Jeffrey M. Slezak

Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate‐specific antigen testing: 15‐year outcome

In the first paper in this section, authors from the Mayo Clinic describe their experience and 15‐year outcomes in the controversial subject of radical prostatectomy in patients with clinical T3 prostate cancer. The findings were interesting in many respects, but the authors concluded that radical prostatectomy as part of multimodal treatment for patients with clinical T3 disease offers cancer control and good survival rates.

DEFINING PROSTATE SPECIFIC ANTIGEN PROGRESSION AFTER RADICAL PROSTATECTOMY: WHAT IS THE MOST APPROPRIATE CUT POINT?

PURPOSE The most appropriate definition of biochemical progression after radical prostatectomy and radiation therapy is uncertain. We analyzed the effect of using various prostate specific antigen (PSA) end point definitions for defining biochemical progression after radical prostatectomy and attempted to determine the best PSA cut point to use. Aspects of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after radiation therapy are also analyzed in our radical prostatectomy cases. MATERIALS AND METHODS A total of 2,782 men with clinically localized prostate cancer (cT1-T2) who had undergone radical prostatectomy between 1987 and 1993 were reviewed. All patients had regular PSA determinations from surgery through followup. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Biochemical, PSA progression-free percent after radical prostatectomy was determined by the Kaplan-Meier method using several PSA cut points, including 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater, as well as 0.4 ng./ml. or greater and increasing. Progression-free percent was also assessed using the ASTRO definition, which is 3 increases in PSA. To determine which PSA level was most appropriate to define progression after radical prostatectomy, the percentage of patients with a continued PSA increase after reaching each cut point was determined. The relationship between the maximum PSA within 3 years of surgery and subsequent development of clinical disease was also assessed. RESULTS Progression-free percent was dependent on the PSA cut point used. Biochemical progression-free percentages for cut points 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater were 62%, 72%, 76% and 78% at 5 years, and 43%, 54%, 59% and 61% at 10 years, respectively. A subsequent increase in PSA was noted in 49%, 62% and 72% of patients who had PSA 0.2, 0.3 and 0.4 ng./ml., respectively. Subsequent clinical progression (local or systemic) was directly related to the maximum PSA attained within 3 years of radical prostatectomy (p=0.0001). Progression-free percent for definitions requiring multiple increases in PSA were dependent on when the event was said to occur. Backdating of events at or before the first PSA (ASTRO definition) resulted in poorer, short-term progression-free percent (78% at 5 years), with little apparent likelihood of long-term failure (78% at 10 years). Coding the event at the last PSA increase when all event criteria had been met resulted in more realistic progression-free percent estimates (85% at 5 and 59% at 10 years). CONCLUSIONS Biochemical, PSA progression rates vary markedly depending on the method used to define PSA failure. Methods that require multiple increasing PSA values, for example the ASTRO definition, give misleading results, especially if the event time is backdated. Standards for defining PSA progression would allow more consistent and comparable progression estimates after radical prostatectomy. PSA 0.4 ng./ml. or greater may be the most appropriate cut point to use since a significant number of patients with lower PSA do not have a continued increase in it.

Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years.

PURPOSE Cure from malignancy is commonly defined as a disease-free state lasting 5 years after treatment. We analyzed clinical and biochemical progression rates after radical prostatectomy for men with clinically localized prostate cancer with particular attention to recurrence beyond 5 years. Annual hazard rates of progression were calculated to determine the probability of recurrence at specific intervals following surgery. MATERIALS AND METHODS The records of 2,782 men with clinically localized prostate cancer (cT1-T2) undergoing radical prostatectomy between 1987 and 1993 were reviewed. All patients were treated in the prostate specific antigen (PSA) era so that serial followup PSA values were available from the time of surgery. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Disease progression was defined as documented local recurrence, systemic progression and/or PSA 0.4 ng./ml. or greater. Lymph node positive cases were eliminated from analysis since almost all received adjuvant hormonal therapy. Annual hazard rates for progression were calculated using the formula: [No. events / No. patients at risk] x 100. Progression-free survival probabilities were determined using the Kaplan-Meier method. RESULTS Pathological stage was pT2a-b, N0 (68%), pT3a, N0 (21%) and pT3b, N0 (11%). Biochemical progression-free survival at 5 and 10 years was 76% and 59%, respectively, for the entire study population while those with pathologically organ confined (pT2, N0) cancers had progression-free survival rates of 82% and 68% at 5 and 10 years, respectively. A total of 819 patients (29%) eventually had disease progression, including 160 (6%) with progression after 5 years. Annual hazard rates were highest during the first 2 years after radical prostatectomy for the entire population. Patients with adverse prognostic features (pT3b, PSA 10 ng./ml. or greater, Gleason score 8-10 and nondiploid cancers) had high initial hazard rates that decreased with time to lower levels. Those with pathologically organ confined cancer had low but constant hazard rates throughout followup. CONCLUSIONS Although progression after radical prostatectomy usually occurs early, reflecting the impact of clinical under staging, a significant number of men, including those with organ confined cancers, will continue to have disease progression after 5 years. Patients undergoing radical prostatectomy should be subjected to long-term followup to allow the option of early intervention should progression occur.

