Early Diagnosis and Staging of Prostate Cancer

13TH INTERNATIONAL PROSTATE CANCER UPDATE Early Diagnosis and Staging of Prostate Cancer Michael K. Brawer, MD Northwest Prostate Institute, Seattle, WA Additional Contributors Georg Bartsch, MD, Anthony V. D’Amico, MD, PhD, Robert E. Donohue, MD, Oottamasathien Siam, MD, Ashutosh Tewari, MD The need for accurate methods of ascertaining the malignant potential of any given man’s prostate cancer has never been greater than it is today. The presenters at the session of the 13th International Prostate Cancer Update addressing early diagnosis and staging of disease discussed combined-modality staging of disease; color Doppler imaging for detection of cancer; pelvic lymphadenectomy as a diagnostic tool; and a new, artificial intelligence–based model to predict survival. A summary of these presentations is provided here. [Rev Urol. 2003;5(suppl 6):S17-S22] © 2003 MedReviews, LLC Key words: Prostate cancer • Diagnosis • Staging • Survival • Color Doppler imaging • Lymphadenectomy ccurate staging of prostatic carcinoma on an individual patient basis remains problematic. Staging is important, not only for identification of the extent and location of the malignancy but also, perhaps more importantly, for determination of malignant potential. We have seen a significant migration in the clinical presentation of prostatic carcinoma, largely related to improved biopsy methods and, especially, to prostate-specific antigen (PSA) testing. Today, a much greater percentage of patients present with more favorable malignancies. Indeed, a number of these might have cancers of low malignant potential—low A VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S17 Early Diagnosis and Staging continued enough that competing causes of mortality might be a more important consideration. Thus, the need for accurate methods of ascertaining the malignant potential of any given man’s cancer has never been greater than it is today. Table 1 Prostate Cancer Risk Stratification Categories Low risk 80% 10-year PSA failure-free survival 1992 AJCC clinical stage T1c, T2a and PSA concentration ≤ 10 ng/mL and biopsy Gleason score ≤ 6 Intermediate risk 50% 10-year PSA failure-free survival 1992 AJCC clinical stage T2b or PSA concentration > 10 and ≤ 20 ng/mL or biopsy Gleason score 7 High risk 33% 10-year PSA failure-free survival 1992 AJCC clinical stage T2c disease or PSA concentration > 20 ng/mL or biopsy Gleason score ≥ 8 Combined-Modality Staging Anthony V. D’Amico, MD, PhD, of Brigham and Women’s Hospital, provided an excellent overview of combined-modality staging and outcome prediction after therapy. He began his discussion with the observation that by identifying high-risk patients (those with a high likelihood of failure after local therapy), one can more readily evaluate marginal increases in therapeutic outcomes and novel approaches to therapy. Dr. D’Amico’s goal was to identify a method that would use readily available clinical parameters to classify 90% of all patients with clinically localized prostate cancer into groups at either low or high risk for biochemical progression. This “combined modality staging" attempted to identify men destined to fail after radical prostatectomy or external beam radi- PSA, prostate-specific antigen; AJCC, American Joint Committee on Cancer. marily transition zone or T1a, b cancer are excluded. Dr. D’Amico then evaluated whether percentage of positive biopsies (defined as the number of positive prostate biopsies times 100 divided by the number of biopsies obtained) could add to these three parameters. This possibility has been suggested by a number of investigators.15,16 He emphasized the report by Presti and colleagues,17 which demonstrated increased prediction of biochemical failure based on whether 50% or less or more than 50% of biopsies were Eighty percent of the men in the intermediate-risk group could be reclassified by use of the positive biopsy information into either a low- or a high-risk cohort. ation therapy, with biochemical failure (according to PSA level) used as the endpoint. Dr. D’Amico accepted risk stratification categories based on serum PSA levels, Gleason score, and T stage (Table 1).1–14 It should be noted that the 1992 American Joint Committee on Cancer (AJCC) clinical staging was used in this report, because it has been shown to be more predictive than the modification based on the 1997 AJCC definition. Men with pri- S18 VOL. 5 SUPPL. 