was 4.4 compared with 2.8 (range, 2-4; SD, 0.75) in the failure group.
These relatively radiation-resistant foci may be the source of failure. Scoring the RT-effect of adenocarcinoma in post-RT biopsy specimens may be clinically useful in predicting subsequent biochemical failure.
Postradiotherapy prostate biopsies: what do they really mean? Results for 498 patients.
Crook J, Malone S, Perry G, Bahadur Y, Robertson S, Abdolell M.
Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.
Int J Radiat Oncol Biol Phys 2000 Sep 1;48(2):355-67 Abstract quote
PURPOSE: Postradiotherapy (RT) prostate biopsies are prone to problems in interpretation. False negatives due to sampling error, false positives due to delayed tumor regression, and indeterminate biopsies showing radiation effect in residual tumor of uncertain viability are common occurrences.
METHODS AND MATERIALS: A cohort of 498 men treated with conventional RT from 06/87-10/96 were followed prospectively with systematic transrectal ultrasound (TRUS)-guided post-RT prostate biopsies, starting 12-18 months after RT. If there was residual tumor but further decline in serum prostate-specific antigen (PSA), biopsies were repeated every 6-12 months. Patients with negative biopsies were rebiopsied at 36 months. Residual tumor was evaluated for RT effect and proliferation markers. The 498 men had 978 biopsies. Median time of the first biopsy (n = 498) was 13 months, biopsy #2 (n = 342) 28 months, biopsy #3 (n = 110) 36 months, biopsy #4 (n = 28) 44 months, and biopsy #5 (n = 4) 55 months. Median follow-up is 54 months (range 13-131). One hundred seventy-five patients (34%) had prior hormonal therapy for a median of 5 months (range 1-60).
RESULTS: Clinical stage distribution was T1b: 46; T1c: 50; T2a: 115; T2b/c: 170; T3: 108; T4: 11; Tx: 1. Distribution by Gleason score was: 28% Gleason score 2-4; 42%: 5-6; 18%: 7; and 12%: 8-10. Seventy-one men have died, 26 of prostate cancer and 45 of other causes. Actuarial failure-free survival by T stage at 5 years is T1b: 78%; T1c: 76%; T2a: 60%; T2b/c: 55%; T3: 30%; and T4: 0%. Actuarial freedom from local failure at 5 years is T1b: 83%; T1c: 88%; T2a: 72%; T2b/c: 66%; T3: 58%; and T4: 0%. The proportion of indeterminate biopsies decreases with time, being 33% for biopsy 1, 24% for biopsy 2, 18% for biopsy 3, and 7% for biopsy 4. Thirty percent of indeterminate biopsies resolved to NED status, regardless of the degree of RT effect, 18% progressed to local failure, and 34% remained as biopsy failures with indeterminate status within the time frame of this report. Positive staining for proliferation markers was associated with both subsequent local failure and also any type of failure. In multivariate analysis, only PSA nadir (p = 0.0002) and biopsy status at 24-36 months (p = 0. 0005) were independent predictors of outcome.
CONCLUSIONS: Post-RT prostate biopsies are not a gold standard of treatment efficacy, but are an independent predictor of outcome. Positive immunohistochemical staining for markers of cellular proliferation is associated with subsequent local failure. Indeterminate biopsies, even when showing marked RT effect, cannot be considered negative.
Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy?
Koppie TM, Grossfeld GD, Nudell DM, Weinberg VK, Carroll PR.
Department of Urology, University of California-San Francisco, USA
J Urol 2001 Jul;166(1):111-5 Abstract quote
PURPOSE: External beam radiotherapy may be given after radical prostatectomy as adjuvant (immediate) or therapeutic (delayed) treatment, the latter in response to evidence of disease recurrence. In patients receiving delayed radiotherapy the necessity of a positive anastomotic biopsy before treatment remains unclear. We determined whether a positive anastomotic biopsy predicted the response to radiation in this setting.
