AUA 2006: Diagnosis and Management of Early Localized Prostate Cancer

AUA 2006: Diagnosis and Management of Early Localized Prostate Cancer

Head of Urologic Oncology, University of Colorado Health Sciences Center 

May 20-25, 2006Atlanta, GeorgiaBy E. David Crawford, MD

Head of Urologic Oncology, University of Colorado Health Sciences CenterThe content presented here was prepared by independent authors under the editorial supervision of OncoEd, Inc. and is not endorsed or sanctioned by the American Urological Association.

Prostate cancer continues to be the most commonly diagnosed type of cancer among men. It is projected that 234,460 new cases of prostate cancer will be diagnosed this year in the United States , and an estimated 27,350 deaths will be attributed to prostate cancer, according to the latest figures from the American Cancer Society.

[1]An observed trend of increased detection and slightly reduced mortality may be attributed to the higher public awareness and active early screening, which has resulted in more early stage prostate cancer cases diagnosed and improved management of early stage disease respectively, among other factors.

[2]Herein, we highlight the results of several studies presented at the recent American Urological Association (AUA) 2006 annual meeting and discuss possible impacts on current clinical practice.

Detection and Screening of Early Stage Prostate Cancer

The quest for novel prostate cancer markers that can improve upon the specificity and the sensitivity of serum PSA was evident in this years AUA meeting.

EPCA is a prostate cancer marker (Tessera Diagnostics Inc., Seattle, Wash.). According to the results presented which evaluated EPCA in men, in combination with PSA resulted in an error rate in correctly identifying prostate cancer of less than 5%.

[3]In a similar study evaluating the expression of EPCA-2 two epitopes (19 and 22) in 368 serum samples from normal controls, men with BPH, organ confined and non-organ confined prostate cancer, and a diverse group of other controls showed a specificity of 100% (AUC 0.99; 95% CI 0.994 to 1), whereas PSA has a specificity of 37% (AUC 0.65; 95% CI 0.59 to 0.74). In addition, EPCA-2.22 epitope was also able to differentiate men with organ confined from those with non-organ confined prostate cancer (AUC 0.84; 95% CI 0.72 to 0.96).

[4]These results appear to be very encouraging, however, larger prospective studies are awaited to confirm the clinical value and cost effectiveness of this novel marker in screening for prostate cancer.

In a proteomic analysis of 385 serum samples from patients who had a first time biopsy and a total PSA (tPSA) between 2.0-10.0 ng/mL, protein C inhibitor (PCI) demonstrated the potential as a biomarker for prostate detection, staging, and prediction of recurrence by partially outperforming tPSA and its derivatives.

[5]

PCA3 mRNA gene expression is highly over-expressed in prostate tumor cells. Quantitative urinary PCA3 levels have shown to be promising tool for the detection of prostate cancer. In a study of 180 biopsy-positive and 237 biopsy-negative subjects, 138 of which had PIN or ASAP, specificity was 76% at 50% sensitivity, AUC of 0.680. By comparison, serum tPSA specificity was 22% for the same group.

[6]In a similar study of 299 patients that were to undergo prostate biopsies, PCA3 gene-based analysis had a high prognostic value, as the ratio PCA3 / PSA mRNA in urine sediments after extended DRE correlates with increasing Gleason score in subsequent prostate biopsies.

[7]

Current Choices for the Management of Early Prostate Cancer

Management choices for early confined prostate cancer vary from active surveillance with delayed intervention to immediate radical treatment. A definitive advantage of aggressive radical treatment in these men remains controversial. However, most experts now agree that a substantial proportion of these men are over treated with dire consequences on quality of life measures.

The current trends of treatment options in the United States for early confined prostate cancer were presented by the initial results of the COMPARE study. Analysis of 678 men from 146 physician sites indicated a preference of 44.5% for radical prostatectomy, external beam radiation in 30.7% and brachytherapy in 13.1%. Combination therapy was observed in the remaining men.

[8]A survival analysis using the SEER/Medicare data of 49,375 men, presented at the 2006 AUA meeting, demonstrated an overall survival advantage of treatment group vs. observation in men with localized prostate cancer.

[9]Nevertheless, this analysis may have an inherent selective bias of cofounders between the groups and should be cautiously interpreted.