6 2003 positive for malignancy at the time of diagnosis. Dr. D’Amico went on to examine his own cohort of men treated with external beam radiation therapy and added the percentage of positive biopsies. This was defined based on sextant biopsies and stratified as 1 to 2 positive biopsies (<34%), 3 positive biopsies (34%–50%), or 4 to 6 positive biopsies (>50%). He demonstrated that 80% of the men in the intermediate-risk group, as defined in Table 1, REVIEWS IN UROLOGY could be reclassified by use of the positive biopsy information into either a low- or a high-risk cohort. Dr. D’Amico and colleagues carried out a second validation study in a different cohort of men undergoing either radical prostatectomy or external beam radiation therapy. With use of the percent biopsy information, 78% and 76% of patients treated with radical prostatectomy or radiation therapy, respectively, who fell into the intermediate-risk group were able to be reclassified into high- or low-risk populations. For the combination of series, the investigators demonstrated that only 10% of all patients would be left in the intermediate-risk group. An important caveat remains, namely that biopsy approaches are changing. Given that the majority of urologists today perform more than six biopsies, these observations need to be examined when more biopsy samples are obtained, to ensure that the useful risk assessment stratification observed are applicable in the modern era. Dr. D’Amico emphasized that biochemical progression is not equivalent to cancer-specific mortality, and longer follow-up is necessary given the long interval between detectable PSA after definitive therapy and the Early Diagnosis and Staging development of metastases or subsequent death.18,19 Contrast-Enhanced Color Doppler Imaging for Cancer Detection It has been well established that angiogenesis and resulting neovascularity is an essential requirement of tumor growth. This phenomenon has been well studied in the prostate.20–22 Georg Bartsch, MD, and associates from the University of Innsbruck have extended these observations and have examined the efficacy of contrast-enhanced color Doppler ultrasound imaging, as compared with standard gray-scale imaging, for the detection of prostate cancer. In his presentation, Dr. Bartsch reviewed reports on the role of color Doppler in prostate imaging23 and demonstrated that in these reports the use of Doppler could significantly improve prostate cancer detection. He went on to review his group’s experience in correlating quantitative microvessel density with contrast-enhanced color pixel density. Twenty-five men with prostate cancer demonstrated a high degree of correlation (P < .001), with a specificity of 95.2% and a positive predictive value of 89% for detection of prostate cancer. Dr. Bartsch presented his group’s experience with 922 men undergoing ultrasound-guided biopsy in their large Tyrollean prostate cancer screening program. Independent investigators compared contrast-enhanced color Doppler ultrasound used with intravenous ultrasound contrast media with standard gray-scale ultrasound. Five targeted biopsies were performed with sampling of hypervascular areas. These were contrasted with 10 systematic sector biopsies performed with standard gray-scale ultrasound. Thirty-one percent of the men had cancer; 25% were detected by targeted biopsy and 22% by the systematic biopsy. Eighty-three subjects had can- cer detected by the targeted biopsy alone, compared with 54 who had cancer found with systematic biopsy. The latter group included 27 transition-zone cancers. Excluding transition-zone cancer, the targeted biopsy showed a statistically significant increase in cancer detection (P < .01). Dr. Bartsch concluded that color Doppler imaging with intravenous contrast enhancement and targeted his personal experience this is of little significance. Among 362 patients undergoing pelvic lymphadenectomy with frozen sections, 6 of 323 had negative frozen sections but cancer found in the permanent section. Intriguingly, one man among the 30 who had a positive frozen section was shown not to have carcinoma on the permanent slides. Based on these data indicating a lower incidence of carcinoma in the Eighty-three subjects had cancer detected by targeted biopsy alone, compared with 54 who had cancer found with systematic biopsy. biopsy results in significant enhancement in identifying cancer. Optimal cancer detection, however, requires targeted and standard systematic techniques. Given the obvious increased cost of contrast-enhanced color Doppler imaging, larger studies in different populations will be needed before this can be recommended for widespread use. Pelvic Lymphadenectomy as a Diagnostic Tool Robert Donohue, MD, of University