MATERIALS AND METHODS: We reviewed the records of 67 patients who received radiotherapy for biochemical or biopsy proved recurrent prostate cancer after radical prostatectomy. Patients underwent surgery at our institution or its affiliated hospitals, or were referred to our institution for radiotherapy. All patients had a negative metastatic evaluation before receiving radiotherapy. Biochemical failure after radiotherapy was defined as serum prostate specific antigen (PSA) 0.2 ng./dl. or greater on 2 or more consecutive occasions. Biochemical recurrence-free survival was calculated using the Kaplan-Meier method. Independent predictors of PSA failure after radiotherapy were identified using the multivariate Cox proportional hazards model.
RESULTS: Of the 67 patients evaluated 33 and 34 received radiotherapy for biochemical failure and biopsy proved local recurrence, respectively. The 3-year recurrence-free survival rate was 49% in patients treated for biochemical failure and 39% in those with biopsy proved local recurrence. There was no significant difference in PSA-free survival in these 2 groups. Only pre-radiotherapy PSA 1 ng./dl. or greater (p = 0.02) and seminal vesicle invasion (p = 0.02) were significant independent predictors of biochemical failure.
CONCLUSIONS: A positive anastomotic biopsy did not predict an improved outcome after radiotherapy following radical prostatectomy. Anastomotic biopsy was associated with a longer time to salvage radiotherapy. However, this delay did not translate into worse disease-free outcomes in patients who underwent anastomotic biopsy. High pre-radiotherapy PSA greater than 1 ng./ml. was the most significant predictor of biochemical failure after therapeutic radiotherapy. Decisions regarding local radiation therapy after radical prostatectomy may be made without documenting recurrent local disease.
Lymphovascular Invasion as a Predictor of Disease Progression in Prostate Cancer
Christopher M. Herman, M.D.; George E. Wilcox, M.D.; Michael W. Kattan, Ph.D.; Peter T. Scardino, M.D.; Thomas M. Wheeler, M.D.
From the Departments of Pathology and the Scott Department of Urology Baylor College of Medicine, The Methodist Hospital, Houston, Texas (C.M.H., G.E.W., T.M.W.) and the Department of Urology Memorial Sloan Kettering Cancer Center, New York, New York, U.S.A. (M.W.K., P.T.S.).
Am J Surg Pathol 2000;24:859-863 Abstract quote
The biologic heterogeneity of prostate cancer (PCa) is evident from the large discrepancy between incidence rates and disease progression and tumor-related deaths. One of the challenges in treating patients with PCa lies in developing nomograms to identify patients who might benefit from adjuvant therapies. Lymphovascular invasion (LVI) is among the variables in PCa recommended to be reported by the Cancer Committee of the College of American Pathologists (CAP), yet few studies have evaluated the prognostic significance and prevalence of LVI in PCa.
In the present study, whole-mount specimens from 263 patients with pT3N0 PCa treated by radical prostatectomy by a single surgeon were evaluated for the presence, location, and number of foci of LVI.
Foci of LVI were identified in 91 patients. In cases with LVI the number of foci ranged from 1 to 40 with the majority of patients having 1 or 2 foci. LVI was found to be a significant predictor of disease progression in univariate analysis (p <0.0001) and was significantly related to Gleason sum (p <0.001), extra prostatic extension (focal vs established; p = 0.033), and seminal vesicle involvement (p <0.001). Furthermore, in multivariate analysis, LVI was a significant independent predictor of disease progression as well (p = 0.0014).
These findings support the CAP recommendations and provide merit for the inclusion of LVI in nomograms to predict disease recurrence in PCa.
Conservative management of prostate cancer in the prostate specific antigen era: the incidence and time course of subsequent therapy.
Zietman AL, Thakral H, Wilson L, Schellhammer P.
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
J Urol 2001 Nov;166(5):1702-6 Abstract quote
PURPOSE: The long natural history of early stage prostate cancer is well recognized and a conservative approach to the treatment of elderly men is often encouraged. We assessed the ability of patients and physicians to adhere to a policy of watchful waiting in the prostate specific antigen (PSA) era.
MATERIALS AND METHODS: We retrospectively reviewed the records of all 199 men with stages T1-2 prostate cancer and PSA less than 20 ng./ml. who in our practice elected watchful waiting. Median followup in the population overall was 3.4 years. We performed Kaplan-Meier actuarial analysis of overall and disease specific survival, and most pertinent survival free from therapy. A questionnaire was administered to record the attitude of patients who ultimately proceeded to treatment to determine how therapy was triggered.
