Early Diagnosis and Staging of Prostate Cancer

Early Diagnosis and Staging of Prostate Cancer

10TH INTERNATIONAL PROSTATE CANCER UPDATE Early Diagnosis and Staging of Prostate Cancer Joseph C. Presti, Jr, MD,* Fritz H. Schröeder, MD,† Peter S. Albert, MD, FACS,‡ John Lynch, MD§ *Stanford University School of Medicine, Stanford, Calif; †Erasmus University, Rotterdam, the Netherlands; ‡Staten Island University Hospital, Staten Island, NY; §Georgetown University School of Medicine, Washington, DC Prostate cancer screening remains controversial. Randomized trials are ongoing, and some early data may suggest a benefit for screening. Refinement in detection strategies has recently demonstrated that 6 systematic biopsies are not adequate. Eight to 10 biopsies improve cancer detection rates by up to 20%. Systematic biopsies can provide additional information with respect to local stage and risk stratification. Newer approaches with extraperitoneal endoscopic lymph node dissection are being studied in patients considered to be at high risk for nodal involvement. Key words: Pelvic lymphadenectomy • Prostate cancer • Screening • Systematic prostate biopsy T he utility of screening and early detection of prostate cancer is debatable, because these processes may identify insignificant tumors better left untreated. Researchers therefore are focusing on the search for ways to pinpoint more accurately the stage and grade of the tumor before surgery. Screening The possible net benefit and risk associated with prostate cancer screening remain controversial. There is some evidence, however, that screening may be beneficial. Prostate cancer mortality is declining in the United States. This decline started around 1994, approximately 5 to 7 years after screening became popular as a result of the introduction of the prostate-specific antigen (PSA) test. The decline in mortality has been greatest in areas of the United States and Europe in which there has been intense screening (ie, Seattle and Innsbruck, Austria). Recently, results of a randomized screening study from Quebec that involved more than 46,000 men (randomized 2:1, screened vs control) have been reported.1 A 69% reduction in prostate cancer mortality was reported in the screened arm. The analysis was not done in an intent-to-treat fashion, however. Contamination in both arms was high, as only 23% of men randomized to the screened arm were actually screened, and 7% in the control (unscreened) arm were actually screened. If the analysis is done in an intent-to-treat fashion, the reduction in mortality is only 6% in the screened arm. The ideal way to determine the value of prostate cancer screening is through the completion of randomized trials. Two large-scale, randomized screening trials are currently ongoing, 1 in the United States (Prostate, Lung, Colorectal, and Ovarian Supplement REVIEWS IN UROLOGY 19 Diagnosis and Staging continued Cancer Screening Trial, with 74,000 men randomized) and 1 in Europe. The European Randomized Study of Screening for Prostate Cancer involves 7 countries in Europe. This study is designed to document or refute a difference in survival between screened and unscreened men in a randomized cohort of 190,000 between the ages of 55 and 74 years. Following the initial screen of digital rectal examination (DRE) and determination of PSA level, patients are rescreened at 4-year intervals. This study has a 90% power (allowing for 10% contamination, ie, patients randomized to the nonscreened arm who are screened outside of the study) to achieve its goal. An interim report of intermediate end points of this European randomized study was recently presented.2 Data from more than 33,000 patients were available. The number of cancers detected in the screened and control arms were 706 and 131, respectively. Of the cancers detected, higher grade, locally advanced (T3-T4), and metastatic cancers were more likely in the control arm than in the screened arm (21% vs 9%; 30% vs 22%; and 8% vs 0.6%, respectively). Contamination resulting from use of PSA outside of the study was higher in the control arm than in the screened arm (7.7% vs 3.3%). Needle Biopsy and Early Detection Systematic sextant biopsy of the prostate under transrectal ultrasonographic (TRUS) guidance was introduced a little more than 10 years ago and has revolutionized our ability to detect carcinoma of the prostate. Recently, several investigators have questioned whether additional biopsies are warranted. It seems naive to assume that 6 biopsies of the prostate are sufficient for all prostate sizes and configurations. While this may be adequate sampling in some prostates, it may be inadequate in larger prostates. Several investigators have demonstrated that prostate cancer detection rates are in- 20 REVIEWS IN UROLOGY Supplement versely proportional to prostate size. In general, studies of alternative