PSA Doubling Time as a Predictor of Clinical Progression After Biochemical Failure Following Radical Prostatectomy for Prostate Cancer

OBJECTIVES To characterize the clinical progression of disease in men who have undergone prostatectomy for clinically localized prostate cancer and have postoperative biochemical failure (elevated prostate-specific antigen [PSA] level) and to identify predictors of clinical disease progression, including the possible effect of PSA doubling time (PSADT). PATIENTS AND METHODS Between 1987 and 1993, 2809 patients underwent radical retropubic prostatectomy for clinically localized (< or =T2) disease. In our database, all patients with postoperative biochemical failure (PSA level > or =0.4 ng/mL) were identified. The PSADT was estimated using log linear regression on all PSA values (excluding those values determined after administration of hormonal therapy) within 15 months after biochemical failure. All patients had regular PSA measurements from the time of surgery through the follow-up period. Systemic progression (SP) was defined as evidence of metastatic disease on a bone scan. Local recurrence (LR) was defined on the basis of digital rectal examination, transrectal ultrasonography, and biopsy. The SP-free survival and LR/SP-free survival (survival free of both LR and SP) after biochemical failure was estimated with use of the Kaplan-Meier method. Patients with prostate cancer treatment after biochemical failure had their follow-up censored from this study at the time of treatment. RESULTS Postoperative biochemical failure occurred in 879 men (31%). The mean follow-up from time of biochemical failure was 4.7 years (range, 0.5-11 years). The mean time to biochemical failure was 2.9 years (median, 2.4 years). The overall mean SP-free survival from time of biochemical failure was 94% and 91% at 5 and 10 years, respectively. The mean LR/SP-free survival was 64% and 53% at 5 and 10 years, respectively. By using univariate analysis on the 587 patients with PSADT data, significant risk factors for SP were PSADT (P<.001) and pathologic Gleason score (P=.005); for LR/SP, significant risk factors included PSADT (P<.001) and pathologic Gleason score (P<.001). In multivariate Cox models analysis, only PSADT remained a significant risk factor for both SP and LR/SP (P<.001). Mean 5-year SP-free survival was 99%, 95%, 93%, and 64% for patients with PSADT of 10 years or longer, 1.0 to 9.9 years, 0.5 to 0.9 year, and less than 0.5 year, respectively; the respective mean LR/SP-free survivals were 87%, 62%, 46%, and 38%. The percentage of patients with PSADT of less than 0.5 year was considerably higher if the type of first clinical event was SP (48%) compared with LR (18%) (P<.001). CONCLUSIONS For patients who have undergone radical prostatectomy, a rising PSA level suggests evidence of residual or recurrent prostate cancer. Many men remain free of clinical disease for an extended time after biochemical failure following radical prostatectomy for clinically localized prostate cancer. The PSADT appears to be an important predictor of SP and also of any clinical progression (local or systemic). These data may be useful when counseling men regarding the timing of adjuvant therapies.

Efficacy of Contralateral Prophylactic Mastectomy in Women With a Personal and Family History of Breast Cancer