RESULTS: Median patient age was 71 years and median PSA was 6.6 ng./ml. The tumor was impalpable in 52% of patients, Gleason sum was 6 or less in 80% and 11% used some form of herbal remedy or nutritional supplementation. Of the 37 men who died during observation, including 35 of co-morbid illness, only 6 underwent treatment. Overall survival at 5 and 7 years was 77% and 63% but disease specific survival was 98% and 98%, respectively. A total of 64 patients underwent treatment and actuarial freedom from treatment was 56% at 5 years, including 51% and 73% in those younger and older than 75 years at diagnosis. The likelihood of being alive and free from treatment was 43% at 5 years and 26% at 7. Of the 63 men treated 48 (76%) underwent radical therapy (brachytherapy in 17, external beam radiotherapy in 29 and prostatectomy in 2), while only 24% received androgen deprivation. The median PSA increase from diagnosis to treatment in treated patients was 2.9 ng./ml., and it was 0.9 ng./ml. from diagnosis to the last followup in those not treated. Of the treated patients 81% believed that the physician had initiated therapy due to a PSA increase or a nodule. However, physicians recorded having advocated treatment in only 24% of cases.
CONCLUSIONS: When patients do not die of co-morbid illness, they are likely to proceed to therapy well within the first decade after diagnosis (57% by 5 years and 74% by 7). Therapy was usually definitive (radical) and triggered by slight, inevitable PSA increases. The patient perception was that the physicians initiated therapy in response to increasing PSA. However, the physicians more often perceived that treatment was initiated by patients. Therefore, watchful waiting in the PSA era often represents radical therapy delayed by a few years.
TREATMENT Surgery Radical prostatectomy is often combined with modalities listed below
Prospective patient-reported continence after laparoscopic radical prostatectomy.
Olsson LE, Salomon L, Nadu A, Hoznek A, Cicco A, Saint F, Chopin D, Abbou CC.
Service d'Urologie, Hopital Henri-Mondor, Creteil, France
Urology 2001 Oct;58(4):570-2 Abstract quote
Objectives. To perform a prospective study using confidential patient-completed questionnaires about their urinary habits before and after laparoscopic radical prostatectomy. Published reports on urinary continence after radical prostatectomy vary depending on the definitions of urinary continence and methods of data collection.
Methods. From May 1998 to February 2000, 228 men underwent laparoscopic radical prostatectomy for clinically localized prostate cancer. The patients were given questionnaires before surgery and at 1, 3, 6, and 12 months postoperatively.
Results. Before surgery, no patient reported incontinence. At 1, 3, 6, and 12 months postoperatively, perfect diurnal urinary control (no pads, no leakage at all) was reported in 9.9%, 28.6%, 57.4%, and 56.8% of patients, respectively. No pads were used in 18.8%, 58.4%, 68.9%, and 78.4% at 1, 3, 6, and 12 months, respectively. No patient reported use of more than 1 pad daily at 6 months of follow-up.
Conclusions. Continence after laparoscopic radical prostatectomy is comparable to the results after traditional radical retropubic prostatectomy. Ongoing use of the laparoscopic route for treating clinically localized prostate cancer is warranted.
Laparoscopic radical prostatectomy: is it feasible and reasonable?
Cadeddu JA, Kavoussi LR.
Department of Urology, Section of Minimally Invasive Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Urol Clin North Am 2001 Aug;28(3):655-61 Abstract quote
Laparoscopic radical prostatectomy is an extremely challenging procedure for even experienced laparoscopic surgeons, and it is not practical to expect most urologists to learn the technique. Nevertheless, it is a feasible procedure and has short-term results comparable with conventional radical prostatectomy. For LRP to be an acceptable and reasonable alternative, the oncologic results must be equivalent to the results of RRP, and significant advantages is morbidity (hospital stay, pain, incontinence, impotence) must be attained; otherwise, the steep learning curve and the additional expense of the procedure make it difficult to justify as an alternative therapeutic modality. Beside a reduction in the transfusion rate, no other significant advantages of LRP over radical prostatectomy have been demonstrated definitively to date.