of Colorado, reviewed the role of pelvic lymphadenectomy in men with prostatic carcinoma. He began his discussion with a quote from H.C. Bumpus from nearly a century ago: “If the iliac glands could be examined satisfactorily, their early involvement would undoubtedly be proved." Dr. Donohue went on to provide an overview of the relevant anatomy and the modifications of pelvic lymphadenectomy for detection of prostatic carcinoma. He described the staggering difference in the rate of positive lymph nodes between the pre-PSA era and modern times. Addressing the issue of frozen sections giving false-negative test results, Dr. Donohue stated that in modern era and reasonable expectations of correct evaluation of frozen sections, Dr. Donohue has refined his indication for pelvic lymphadenectomy to those men with a PSA level greater than 15.0 ng/mL, clinical T2b or greater clinical stage, and Gleason pattern 4 and 5 or Gleason score 7 or any Gleason grade 4 or 5 as a “third pattern" on the biopsy. Dr. Donohue reviewed complications of pelvic lymphadenectomy, summarizing that node “plucking" has minimal complications, whereas standard node dissection according to the classic method results in significant incidence of deep vein thrombosis, pulmonary embolism, lymphocele, and pelvic structure injury. Dr. Donohue reviewed the use of sophisticated molecular techniques, such as reverse transcriptase polymerase chain reaction with primers of prostate-specific membrane antigen and PSA, to detect micrometastases in lymph nodes. Although these techniques provide interesting exercises in the potential of so-called “molecular staging," their clinical utility remains doubtful. Donohue noted that so-called “sentinel node biopsy" with a specific lymph node would provide the high- VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S19 Early Diagnosis and Staging continued Table 2 Estimated Mean Probability of Death in 10 Years in White Male Patients with Clinically Localized Prostate Cancer (T1-T2) Comorbidity Charlson 0–1 ≤60 y Age Grade Charlson >1 61–70 y ≤60 y >70 y 61–70 y >70 y 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 2 4 8 3 7 13 3 7 13 3 6 11 5 9 17 5 9 17 12 14 15 33 36 40 33 36 40 52 56 61 71 75 80 Watchful waiting PSA 0.0–9.9 ng/mL PSA 10–20 ng/mL PSA >20 ng/mL 21 24 26 4 8 15 7 13 25 7 13 24 6 11 21 10 18 32 9 18 21 23 31 35 38 47 51 56 47 51 56 69 73 78 86 17 89 92 31 10 19 35 17 30 51 16 29 50 14 26 45 22 39 63 22 38 62 17 19 22 29 33 36 44 49 53 44 49 53 66 71 75 84 87 90 3 7 2 53 57 Radiation therapy PSA 0.0–9.9 ng/mL PSA 10–20 ng/mL PSA >20 ng/mL 1 1 3 12 14 16 1 2 5 22 24 27 3 5 9 1 2 5 1 2 4 34 37 41 34 37 41 9 2 4 8 48 52 57 48 52 57 5 3 6 62 72 76 80 7 13 3 7 12 70 74 79 87 90 92 19 9 16 29 8 16 29 54 67 72 76 85 88 91 3 6 1 3 5 28 31 34 42 46 51 6 11 2 3 6 19 21 24 4 7 14 6 12 22 6 12 22 5 10 18 20 22 30 33 37 45 50 54 45 50 4 1 2 3 16 18 20 16 18 20 32 35 39 2 2 3 Radical prostatectomy PSA 0.0–9.9 ng/mL PSA 10–20 ng/mL PSA >20 ng/mL 1 1 2 1 6 6 7 10 2 2 4 11 13 4 8 1 2 2 4 1 1 3 5 8 2 3 7 6 11 3 9 10 11 15 17 19 24 27 30 24 27 30 40 44 3 49 58 63 67 3 6 12 5 10 19 5 10 19 4 9 16 7 14 26 7 13 25 8 9 10 14 16 18 23 26 29 23 26 29 38 42 46 55 60 65 Light blue rows indicate percent probability of death due to prostate cancer; dark blue rows indicate percent probability of death due to other causes. est yield for sampling if one could determine the primary drainage site from the prostate. Scintigraphy with injection of markers in the prostate can help determine which lymph node is most likely to be the drain site for malignancy. Sentinel node biopsy has been used successfully in breast cancer, colon cancer, and melanoma. Its value in prostate cancer must still be determined, because experience with it to date is minimal. Also, the sentinel node must first be S20 VOL. 5 SUPPL. 6 2003 identified. Up to 8% of patients do not have a sentinel node! Accurate information as to the technique of injection, site or sites of injection, transition zone versus peripheral zone, bilateral injections, and most importantly, the timing of the injection relative to the start of the surgical procedure of node dissection must be determined. The urologist might then be able to enter the era of surgical molecular oncology. REVIEWS IN UROLOGY A Model for the Prediction of Survival Ashutosh Tewari, MD, of the Josephine Ford Cancer Center, described a model to predict survival in patients with clinically localized prostate cancer.24 He began his presentation with the observation that although the goal for treatment of clinically localized prostate cancer is to