PURPOSE To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

VALIDATION OF PARTIN TABLES FOR PREDICTING PATHOLOGICAL STAGE OF CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE The accurate prediction of pathological stage of prostate cancer using preoperative factors is a critical aspect of treatment. In 1997 Partin et al published tables predicting pathological stage using clinical stage, Gleason score and prostate specific antigen (PSA). We tested the validity of the Partin tables. MATERIALS AND METHODS From 1990 to 1996 inclusively 5,780 patients underwent bilateral pelvic lymphadenectomy and radical prostatectomy for prostate cancer at the Mayo Clinic. However, only 2,475 of these patients met all inclusion criteria of no preoperative treatment, known biopsy Gleason score, available preoperative PSA done either before biopsy or more than 28 days after biopsy and clinical stage T1, T2 or T3a. Among the 2,475 patients 15 had positive lymph nodes and planned prostatectomy was abandoned. The receiver operating characteristics (ROC) curve area, observed and predicted Partin rates of each pathological stage, and positive and negative predictive values were used to compare the Mayo study to the Partin tables. RESULTS The distribution of pathological stage was organ confined in 67% of Mayo cases versus 48% in the Partin study, extracapsular without seminal vesicle or node involvement in 18% versus 40%, seminal vesicle involvement without nodes in 9% versus 7% and were positive nodes in 6% versus 5%. Using the predicted probabilities of Partin et al the ROC curve area for predicted node positive disease was 0.84 for Mayo cases compared to an estimated 0. 82 in the Partin series. The ROC curve area for predicting organ confined cancer was 0.76 for the Mayo Clinic compared to an estimated 0.73 for the Partin series. The observed rates of node positive disease were similar to those predicted (Partin) based on clinical stage, PSA and Gleason score. For organ confined disease Mayo rates were consistently higher than those predicted from the Partin series using a cut point of 0.50 or greater. Positive and negative predictive values were 0.83 and 0.49 versus 0.63 and 0.70 for the Mayo Clinic and Partin series. CONCLUSIONS Our study provides strong evidence that sensitivity and specificity of the Partin tables for external clinical sites are similar to what was reported.

Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype

BACKGROUND Patients with autosomal dominant polycystic kidney disease (ADPKD) are at risk of developing intracranial aneurysms, and subarachnoid haemorrhage is a major cause of death and disability. Familial clustering of intracranial aneurysms suggests that genetic factors are important in the aetiology. We tested whether the germline mutation predisposes to this vascular phenotype. METHODS DNA samples from patients with ADPKD and vascular complications were screened for mutations throughout the PKD1 and PKD2 genes. Comparisons were made between the PKD1 and PKD2 populations and with a control PKD1 cohort (without the vascular phenotype). FINDINGS Mutations were characterised in 58 ADPKD families with vascular complications; 51 were PKD1 (88%) and seven PKD2 (12%). The median position of the PKD1 mutation was significantly further 59 in the vascular population than in the 87 control pedigrees (aminoacid position 2163 vs 2773, p=0.0034). Subsets of the vascular population with aneurysmal rupture, early rupture, or families with more than one vascular case had median mutation locations further 59 (aminoacid position 1811, p=0.0018; 1671, p=0.0052; and 1587, p=0.0003). INTERPRETATION Patients with PKD2, as well as those with PKD1, are at risk of intracranial aneurysm. The position of the mutation in PKD1 is predictive for development of intracranial aneurysms (59 mutations are more commonly associated with vascular disease) and is therefore of prognostic importance. Since the PKD1 phenotype is associated with mutation position, the disease is not simply due to loss of all disease allele products.

Satisfaction After Contralateral Prophylactic Mastectomy: The Significance of Mastectomy Type, Reconstructive Complications, and Body Appearance

PURPOSE Contralateral prophylactic mastectomy (CPM) is one option for reducing the risk of a second breast cancer in women with a personal and family history of breast cancer. Few data are available regarding satisfaction, psychological, and social function after CPM. The purpose of this research is to evaluate womens long-term satisfaction with CPM, factors influencing satisfaction, and psychological and social function after CPM. PATIENTS AND METHODS This was a descriptive study of all women with a family history of breast cancer, known to be alive, who elected CPM at Mayo Clinic (Rochester, MN) between 1960 and 1993 (n = 621). Ninety-four percent of the women (n = 583) completed a study-specific questionnaire. RESULTS A mean of 10.3 years after the procedure, the majority of women (83%) were satisfied with their CPM. A smaller number were neutral (8%) or dissatisfied (9%). Women who had a subcutaneous mastectomy had more problems with reconstruction, and fewer of these women were satisfied than women with simple mastectomy. Decreased satisfaction with CPM was associated with decreased satisfaction with appearance, complications with reconstruction, reconstruction after CPM, and increased level of stress in life. The majority of women experienced no change or favorable effects in self-esteem (83%), level of stress in life (83%), and emotional stability (88%). Satisfaction with body appearance, feelings of femininity, and sexual relationships were the most adversely affected with 33%, 26%, and 23% of the women responding negatively. CONCLUSION Although most women are satisfied with CPM, each woman should weigh the benefits alongside the potential adverse effects.