As a result, the role of LRP in the management of prostate cancer remains investigational, and patients should be informed appropriately. The oncologic results and low morbidity of nerve-sparing RRP set a high standard for a laparoscopic technique to equal.
Long-term results of treatment for prostate carcinoma by staging pelvic lymph node dissection and definitive irradiation using low-dose rate temporary iridium-192 interstitial implant and external beam radiotherapy.
Puthawala AA, Nisar AM, Austin PA, Cherlow JM, Perley JM, Shanberg AM, Sawyer DE, Ingram JE, Baghdassarian R, Wachs BH, Perley JE, Londrc A, Espinoza-Ferrel T.
Department of Radiation Oncology, Long Beach Memorial Medical Center, Long Beach, California.
Cancer 2001 Oct 15;92(8):2084-94 Abstract quote
BACKGROUND: The objective of this study was to evaluate long-term treatment outcome of definitive irradiation by using temporary interstitial implant and limited dose of external beam radiotherapy in treatment of localized prostate carcinoma.
METHODS: In total, 536 patients with biopsy-proven adenocarcinoma of the prostate, classification T1-T3, underwent staging pelvic lymph node dissection and brachytherapy delivering an average tumor dose of 30 grays (Gy), supplemented by external beam radiation therapy for an additional dose of 36 Gy delivered over 4 weeks. One hundred of 536 (18%) patients had pathologic D1 disease. A total of 181 patients had undergone transurethral prostatectomy before the treatment. Repeat prostate biopsy was performed on 132 patients 18 or more months after treatment. None of the patients received neoadjuvant or adjuvant hormone therapy.
RESULTS: Cumulative disease free survival (DFS) including biochemical DFS at 10 and 15 years for classification T1B,C was 78% and 72%; for T2A, 78% and 78%; for T2B,C, 68% and 66%; and for T3A-C, 45% and 45%, respectively. Cause specific survival for the entire group at 10 and 15 years was 89% and 87%, respectively. Severe complications occurred only in the early developmental phase of the study.
CONCLUSIONS: In univariate analysis, the clinical stage, histologic grade, pretreatment PSA level, lymph node status, and results of repeat posttreatment biopsy were all independently significant prognostic factors. However, the authors' study indicates that in multivariate analysis, only two factors emerged with statistical significance-the status of pelvic lymph nodes and the results of posttreatment biopsy. This signifies the importance of local tumor control to achieve ultimate cure and the importance of assessment of pelvic lymph nodes before definitive local therapy other than radical prostatectomy, especially in the high-risk group.
A centralized comparison of radical perineal and retropubic prostatectomy specimens: is there a difference according to the surgical approach?
Korman HJ, Leu PB, Huang RR, Goldstein NS.
Department of Urology, William Beaumont Hospital, Royal Oak, Michigan, USA.
J Urol 2002 Sep;168(3):991-4 Abstract quote
PURPOSE: We performed a central review of pathology specimens from radical perineal and radical retropubic prostatectomies performed by a single surgeon. We determined whether differences exist in the 2 approaches in regard to the ability to obtain adequate surgical margins around the tumor and adequate extracapsular tissue around the prostate, and avoid inadvertent capsular incision.
MATERIALS AND METHODS: The review included whole mount prostates from 60 patients who underwent radical retropubic prostatectomy and 40 who underwent radical perineal prostatectomy. The pathologist (N. S. G.) was blinded to the surgical approach. All prostatectomies were consecutive and performed by the same surgeon (H. J. K.). To ensure consistency of the pathological measurements patients were excluded from analysis if they had undergone preoperative androgen ablation or a nerve sparing procedure, leaving 45 retropubic and 27 perineal prostatectomy specimens for further evaluation. Pertinent clinical parameters were assessed and a detailed pathological analysis of each specimen was performed.
RESULTS: In the retropubic and perineal groups 78% of the tumors were organ confined (stage pT2) with extracapsular extension (stage pT3) in the majority of the remaining patients. There was no significant difference in the positive margin rate for the retropubic and perineal procedures (16% and 22%, p = 0.53) or for Gleason 6 and 7 tumors only in the 2 groups (10% and 17%, respectively, p = 0.47). The capsular incision rate was 4% in each group. The distance of the tumor from the posterolateral margins and the amount of extracapsular tissue excised were equivalent in each group. Subgroups of patients with a prostate of less than 50 gm. and containing only low grade, low stage neoplasms were also analyzed. Subgroup analysis showed no difference in any variable.