biopsy schemes have used 1 of 2 approaches: (1) computer modeling of biopsy schemes or (2) prospective evaluations of different biopsy schemes on referral-based populations. Computer modeling. Several investigators have used computer simulations and modeling to refine systematic biopsy schemes for evaluation of the prostate. One approach uses step-sectioned radical prostatectomy specimens. Data are obtained from wellmapped specimens, including total prostate volume measurements as well as total tumor volume measurements. Computer-generated prostate models with varying tumor sizes are then created, and systematic sampling is simulated. Different biopsy schemes can be tested to determine their efficiency for cancer detection. Limitations of such simulated models include the fact that tumors must typically be simulated as spheres within the prostate and the differential zonal incidence of carcinoma is often neglected. Other considerations include assumptions that the full 15-mm needle core will be obtained, the angle of needle entry into the prostate will be a constant 30 degrees, and prostate shape in vivo and in vitro is identical. In addition, since most data for these models are derived from radical prostatectomy specimens, the means of cancer detection that resulted in the patient undergoing surgery must be acknowledged. If sextant sampling detected the cancers in a given radical prostatectomy series used to construct a computer model, then the applicability of those models in studying novel biopsy regimens employing sites outside the traditional sextant regions is unknown. A computer model study from the Walter Reed Army Medical Center has demonstrated that 6 systematic biopsies may detect only 75% of cancers, while 10 systematic biopsies may detect 95% of cancers.3 Prospective evaluation of biopsy schemes. Several investigators have prospectively evaluated alternative systematic biopsy regimens in referralbased populations. One group of researchers studied a 5-region technique of systematic biopsy in a series of 119 patients.4 The 5 regions included the standard sextant biopsy regimen obtained halfway between the lateral border and midline of the prostate on both right and left sides (regions 2 and 4) as well as 2 biopsies from each lateral aspect of the prostate (regions 1 and 5) and 3 biopsies from the midline at the apex, midgland, and base. Biopsy showed evidence of cancer in 48 (40%) of the 119 patients. Of these, 17 (35%) were detected only in regions 1, 3, and 5. Of note, only 2 cancers were detected solely by the 3 centrally placed biopsies of region 3. With respect to complications, these investigators reported an 80% incidence of gross hematuria. The researchers attributed this complication to the region 3 biopsies, which probably penetrated the urethra. Another group of researchers prospectively evaluated an 8- or 10-biopsy regimen, depending on gland size, in 512 patients.5 In this protocol, all patients underwent 8 biopsies of the peripheral zone, 4 in each lobe, at the apex, midgland, base, and lateral midgland. When prostate length exceeded 4 cm, 2 additional biopsies were performed in the transition zone. Overall cancer detection rates increased from 85% with the standard sextant biopsy regimen to 97% with the extended biopsy regimen. If lesion-directed biopsies had been added to the standard sextant biopsy regimen, then cancer detection rates would have increased to 93%. The New York University group has investigated the utility of performing 2 consecutive sets of sextant biopsies of the prostate in a single office visit in 137 consecutive patients in a referralbased population.6 A total of 43 cancers were detected in the entire study population (31% cancer detection rate). If the first sextant biopsy set is considered the reference set, 30 cancers were Diagnosis and Staging detected (70% of all cancers), so the second biopsy set increased the detection rate by 30%. If the second biopsy set is used as the reference, 40 cancers were detected (93% of all cancers), so the first biopsy set increased the detection rate by only 7%. The benefit of this approach needs further study with a larger patient cohort, since sextant sampling, presumably from similar locations, resulted in widely varying detection rates (70% vs 93%). These studies prompted us prospectively to evaluate the utility of adding 4 lateral biopsies of the peripheral zone to the routine sextant biopsy regimen. We performed TRUS and systematic biopsies, along with lesion-directed biopsies, in 273 consecutive patients referred because results from a DRE were abnormal and/or PSA level was greater than 4 ng/mL.7 Sextant biopsies were obtained in the midlobar sagittal plane, halfway between the lateral edge and midline of the prostate gland, at the base, midgland, and apex. The lateral peripheral zone biopsies were performed by positioning of