DEOXYRIBONUCLEIC ACID PLOIDY AND SERUM PROSTATE SPECIFIC ANTIGEN PREDICT OUTCOME FOLLOWING SALVAGE PROSTATECTOMY FOR RADIATION REFRACTORY PROSTATE CANCER

PURPOSE We assessed clinical and pathological variables for the ability to predict improved outcome following salvage prostatectomy for radiation refractory prostate cancer. We identify factors that might assist in selection of candidates for this procedure. MATERIALS AND METHODS Between 1966 and 1996, 108 patients (mean age 64.7 years) underwent salvage radical retropubic prostatectomy for radiation refractory prostate cancer. Preoperative serum prostate specific antigen (PSA), available in 70 patients treated since 1987, was less than 4 in 19, 4 to 10 in 31 and greater than 10 ng./ml. in 20. Serum PSA before radiotherapy was available in 37 patients. Serum PSA before radiotherapy and salvage surgery, tumor grade, deoxyribonucleic acid (DNA) ploidy and margin status were analyzed for the ability to predict cancer specific and progression-free survival (local, systemic and PSA 0.2 ng./ml. or greater). Complication rates were compared between early (before 1990) and late (1990 to 1996) salvage prostatectomy groups. RESULTS Overall cancer specific and progression-free survival at 10 years was 70 and 44%, respectively. The pathological stage was pT2N0 in 39%, pT3-4N0 in 42% and pTxN+ in 19% of cases. DNA ploidy was predominately nondiploid, that is diploid in 25%, tetraploid in 64% and aneuploid in 11% of tumors. Although preoperative serum PSA was not predictive of pathological stage, patients with preoperative PSA less than 10 ng./ml. had better progression-free survival than those with higher levels (p = 0.05). DNA ploidy was the strongest predictor of cancer specific (p = 0.002) and progression-free (p = 0.002) survival. Controlling for grade and PSA using the Cox proportional hazards model, DNA ploidy remained a significant predictor of prostate cancer death (p <0.001) and disease progression (p <0.001). Complication rates improved somewhat in more recently treated patients but incontinence and bladder neck contracture rates remained significant. CONCLUSIONS DNA ploidy and preoperative serum PSA appear to be the most important predictors of outcome following salvage prostatectomy for radiation refractory prostate cancer. Preoperative consideration of these factors may be helpful in selecting candidates for this procedure.

RADICAL PROSTATECTOMY FOR PATHOLOGICAL GLEASON 8 OR GREATER PROSTATE CANCER: INFLUENCE OF CONCOMITANT PATHOLOGICAL VARIABLES

PURPOSE We evaluated the long-term outcome of radical prostatectomy for pathological Gleason score 8 or greater prostate cancer and characterized the prognostic significance of other pathological variables. MATERIALS AND METHODS A total of 6,419 patients underwent radical prostatectomy between 1987 and 1996. There were 407 patients classified as having pathological Gleason 8 or greater, including 8 in 48%, 9 in 49% and 10 in 3%. Adjuvant treatment was used in 45% of patients and adjuvant hormonal therapy was administered to 155 (38%). Progression-free, including local or systemic, and/or prostate specific antigen (PSA) 0.4 ng./ml. or greater, and cancer specific survival were determined by the Kaplan-Meier method. The effect of pathological grade and stage, preoperative PSA, DNA ploidy, margin status, tumor dimension, seminal vesicle invasion, and adjuvant treatment was assessed with the univariate and multivariate analyses. RESULTS Pathological stage distribution was pT2 in 26% of patients, pT3 48% and pTxN+ 27%. Overall and progression-free survival at 10 years was 67% and 36%, respectively, compared to cancer specific survival 85%. Adjuvant treatment, pathological stage, preoperative PSA and pathological grade were significant (less than 0.05) univariate predictors of progression-free survival. Pathological stage, margin status and ploidy were univariately associated with cancer specific survival. Progression-free survival at 10 years of those patients who did and did not receive adjuvant treatment was 52% and 23%, respectively. In the multivariate analysis pathological grade (p=0.02), preoperative PSA (p <0.0001), adjuvant therapy (p <0.0001) and pathological stage (p=0.036) were significant independent predictors of progression-free survival. CONCLUSIONS High grade prostate cancer can be controlled with radical prostatectomy in some patients with disease confined pathologically, and 10-year cause specific survival is 96%. Predictors of outcome in patients with Gleason 8 disease or greater are similar to established predictors derived by using all grades. Although adjuvant hormonal therapy appears to improve disease progression rates after radical prostatectomy on the basis of this nonrandomized study, it may not affect prostate cancer death rates within 10 years in patients with high grade cancer.