preserve longevity, clinicians are handicapped by the difficulty of estimating survival in an individual Early Diagnosis and Staging Table 3 Estimated Mean Probability of Death in 10 Years in African American Male Patients with Clinically Localized Prostate Cancer (T1-T2) Comorbidity Charlson 0–1 ≤60 y Age Grade Charlson >1 61–70 y ≤60 y >70 y 61–70 y >70 y 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 2 4 7 3 6 11 3 6 11 2 5 9 4 8 15 4 8 15 10 11 12 27 30 33 44 48 52 62 4 Watchful waiting PSA 0.0–9.9 ng/mL PSA 10–20 ng/mL PSA >20 ng/mL 17 19 21 27 30 33 6 11 21 71 7 13 6 12 21 10 18 8 16 28 8 15 28 15 17 19 26 28 32 39 43 47 39 43 47 60 65 69 79 83 86 9 17 31 15 27 46 14 26 45 12 23 40 20 35 57 19 34 56 14 16 17 24 27 30 37 37 41 45 57 62 67 76 80 84 4 1 2 3 1 31 34 28 31 34 45 2 4 7 3 6 11 3 40 44 48 61 66 70 79 83 87 41 45 5 67 Radiation therapy PSA 0.0–9.9 ng/mL PSA 10–20 ng/mL PSA >20 ng/mL 1 1 2 10 11 13 1 3 5 15 17 19 3 1 4 1 17 20 22 28 2 2 4 8 26 29 32 6 12 5 10 19 14 16 18 25 27 30 2 2 4 8 40 44 48 5 10 19 38 42 46 4 3 6 1 49 53 63 3 5 68 72 6 11 9 16 7 14 26 7 14 25 38 42 46 58 63 68 77 81 85 1 3 1 13 15 16 23 Radical prostatectomy PSA 0.0–9.9 ng/mL PSA 10–20 ng/mL PSA >20 ng/mL 1 1 2 1 2 3 4 5 6 8 9 10 1 2 4 2 4 7 8 9 3 5 10 6 7 8 7 12 14 16 5 1 2 3 13 15 16 2 3 7 20 22 25 1 2 2 5 1 25 28 35 2 5 39 43 3 6 3 5 10 2 20 22 25 33 37 41 50 54 59 5 9 9 17 4 9 16 4 7 14 6 12 22 6 12 22 11 13 15 19 21 23 19 21 23 31 35 39 47 51 56 Light blue rows indicate percent probability of death due to prostate cancer; dark blue rows indicate percent probability of death due to other causes. patient. This, of course, is largely related to the fact that the natural history of prostate cancer is highly variable among individuals; furthermore, age and comorbidity are often significant competing causes of mortality. Dr. Tewari reviewed the predictive modeling approaches that have been derived from artificial intelligence theories. Dr. Tewari conducted an investigation to calculate the ability of race, age, comorbidity, PSA level, stage, and grade to predict 10-year survival in patients with prostate cancer. He derived his database from a registry of 3074 screening patients, excluding those who died from other causes, those with metastatic cancer, or those lost to follow-up. He developed his propensity score by modeling data from 1611 patients, using the variables of age, race, treatment received, biopsy grade, year of treatment, clinical stage, comorbidity index, socioeconomic status, serum PSA level, and overall cancer-specific survival. He contrasted the prostate cancer database with data from 10,000 control subjects who did not have prostate cancer. The Charlson index was used for evaluating comorbidity. To minimize the bias of retrospective cohort studies, the propensity score modeling system was used. This is an analytic technique that calculates conditional probabilities of receiving a treatment based on measured comorbidity and VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S21 Early Diagnosis and Staging continued reduces the selection bias. Using an analysis of maximum likelihood estimates following propensity risk adjustment, statistically significant stratification based on hazard ratio was seen with the parameters of comorbidity and whether treatment with either radical prostatectomy or radiation therapy was shown. Comorbidity provided a 2.1-fold increased hazard ratio of death, and radical prostatectomy and radiation therapy reduced the hazard ratio by 0.31 and 0.56 times, respectively. Interestingly, stage, grade, and PSA level did not meaningfully stratify patients with respect to hazard ratio for dying of prostate cancer. Using this model, Dr. Tewari has created simple look-up tables (Tables 2 and 3). This excellent study, with further validation in distinct populations, is extremely encouraging and might provide useful information for counseling patients. 3. 4. 5. 6. 7. 8. 9. 10. References 1. 2. Kupelian PA, Katcher J, Levin HS, Klein EA. Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys. 1997;137:1043–1052. D’Amico AV, Whittington R, Kaplan I, et al. Equivalent biochemical failure free survival after external beam radiation therapy or radical prostatectomy in patients with pretreatment prostate-specific antigen of >4-20 ng/mL. Int J Radiat Oncol Biol Phys. 1997;79:1053–1058. 11. 12. 13. Zagars GK, Pollack A, Kavadi VS, von Escherbach AC. Prostate specific antigen and radiation therapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 1995;32:293–306. Pisansky TM, Cha SS, Earle JD. Prostate-specific antigen as a pretherapy prognostic factor in patients treated with radiation therapy for clinically localized prostate cancer. J Clin Oncol. 