the probe just medial to the lateral edge of the prostate. Standard sextant biopsies detected 82% of the cancers in the series, while the addition of 4 lateral biopsies increased cancer detection rates to 96%. Recently, a California group began investigating the utility of each of the specific biopsy sites in a 10-biopsy scheme of the peripheral zone.8 They found evidence of cancer by biopsy in 202 (42%) of the 483 patients referred because results from a DRE were abnormal and/or the PSA level was greater than 4 ng/mL. In the entire population, traditional sextant biopsies missed 20% of the cancers (41 of 202). Evaluation of the 10-biopsy scheme of the peripheral zone showed the midlobar base to be the least efficient location for the systematic biopsies. Eliminating these mid-lobar base biopsies from the systematic 10-biopsy regimen, and thus converting it to an 8biopsy regimen, would have decreased the detection rate of this regimen by only 1%. Needle Biopsy and Tumor Volume Careful step-sectioned histopathologic analyses of radical prostatectomy specimens have demonstrated a direct correlation between measured tumor volume and probability of extracapsular extension, seminal vesicle invasion, and lymph node metastases.9,10 Extracapsular extension is rare in tumors less than 4 cc and is almost uniformly present in tumors larger than 12 cc. Some investigators have demonstrated that the length of core involved with cancer correlates with tumor volume. This correlation appears to be highest for large cancers. A large degree of involvement of the core biopsies with cancer is strongly suggestive of high-stage disease.11,12 A threshold of 3 mm of core length involvement on 1 core biopsy reliably predicts cancer volumes of 0.5 cc or larger.13 The converse is not always true; focal cancer on the needle biopsy is not always associated with an insignificant cancer volume at radical prostatectomy.14 A recent study has suggested that the performance of additional systematic biopsies may more accurately assess tumor volume. A scheme utilizing 10 biopsies (conventional sextant biopsies in the peripheral zone bilaterally from the apex, mid, and base of the gland, plus bilateral biopsies of the transition zone and laterally directed biopsies of the peripheral zone in the midgland) more accurately predicted tumor volume than sextant biopsies alone (correlation coefficients of 0.56 and 0.39, respectively).15 Needle Biopsy and Local Staging and Risk Assessment The number of biopsies with positive results has been suggested by several investigators to correlate with extracapsular extension at radical prostatectomy. This type of information might, in fact, differ from the quantitation of core length involvement, because it represents a “mapping” of the prostate. This regional sampling of the prostate may give an idea of tumor volume and thus may contribute to the more accurate prediction of extracapsular extension or risk of treatment failure. In 1 series, 100 patients with radical prostatectomies were analyzed, and several preoperative clinical parameters were studied in their ability to predict extracapsular extension and recurrence.16 Several parameters correlated with extracapsular extension: a palpable nodule greater than half of 1 lobe, a PSA level greater than 25 ng/mL, a PSA density greater than 0.6, perineural invasion evident on the needle core, and positive results from more than 66% of the core biopsies obtained. The same parameters also correlated with serologic recurrence. In addition, positive results from bilateral biopsies and a Gleason score of 7 or more on the biopsy were also predictive of recurrence. Peller and associates17 analyzed 102 radical prostatectomy specimens and evaluated the role of systematic sextant biopsies in predicting extracapsular extension. The risk of extracapsular extension was lower in patients with positive results on 3 or fewer biopsies than in those with positive results on 4 or more biopsies (20% vs 76%). The risk of extracapsular extension was much higher in patients with positive results on 4 or more sextant biopsies and a Gleason score of 7 or higher than in those with positive results on fewer biopsies and lower-grade tumors (greater than 80% vs less than 40%, respectively). Huland and coworkers18 demonstrated that the number of sextant biopsies with positive results and the Gleason score correlated with extracapsular extension (P < .0001 and P = .0004, respectively) based on data from 257 consecutive radical prostatectomy patients with and without extracapsular extension. Patients with positive results on fewer than 3 biopsies and a Gleason score of less than 7 were at low risk for serologic recurrence, irrespective of preoperative PSA levels (14% risk with a mean follow-up of 2 years). Analysis of data from another series of 480 patients demonstrated that the probability of having organ-confined Supplement REVIEWS IN UROLOGY 21 Diagnosis and Staging continued prostate cancer at radical prostatectomy decreased with the increasing percentage of sextant biopsies with positive results.19 In patients with positive results from less than 33%, 33% to 50%, and 50% or greater of the sextant biopsies, the probability of organconfined disease was 84%, 62%, and 38%, respectively. Disease-free survival at 2 years was more than 80% in patients with positive results from less than 50% of systematic biopsies. Borirakchanyavat and associates20 recently reported data on 104 patients who had undergone systematic sextant biopsy before radical prostatectomy. They performed a side-for-side analysis and demonstrated that the risk of extracapsular extension was 8% and 14% on sides yielding positive results on no or 1 positive biopsy, while it was 37% and 43% on sides yielding positive results on 2 or 3 biopsies, respectively. More recently, Presti and colleagues21 reported on a different patient population consisting of 109 patients who had undergone systematic sextant biopsy before radical prostatectomy. No patients in this series received neoadjuvant or adjuvant therapy. The investigators correlated preoperative clinical parameters with risk of serologic recurrence. They demonstrated that patients who had positive results from 4 or more sextant biopsies were at a significantly higher risk for failure following radical prostatectomy than patients with positive results from 3 or fewer biopsies (relative risk = 2.4). In a multivariate Cox regression model, systematic biopsy results and tumor grade were the most powerful predictors of serologic relapse (relative risk = 2.3 and 1.9, respectively). Extraperitoneal Endoscopic Pelvic Lymph Node Dissection Patients with high-grade cancers (a Gleason score of 7 or higher), high PSA levels (greater than 20 ng/mL), or high-stage disease (T3 or higher) are suitable candidates for pelvic lymphadenectomy. Recently, interest in endoscopic extraperitoneal lymphadenecto- 22 REVIEWS IN UROLOGY Supplement my has grown. Advantages of this approach over conventional laparoscopic surgery relate to the avoidance of intra-abdominal complications. In this technique, a small, low midline incision is made below the umbilicus. A small fascial incision is made, and blunt technique used to develop the retroperitoneal space. A visual balloon dilator is then placed in this space and, under direct vision with the use of a 0degree lens, the balloon is inflated. The balloon is removed, a Hassan trocar is introduced, and carbon dioxide insufflation performed. A 10-mm trocar is placed in the midline 2 fingerwidths above the umbilicus. Two 5-mm ports are placed lateral to the epigastric vessels in line with the midline port and the anterior superior iliac spine. Lymphadenectomy is then performed. Albert and associates22 have reported on their experience with 200 patients undergoing this procedure. The mean operative time was 60 minutes (range, 25 to 198) and the mean nodal yield was 10.2 (range 2 to 23). Conversion to open lymphadenectomy was done in 6 patients (3%). Symptomatic lymphoceles occurred in 6 patients (3%). Operative mortality occurred in 2 patients (massive pulmonary embolus and myocardial infarction). Length of stay was typically less than 24 hours. Studies are needed to compare this technique with minilaparotomy pelvic lymphadenectomy with respect to costs, morbidity, and loss of patient work days.23 ■ 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. References 1. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate. 1999;38:83-91. 2. Schroeder FH. Optimal use of screening for prostate cancer. Paper presented at: Tenth International Prostate Cancer Update; February 2-6, 2000; Vail, Colorado. 3. Bauer JJ, Zeng J, Weir J, et al. Three-dimensional computer-simulated prostate models: lateral prostate biopsies increase the detection rate of prostate cancer. Urology. 1999;53:961-967. 4. Eskew LA, Bare RL, McCullough DL. Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol. 1997;157:199-203. 5. Norberg M, Egevad L, Holmberg L, et al. The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology. 1997;50:562-566. 6. Levine MA, Ittman M, Melamed J, Lepor H. Two 20. 21. 22. 23. consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol. 1998;159:471-476. Chang JJ, Shinohara K, Bhargava V, Presti JC Jr. Prospective evaluation of lateral biopsies of the peripheral zone for prostate cancer detection. J Urol. 1998;160:2111-2114. Presti JC Jr, Chang JJ, Bhargava V, Shinohara K. The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J Urol. 2000;163:163166. McNeal JE, Villers AA, Redwine EA, et al. Histologic differentiation, cancer volume, and pelvic lymph node metastasis in adenocarcinoma of the prostate. Cancer. 1990;66:1225-1233. McNeal JE. 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