Although several other studies indicated that active early treatment of confined prostate cancer may harbor better survival outcomes than watchful waiting, emerging evidence exists, that this is not true for all men diagnosed with prostate cancer. In a study presented by Dr. Warlick, the adverse pathological extent of cancer (incurability) was not significantly different between men in the delayed intervention cohort (9 of 38) men (23.7%) with median delay of 26.5 months as compared to 24 of 150 men (16.0%) in the immediate intervention group with median delay of less than 3 months from diagnosis.

[10]Roobel et al from the Netherlands indicated in a validation study that prostate caner identified by active screening has a substantial likelihood of being not clinically significant.

[11]These and other studies indicate that a sizable proportion of men diagnosed with early prostate cancer may benefit from a less aggressive treatment options.

According to a study presented by Klotz et al, active surveillance with selective delayed intervention (RRP was offered if PSADT < 3 years and GS > 7 on rebiopsy) for select early stage prostate cancer men, appears to have favorable disease-free survival after 10 year follow up.

[12]Initial management with active surveillance was also supported by a retrospective analysis presented by the UCSF group. In this select cohort of men with PSA < 10 ng/mL, GS 6 with no pattern 4 or 5, cancer involvement of <33% of biopsy cores and clinical stage T1/T2a were managed expectantly and compared to men who did not match these criteria. Risk of disease progression at 5 years was 9.7% for those meeting all inclusion criteria compared to 31.7% for those who were observed but did not meet all the inclusion criteria.

[13]Such an expectant management option may have a significant impact on patient quality of life without compromising survival rates.

In a recent study published in the Journal of the American Medical Association, men aged 75 or older may not have a survival benefit from aggressive treatment which adversely affects quality of life measurements. Furthermore, the authors of this study suggested that active screening may not be clinically beneficial.

[14]

Racial and Ethnic Background and Quality of Life Post Initial Treatment

Racial/ethnic background has been reported to affect quality of life post primary treatment of early prostate cancer. However, a QOL assessment study presented by Zagory et al, suggested that although QOL is more closely associated with race/ethnicity than literacy, poor QOL following initial treatment among African-American men appears to reflect worse QOL prior to treatment rather than greater treatment-related toxicity.

[15]

Race/ethnic background may also have a significant impact on primary therapy choices in men diagnosed with early prostate cancer. Wood et al analyzed the records of 2910 men treated by prostatectomy for prostate cancer between 1987 and 2004. The authors compared the rate of biochemical failure between African-American and Caucasian men. They concluded that African-American men continue to show significantly lower rates of cure after surgery that are not explained by differences in pre- or post-treatment tumor characteristics, such as clinical stage, GS, and initial PSA levels.

[16]

Outcome and Risk Predictors After Radical Prostatectomy (RP) for Early Prostate Cancer

In a large retrospective study of 3,521 men treated with RP from 1985 to 2005, the majority of PSA failure cases occur within 10 years after surgery. Almost two-thirds of these cases occurred within 5 years and, as expected, men with favorable pathological feature tend to fail later when compared to others (Table 1).

[17]

Clinical stage, pathological grade, PSA level at the time of diagnosis and its time dynamics thereafter, and tumor volume have all been suggested to be significant surrogates for disease specific survival.  In the PSA era, progression-free survival 10 years after RP with curable intent correlates significantly with tumor stage and grade according to a follow up study of 3459 RP cases presented at the 2006 AUA.

[18]In a similar large study of 4590 consecutive patients with clinical stage T1- T3, long-term (12-year) metastatic free progression was 97% for T1C, 95% for T2A, 85% for T2B, and 83% for T2C-T3. This indicates that the overall long-term risk of metastatic progression of prostate cancer following RP is low.

[19]A nomogram was suggested by the same authors based on these variables with estimated predictive value of 0.826.

[20]

An interesting multinational analysis of 1224 men who had undergone 10 core diagnostic prostate biopsies showed a significant positive correlation between prostate (gland) volume and cancer detection rate. According to this study, the addition of prostate volume as a clinical variable increased the accumulative accuracy of a nomogram based on age, PSA, % fPSA, and DRE by 5.5% to 70.0%.

[21]

The impact of family history on the aggressiveness of prostate cancer was addressed in a report by Kupelian et al in a cohort of 4112 men with stage T1-T3 who underwent primary treatment between 1985 and 2002. The authors concluded that men with a positive first degree family history of prostate cancer presented with more favorable disease late in the PSA era. This indicates that although genetic predisposition still plays a role in the prognosis of prostate cancer, the observed stage migration appears to lessen its value as a predictor of biochemical failure post primary treatment.

Conclusions

The quest for novel new markers that predict early, clinically significant prostate cancer with higher sensitivity and specificity continue to be high on the agenda of research centers nationwide and internationally. The observed stage migration of prostate cancer in the PSA era has generated an interest in less radical treatments including watchful waiting and delayed therapy. More emphasis on candidate selectivity for treatment choices is emerging as a central management policy accentuating the patients quality of life on equal footing with survival benefits of primary treatment.

References

[1]Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106-30.

[2]Bartsch G , Horninger W , Oberaigner W , et al . Tyrolean screening study: update 2005 stage migration and decrease of mortality. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 473.

[3]Yeater D , Mangold L , Partin A , et al. Early prostate cancer antigen and prostate specific antigen: Two better than one. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 851.

[4]Leman ES , Cannon GW , Sokoll L , et al. EPCA-2: A highly specific serum marker for prostate cancer . Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 852.

[5]Zhang Z , Rosenzweig CN , Sokoll L , et al . Protein c inhibitor as a biomarker for prostate cancer: detection, staging, and prediction of recurrence. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 860.

[6]Fradet Y , Canada Q , Groskopf J , et al. Protoype aptima® pca3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Proceedings from the 2006 annual meeting of the American Urological Association. May 2006. Abstract # 538.

[7]Hessels D , van Gils M , Witjes JA , et al . The prognostic value of PCA3 gene-based analysis of urine sediments after extended digital rectal examination. Proceedings from the 2006 annual meeting of the American Urological Association. May 2006. Abstract # 539.

[8]McLeod DG , Sartor O , Schellhammer PF , et al. Choices for definitive treatment of early-stage prostate cancer: results from the COMPARE registry.  Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 1596.

[9]Wong Y , Wan F , Mitra N , et al. Treatment of Localized Prostate Cancer: A Survival Analysis Using SEER-Medicare Data. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 658.

[10] Warlick CA, Trock B, Landis PK, et al . Pathological outcomes are similar for men in an expectant management program undergoing delayed surgical intervention compared to those undergoing immediate intervention. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 654.

[11]Roobol MJ , Steyerberg EW , Kattan MW , et al. Prediction of indolent prostate cancer: validation and updating of a prognostic nomogram. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract #1392.

[12]Klotz LH , Loblaw A , Holden L , et al . Active surveillance with selective delayed intervention for favorable risk prostate cancer: Updated experience with 500 patients. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 655.

[13]Master V , Konety BR , Perez N , et al. Prostate cancer progression in a watchful waiting cohort: The UCSF experience. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 488.

[14]Hoffman RM, Barry MJ, Stanford JL, Hamilton, AS, Hunt WC, Collins MM. Health outcomes in older men with localized prostate cancer: results from the Prostate Cancer Outcomes Study. Am J Med. 2006;119:418-25.

[15]Zagory JA , Chang CH , Carson K , et al . Race/ethnicity and health literacy associated variations in quality of life (QOL) following treatment for Veterans with newly diagnosed localized prostate cancer (PCa). Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 683.

[16]Wood HM , Reuther AM , Kupelian PA , et al . Blacks continue to lag Caucasians in cure rates after radical prostatectomy late in the PSA era despite PSA-induced clinical stage migration. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 681.

[17]Allaf M , Partin AW , Walsh PC . Who is cured? How long after radical prostatectomy can PSA rise? Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 654.

[18]Desireddi VN , Roehl KA , Loeb S. Progression-Free Survival Rates for Radical Prostatectomy in the PSA Era. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 650.

[19]Stephenson AJ , Eastham JA , Kattan MW , et al. Long-term risk of metastatic progression of prostate cancer following radical prostatectomy. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 651.

[20]Baccala JA, Reuther AM , Bianco FJ , et al. A postoperative nomogram for detecting 13-year probability of disease recurrence from prostate cancer. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 660.

[21]Chun K , Briganti A , Ahyai S , et al . Prostate volume at initial biopsy is the most important predictor of repeat biopsy outcome. Validation of a novel predictive tool. Proceedings from the 2006 annual meeting of the American Urological Association. Atlanta, Ga. May 2006. Abstract # 484.

Comments