CONCLUSIONS: Radical perineal prostatectomy is comparable to radical retropubic prostatectomy for obtaining adequate surgical margins, avoiding inadvertent capsular incisions and excising adequate extracapsular tissue around tumor foci. Additional patient accrual and prostate specific antigen followup would further help validate the similar efficacy of the 2 surgical approaches as treatment for prostate cancer.
Neoadjuvant Androgen Ablation Combined with External-Beam Radiation Therapy and Permanent Interstitial Brachytherapy Boost in Localized Prostate Cancer.
Sylvester J, Blasko JC, Grimm PD, Meier R, Goy B, Colburn G, Cavanagh W.
Seattle Prostate Institute, Seattle, Washington.
Mol Urol 1999;3(3):231-236 Abstract quote
Androgen ablation therapy has been combined with permanent interstitial brachytherapy in order to downsize the gland prior to seed implantation. It also has been employed in an attempt to improve the effectiveness of therapy in patients with a poor prognosis.
We report on 50 patients consecutively treated and prospectively followed. All received neoadjuvant hormonal therapy (NHT) and 45 Gy of external-beam therapy to a limited pelvic field, followed by permanent implantation of (125)I or (103)Pd seeds. The median follow-up is 42.1 months (range 9.0-90.8 months). The prostate specific antigen (PSA) progression-free survival rate (<1.0 ng/mL) was 76% at 5 years (Kaplan-Meier method). Local control was achieved in 100% of the patients and distant disease-free survival in 85%. High-risk patients treated contemporaneously with these patients, who received external-beam radiation and a seed boost without NHT, had a 62% rate of 5-year PSA progression-free survival.
Although the modest improvement in PSA progression-free survival is not statistically significant at 5 years (P = 0.5), the patients treated with NHT in addition to combined radiotherapy presented with significantly higher serum PSA concentrations (mean 21.0 ng/mL; median 17.0 ng/mL) than those treated with combination radiotherapy alone (mean 15.6 ng/mL; median 10.6 ng/mL) and thus had a worse prognosis.
Androgen deprivation therapy for prostate cancer chemoprevention: current status and future directions for agent development.
Prostate and Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA
Urology 2001 Aug;58(2 Suppl 1):83-90 Abstract quote
Prostate cancer chemoprevention is defined as the administration of natural and synthetic agents that inhibit >/=1 steps in the natural history of prostate carcinogenesis.
The goal is to find agents that modulate the progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and systemic disease. Another important goal for chemoprevention is the maintenance of an androgen-sensitive clinical state and delay of the emergence of androgen independence. There is a strong rationale for androgen deprivation therapy (ADT) as a chemoprevention strategy for prostate cancer based on evidence from epidemiologic, experimental, molecular pathophysiologic, and randomized, controlled clinical trials. This includes the fact that HGPIN, the most likely precursor of invasive cancer, is androgen dependent and responds to ADT. Although the large, phase-3 Prostate Cancer Prevention Trial (PCPT) of finasteride versus placebo has established the feasibility and role of ADT for primary prevention, nevertheless, limitations of the anticipated treatment-effect size (eg, 25% reduction) and the potential for selection of androgen resistance provide incentive for finding other effective chemopreventive agents. The availability of novel noncytotoxic pharmaceutical and natural products in clinical development create opportunities for improving the therapeutic index through the principles of combination therapy.
The emergence of new powerful tools, such as gene chip complementary DNA microarrays for multiplex gene expression profiling, will accelerate the identification of new molecular targets and the design of rational combinations. Several agent classes have a strong basis for combination with ADT, including antiproliferatives, antioxidant micronutrients (selenium), antiestrogens, and nonsteroidal anti-inflammatory drugs (selective cyclooxygenase-2 inhibitors).
A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy.
Lee WR, Hall MC, McQuellon RP, Case LD, McCullough DL.
Comprehensive Cancer Center of Wake Forest University School of Medicine, Winston-Salem, NC, USA
Int J Radiat Oncol Biol Phys 2001 Nov 1;51(3):614-23 Abstract quote
Purpose: To prospectively assess the health-related quality of life (HRQOL) and changes in HRQOL during the first year after 3 different treatments for clinically localized prostate cancer.
Methods and Materials: Ninety men with T1-T2 adenocarcinoma of the prostate were treated with curative intent between May 1998 and June 1999 and completed a quality-of-life Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire before treatment (T0) and 1 month (T1), 3 months (T3), and 12 months (T12) after treatment. Forty-four men were treated with permanent source interstitial brachytherapy (IB), 23 received external beam radiotherapy (EBRT), and 23 men were treated with radical prostatectomy (RP). The mean age of the entire study population was 65.9 years (median 67, range 42-79). The mean pretreatment prostate-specific antigen level of the entire study population was 6.81 ng/mL (median 6.25, range 1.33-19.6). The Gleason score was =6 in 65 (72%) of 90. The repeated measures analysis of variance and analysis of covariance were conducted on all quality-of-life and urinary outcome measures.
Results: A comparison of the demographic characteristics of the 3 treatment groups demonstrated significant differences. The men treated with RP were significantly younger than the men in either the IB or EBRT group (median age 61.0 RP, 67.1 IB, 68.8 EBRT; p = 0.0006). The men in the IB group were more likely to have a Gleason score of =6 than the EBRT group (Gleason score =6, 86% IB and 48% EBRT; p = 0.015). The mean score (standard deviation) at T0, T1, T3, and T12 for the FACT-P questionnaire for each group was as follows: IB 138.4 (17.0), 120.5 (21.7), 130.0 (18.4), and 138.5 (14.2); EBRT 137.1 (12.1), 129.5 (21.0), 134.4 (19.2), and 136.9 (15.6); and RP 138.3 (14.7), 117.7 (18.3), 134.4 (17.8), and 140.4 (14.9), respectively. Statistically significant differences over time were observed for the FACT-P in the IB and RP groups (p <0.0001), but not for the EBRT group (p = 0.08). The examination of the subscales within the FACT-P instrument demonstrated statistically significant changes over time in the IB and RP groups for the following: physical well-being, functional well-being, and prostate cancer symptoms. After adjusting for age, race, T stage, Gleason score, use of hormonal therapy, and baseline FACT-P scores, statistically significant differences in the FACT-P score at T1 according to treatment group were observed. At T12, the FACT-P scores were not significantly different than the baseline FACT-P scores for any group.
Conclusions: The results of this analysis suggest that significant decreases in HRQOL, as measured by the FACT-P instrument, are evident in the first month after IB or RP, but not after EBRT. One year after treatment, however, the FACT-P scores were not statistically different from the baseline measures for any group. For all treatment groups, most of the HRQOL decreases were observed in the physical, functional, and prostate cancer-specific domains. These results suggest that the HRQOL changes are likely to be treatment-specific, further emphasizing the importance of a randomized trial comparing the different treatment options in this population of men.
Prostate cancer chemoprevention: Strategies for designing efficient clinical trials.
National Cancer Institute, Rockville, Maryland 20852, USA.
Urology 2001 Apr;57(4 Suppl 1):224-9 Abstract quote
A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required (eg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions.
Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life.
Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3; family history of PCa; carriers of PCa susceptibility genes [ELAC2, CYP3A4, SRD5A2, etc.]; and histology such as atypia and HGPIN) that could be combined into a multivariate risk model for PCa. The probability of cancer risk (recurrence) is a key factor that impacts on the clinical trial design (power, sample size, and primary endpoint). Multivariate predictive mathematical models for biochemical recurrence after radical prostatectomy by decreasing sample size and time to clinical outcomes maximize trial efficiency and identify the patients most likely to benefit from secondary prevention.
The two large primary prevention trials, Prostate Cancer Prevention Trial/Seleninium and Vitamin E Chemoprevention Trial (PCPT/ SELECT), in low- and average-risk subjects have sample sizes of 18,000 to 32,000, with a treatment duration of 7 years to detect a 25% reduction in biopsy-proven PCa. Subjects with HGPIN have the highest known cancer risk (approximately 50% at 3 years), and thus require a small sample size (n = 450) to detect a 33% reduction in cancer incidence. A schema involving three sequential trials for agent registration is described. In summary, a CP strategy that incorporates well-defined agents, clinical and validated SE, and high-risk cohorts defined by genetic and acquired risk factors in a series of well-designed randomized controlled trials provides an efficient pathway for evaluating and approving new agents for PCa prevention.
External beam radiotherapy CA 2000;50:349-375
20-year outcome of patients with T1-3N0 surgically staged prostate cancer treated with external beam radiation therapy.
Gray CL, Powell CR, Riffenburgh RH, Johnstone PA.
Department of Urology, Naval Medical Center San Diego, San Diego, California, USA.
J Urol 2001 Jul;166(1):116-8 Abstract quote
PURPOSE: Patients with surgically staged localized prostate cancer treated with external beam radiation therapy were retrospectively analyzed for 15 and 20-year overall and cause specific survival. The need for additional therapy was also evaluated.
MATERIALS AND METHODS: We analyzed 145 patients who received external beam radiotherapy after negative staging pelvic lymphadenectomy. Followup data were available for 129 patients. Overall and cause specific survival was calculated with the Kaplan-Meier method.
RESULTS: Median followup was 14.9 years. Actuarial overall survival at 15 and 20 years was 45.9% and 24.6%, respectively. Cause specific survival at 15 and 20 years was 64.5% and 37.7% for having all patients dying of unknown causes censored, and 54.4% and 30.1% for those dying of unknown causes categorized as having prostate cancer, respectively. Of the patients who survived 47% were on hormonal therapy.
CONCLUSIONS: Longer followup after external beam radiation therapy continues to demonstrate a decrease in cause specific survival. Many patients ultimately require hormonal therapy.
Lymph node-positive prostate cancer: evaluation of the results of the combination of androgen deprivation therapy and radiation therapy.
Buskirk SJ, Pisansky TM, Atkinson EJ, Schild SE, O'Brien PC, Wolfe JT, Zincke H.
Department of Radiation Oncology, Mayo Clinic, Jacksonville, Fla 32082, USA
Mayo Clin Proc 2001 Jul;76(7):702-6 Abstract quote
OBJECTIVE: To evaluate the outcome of patients with pathologic stage IV prostate cancer treated with androgen ablation plus external-beam radiation therapy.
PATIENTS AND METHODS: Sixty consecutive patients treated between August 1986 and February 1995 with androgen ablation plus radiation therapy for stage IV (T1-4 N1 M0) adenocarcinoma of the prostate were selected for outcome analysis in this retrospective study. Bilateral pelvic lymphadenectomy was performed in 56 patients (93%). The 4 remaining patients had pelvic adenopathy on computed tomography, which was confirmed histologically in all patients. The median pretreatment prostate-specific antigen (PSA) level was 28.8 ng/mL (mean, 55 ng/ mL; range, 0.1-428 ng/mL). All patients received radiation therapy to the prostate, and 29 (48%) had pelvic node radiation. Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology criteria of 3 successive increases in the PSA level.
RESULTS: The median follow-up duration for surviving patients was 101.1 months (range, 20-134 months). Biochemical failure with (in 2 patients) or without (in 10 patients) clinically evident disease relapse was noted in 12 patients (20%). Four additional patients (7%) had clinical relapse without biochemical failure. Local recurrences were observed in 6 patients (10%), and this clinical impression was confirmed by biopsy in 4 patients. Thirteen patients (22%) died of causes related to prostate cancer. The biochemical relapse-free, clinical disease-free, overall, and cause-specific survival rates at 5 years were 82%, 84%, 76%, and 80%, respectively.
CONCLUSIONS: This observational case series of patients treated with the combination of external-beam radiation therapy and permanent androgen ablation for pathologic stage IV prostate cancer suggests that the addition of androgen deprivation therapy to radiation therapy may improve disease outcome. In the absence of randomized trial results, these observations may be beneficial in clinical decision making.
Brachytherapy CA 2000;50:380-393
Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial.
Martinez AA, Kestin LL, Stromberg JS, Gonzalez JA, Wallace M, Gustafson GS, Edmundson GK, Spencer W, Vicini FA.
Department ofRadiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Int J Radiat Oncol Biol Phys 2000 May 1;47(2):343-52 Abstract quote
PURPOSE: We analyzed our institution's experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach.
METHODS AND MATERIALS: From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) >/= 10.0 ng/ml, Gleason score >/= 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2-7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition.
RESULTS: The pretreatment PSA level was >/= 10.0 ng/ml in 51% of patients. The biopsy Gleason score was >/= 7 in 58% of cases, and 75% of cases were clinical stage T2b or higher. Despite the high frequency of these poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. On multivariate analysis, a higher pretreatment PSA level, higher Gleason score, higher PSA nadir level, and shorter time to nadir were associated with biochemical failure. In the entire population, 14 patients (10%) experienced clinical failure at a median interval of 1.7 years (range: 0.2-4.5 years) after completing RT. The 5-year actuarial clinical failure rate was 22%. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. For all patients, the 5-year disease-free survival, overall survival, and cause-specific survival rates were 89%, 95%, and 96%, respectively. The 5-year actuarial rate of RTOG Grade 3 late complications was 9% with no patient experiencing Grade 4 or 5 acute or late toxicity.
CONCLUSION: Pelvic EBRT in combination with image-guided conformal HDR brachytherapy boosts appears to be an effective treatment for patients with unfavorable prostate cancer with minimal associated morbidity. Our dose-escalating trial will continue.
Five-year biochemical outcome following permanent interstitial brachytherapy for clinical T1-T3 prostate cancer.
Merrick GS, Butler WM, Galbreath RW, Lief JH.
Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV 26003-6300, USA.
Int J Radiat Oncol Biol Phys 2001 Sep 1;51(1):41-8 Abstract quote
PURPOSE: To evaluate 5-year biochemical disease-free outcome for men with clinical T1b-T3a NxM0 1977 American Joint Committee on Cancer (1997 AJCC) adenocarcinoma of the prostate gland who underwent transperineal ultrasound-guided permanent prostate brachytherapy.
METHODS AND MATERIALS: Four hundred twenty-five patients underwent transperineal ultrasound-guided prostate brachytherapy using either 103Pd or 125I, for clinical T1b-T3a NxM0 (1997 AJCC) adenocarcinoma of the prostate gland, from April 1995 to October 1999. No patient underwent pathologic lymph-node staging. One hundred ninety patients were implanted with either 103Pd or 125I monotherapy; 235 patients received moderate-dose external beam radiation therapy (EBRT), followed by a prostate brachytherapy boost; 163 patients received neoadjuvant hormonal manipulation, in conjunction with either 103Pd or 125I monotherapy (77 patients) or in conjunction with moderate-dose EBRT and a prostate brachytherapy boost (86 patients). The median patient age was 68.0 years (range, 48.2-81.3 years). The median follow-up was 31 months (range, 11-69 months). Follow-up was calculated from the day of implantation. No patient was lost to follow-up. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology (ASTRO) consensus definition.
RESULTS: For the entire cohort, the 5-year actuarial biochemical no evidence of disease (bNED) survival rate was 94%. For patients with low-, intermediate-, and high-risk disease, the 5-year biochemical disease-free rates were 97.1%, 97.5%, and 84.4%, respectively. For hormone-naive patients, 95.7%, 96.4%, and 79.9% of patients with low-, intermediate-, and high-risk disease were free of biochemical failure. Clinical and treatment parameters predictive of biochemical outcome included: clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, risk group, age > 65 years, and neoadjuvant hormonal therapy. Isotope choice was not a statistically significant predictor of disease-free survival for any risk group. The median postimplant PSA was < or = 0.2 for all risk groups, regardless of hormonal status. The mean posttreatment PSA, however, was significantly lower for men implanted with 103Pd (0.14 ng/mL) than for those implanted with 125I (0.25 ng/mL), p < or = 0.001.
CONCLUSION: With a median follow-up of 31 months, permanent prostate brachytherapy results in a high probability of actuarial 5-year biochemical disease-free survival (DFS) for patients with clinical T1b-T3a (1997 AJCC) adenocarcinoma of the prostate gland, with an apparent plateau on the PSA survival curve.
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