1993;11:2158–2166. Zietman AL, Coen JJ, Shipley WV, et al. Radical radiation therapy in the management of prostatic adenocarcinoma: the initial PSA value as a predictor of treatment outcome. J Urol. 1994;151:640–645. Hanks GE, Lee WR, Schultheiss TE. Clinical and biochemical evidence of control of prostate cancer at 5 years after external beam radiation. J Urol. 1995;154:456–459. Partin A, Piantadosi S, Sanda M, et al. Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy. Urology. 1995;45:831–838. Lerner SE, Blute ML, Bergstralh EJ, et al. Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy. J Urol. 1996;156:137–143. Zietman AL, Edelstein RA, Coen JJ, et al. Radical prostatectomy for adenocarcinoma of the prostate: the influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology. 1994;43:828–833. D’Amico AV, Whittington R, Malkowicz SB, et al. PSA failure despite pathologically organ confined and margin negative disease: the basis for an adjuvant therapy trial. J Clin Oncol. 1997;15:1465–1469. D’Amico AV, Whittington R, Schultz D. Outcome based staging for clinically localized adenocarcinoma of the prostate. J Urol. 1997;158:1422–1426. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer. 1997;80:442–453. Blasko JC, Wallner K, Grimm PD, Ragde H. Prostate-specific antigen based disease control 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. following ultrasound guided iodine implantation for stage T1/T2 prostatic carcinoma. J Urol. 1995;154:1096–1099. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol. 1996;14:449–453. Borirakchanyavat S, Bhargava V, Shinohara K, et al. Systematic sextant biopsies in the prediction of extracapsular extension at radical prostatectomy. Urology. 1997;50:373–378. Narayan P, Gajendran V, Taylor SP, et al. The role of transrectal ultrasound-guided biopsy based staging, preoperative prostate-specific antigen, and biopsy Gleason score in prediction of final pathologic diagnosis in prostate cancer. Urology. 1995;46:205–210. Presti JC Jr, Shinohara K, Bacchetti P, et al. Positive fraction of systematic biopsies predicts risk of relapse after radical prostatectomy. Urology. 1998;52:1079–1084. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591–1597. Sandler HM, Dunn RL, McLaughlin PW, et al. Overall survival after prostate-specific-antigendetected recurrence following conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2000;48:629–633. Bigler SA, Deering RE, Brawer MK. Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol. 1993;24:220–226. Brawer MK, Deering RE, Brown M, et al. Predictors of pathologic stage in prostatic carcinoma: the role of neovascularity. Cancer. 1994;73:678–687. Siegal JA, Yu E, Brawer MK. Topography of neovascularity in human prostate carcinoma. Cancer. 1995;75:2545–2551. Frauscher F, Helweg G, Strasser H, et al. Contrast enhanced color Doppler ultrasound in the diagnostic evaluation of prostate cancer. Eur Radiol. 1999;9(suppl 1):S18. Tewari A. Predicting outcome of treatment with artificial neural networks. BJU Int. In press. Main Points • Patients classified as being at intermediate-risk for survival based on prostate-specific antigen (PSA) levels, Gleason score, and T stage can be reclassified as either low- or high-risk when percentage of positive biopsies is also taken into consideration. • Color Doppler imaging with intravenous contrast enhancement and targeted biopsy can result in significant enhancement in identifying prostate cancer; optimal cancer detection requires both targeted and standard systematic techniques. • Pelvic lymphadenectomy is indicated in men with a PSA level greater than 15.0 ng/mL, clinical T2b or greater clinical stage, and Gleason pattern 4 and 5 or Gleason score 7 or any Gleason grade 4 or 5 as a “third pattern" on the biopsy. • “Sentinel node biopsy" with a specific lymph node would provide the highest yield for sampling, provided the primary drainage site from the prostate can be located; scintigraphy with injection of markers in the prostate can help determine which lymph node is most likely to be the drain site. • Data collected from 1611 patients indicate that comorbidity provides a 2.1-fold increased hazard ratio of death from prostate cancer, and radical prostatectomy and radiation therapy reduce the hazard ratio by 0.31 and 0.56 times, respectively. Stage, grade, and PSA level did not meaningfully stratify patients with respect to hazard ratio for dying of prostate cancer. S22 VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY