Undetectable Serum Prostate Specific Antigen Research Articles

Clinicopathologic Study of Gleason Pattern 5 Prostatic Adenocarcinoma With "Single-cell" Growth Reveals 2 Distinct Types, One With "Plasmacytoid" Features.

Each Gleason score category of prostatic adenocarcinoma (or Grade Group) may encompass a diverse group of architectural patterns such as well-formed glands, poorly formed glands, cribriform structures, single cells, and/or solid sheets. We have noted heterogeneity within the single-cell subtype of Gleason pattern 5 prostatic adenocarcinoma that has not been fully addressed. Therefore, we retrospectively reviewed a series of radical prostatectomies with high-grade prostatic adenocarcinoma (Grade Group 4 or 5), identifying tumors with a component of single-cell infiltration. Additional cases identified prospectively were also included. TNM status, association with other histologic patterns, and clinical follow-up status were determined. Immunohistochemistry for NKX3.1, E-cadherin, p120 catenin, and prostate-specific antigen (PSA) were performed in each case. Eighteen cases with a component of well-developed Gleason pattern 5 characterized by single infiltrative cells that comprised ≥5% of the tumor were identified (15/202 retrospective radical prostatectomies with the high-grade disease [7.5%]). The single-cell pattern ranged from 5% to 50% of the tumor volume, with 5 cases containing ≥40%, and variable secondary architecture included diffuse infiltrating single cells with targetoid growth pattern around benign glands, solid expansive nests of noncohesive cells, and corded/single file growth pattern. Further morphologic analysis demonstrated 2 distinct histologic subtypes: (1) (subtype 1; n=9) monomorphic "plasmacytoid" tumor cells with eccentrically placed nuclei and variable intracytoplasmic vacuoles with bland cytology and discohesion and (2) (subtype 2; n=9) more cohesive tumor cells with greater cytologic atypia characterized by prominent nucleoli, greater variability in nuclear size/shape, occasional mitotic figures, and more irregular infiltration. By immunohistochemistry, NKX3.1 nuclear expression and PSA cytoplasmic expression was retained in all cases. Concomitant membranous E-cadherin loss and strong cytoplasmic p120 catenin expression were present in 5 of the 18 (28%) cases, all in subtype 1 (5/9, 56%). Overall, 56% (10/18) of patients had advanced-stage disease (≥pT3b), and 70% (7/10) of these patients had associated lymphovascular invasion. All patients had concomitant cribriform patterns of carcinoma. The outcome was available for 14 patients: 4 died of unknown cause; 6 had biochemical recurrence with distant bone metastasis in 5 of the 6; and 4 patients with <3 years of follow-up currently have undetectable serum PSA levels (2 patients received salvage radiotherapy with androgen deprivation and 2 remain on routine follow-up). In summary, the single-cell pattern of Gleason pattern 5 prostatic adenocarcinoma is uniformly associated with other high-risk histologic patterns (eg, cribriform growth), and high-stage disease with distant metastasis is not uncommon. Our data suggest that the "single-cell" Gleason pattern 5 prostatic adenocarcinoma contains 2 distinct subtypes. Somatic CDH1 alterations may play a role in the development of the "plasmacytoid" pattern characterized by monomorphic cytology with concomitant E-cadherin loss and aberrant p120 catenin expression.

225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study

BackgroundA remarkable therapeutic efficacy has been demonstrated with 225Ac-prostate-specific membrane antigen (PSMA)-617 in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients. We report our experience with 225Ac-PSMA-617 therapy in chemotherapy-naïve patients with advanced metastatic prostate carcinoma.MethodsSeventeen patients with advanced prostate cancer were selected for treatment with 225Ac-PSMA-617 in 2-month intervals, with initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In one patient, activity was escalated to 13 MBq in the third cycle. Fourteen patients had three treatment cycles administered, while in three patients treatment was discontinued after two cycles due to good response. Six out of 17 patients received additional treatments after the third cycle. Prostate-specific antigen (PSA) was measured every 4 weeks for PSA response assessment. 68Ga-PSMA-PET/CT was used for functional response assessment before each subsequent treatment cycle. Serial full blood count, renal function test, and liver function were obtained to determine treatment-related side effects.ResultsGood antitumor activity assessed by serum PSA level and 68Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, PSA decline ≥90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of 225Ac-PSMA-617. Fifteen of 17 patients had a > 50% decline in lesions avidity for tracer on 68Ga-PSMA-PET/CT including 11 patients with complete resolution (PET-negative and either stable sclerosis on CT for bone or resolution of lymph node metastases) of all metastatic lesions. Grade 1/2 xerostomia was seen in all patients, and none was severe enough to lead to discontinuation of treatment. One patient had with extensive bone marrow metastases and a background anemia developed a grade 3 anemia while another patient with solitary kidney and pre-treatment grade 3 renal failure developed grade 4 renal toxicity following treatment. The group presented with significant palliation of bone pain and reduced toxicity to salivary glands due to de-escalation.Conclusions225Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.

Chromosome 8 markers of metastatic prostate cancer in African American men: Gain of the MIR151 gene and loss of the NKX3‐1 gene

Radical prostatectomy (RP) is not curative if patients have undetected metastatic prostate cancer. Markers that indicate the presence of metastatic disease would identify men who may benefit from systemic adjuvant therapy. Our approach was to analyze the primary tumors of men with metastatic disease versus organ-confined disease to identify molecular changes that distinguish between these groups. Patients were identified based on long-term follow-up of serum prostate specific antigen (PSA) levels following RP. We compared the tumors of African American (AA) men with undetectable serum PSA for >9 year after RP (good outcome) versus those of AA men with a rising PSA and recurrence after radiation or androgen ablation or both (poor outcome). We used real-time quantitative PCR to assay gene copy number alterations in tumor DNA relative to patient-matched non-tumor DNA isolated from paraffin-embedded tissue. We assayed several genes located in the specific regions of chromosome 8p and 8q that frequently undergo loss and/or gain, respectively, in prostate cancer, and the androgen receptor gene at Xq12. Gain of the MIR151 gene at 8q24.3 (in 33% of poor outcome vs. 6% of good outcome tumors) and/or loss of the NKX3-1 gene at 8p21.2 (in 39% of poor outcome vs. 11% of good outcome tumors) affected 67% of poor outcome tumors, compared to only 17% of good outcome tumors. Copy number gain of the MIR151 gene and/or loss of the NKX3-1 gene in the primary tumor may indicate the presence of metastatic disease.

High detection rate of circulating tumor cells in blood of patients with prostate cancer using telomerase activity

Circulating tumor cells (CTCs) cannot be readily detected with currently available methods in the majority of patients with prostate cancer. Telomerase activation, one of the major immortalization events, is found in most cases of prostate cancer. We attempted to develop a method using telomerase activity to isolate CTCs in patients with prostate cancer. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood using Ficoll-Hypaque. Immunomagnetic beads coated with an epithelial cell-specific antigen antibody (BerEP4) were used to harvest epithelial cells from PBMCs. Telomerase activity was detected in harvested epithelial cells using the telomerase-PCR-enzyme-linked immunosorbent assay method. Blood samples from 107 patients with prostate cancer were studied. CTCs were detected in 19 of 24 (79%) patients with advanced prostate cancer. In contrast, CTCs were not detected in blood samples from 22 healthy male volunteers. CTCs were even identified in patients with an undetectable (<0.1 ng/ml) serum prostate-specific antigen (PSA). CTCs were detected in 55 of 70 (79%) patients with localized prostate cancer before radical prostatectomy (n = 30) or brachytherapy (n = 40). CTCs were also detected in 3 of 13 patients (23%) with an undetectable serum PSA measured at least 1 year after radical prostatectomy, which is consistent with the expected relapse rate in this setting. CTCs can be detected using telomerase activity in a large majority and a wide variety of patients with prostate cancer, including those with localized disease.

MANUAL LYMPHATIC DRAINAGE FOR THE TREATMENT OF ACUTE GENITAL LYMPHEDEMA

Lymphedema is the swelling of a body part due to the accumulation of excessive amounts of regional interstitial fluid and decrease or blockage of lymphatic transport.1 Secondary lymphedema is the most common form and usually results from surgical, traumatic or inflammatory disruption or obstruction of the lymphatic pathways. Acute genital lymphedema usually resolves spontaneously but occasionally becomes chronic and may require surgical treatment.2 We report a case of severe acute postoperative genital edema following radical retropubic prostatectomy and bilateral pelvic lymphadenectomy that was successfully managed with 2 weeks of manual lymphatic drainage (MLD) therapy. To our knowledge this is the first case reported in the urological literature of postoperative genital edema treated with decongestive lymphatic therapy. CASE REPORT A 71-year-old man with a prostate specific antigen of 4.5 ng/ml and clinical stage T2a Gleason grade 5 4 9 adenocarcinoma of the prostate underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. Lymphadenectomy included removal of all the tissue from the obturator fossa and along the hypogastric vessels bilaterally. Both neurovascular bundles were excised widely around the prostate because of high volume, poorly differentiated tumor. Final pathological evaluation revealed bilateral Gleason grade 5 4 9 adenocarcinoma of the prostate confined within the prostatic capsule, with all surgical margins, seminal vesicles and lymph nodes negative for tumor. Postoperative hospital stay was uneventful, and the patient was discharged home on postoperative day 3. At postoperative day 11 the patient complained of severe debilitating swelling and pain in the penis and scrotum that interfered with sitting and walking. Physical examination demonstrated the genitalia to be markedly edematous with the scrotum the size of a grapefruit. There was mild penile edema that was not troublesome, and there was no lower extremity edema. There was no evidence of cellulitis. Venous duplex ultrasonography showed no evidence of either deep venous thrombosis or venous obstruction in the lower extremities or pelvis, and pelvic computerized tomography revealed no evidence of a pelvic fluid collection. During the next week the genital edema persisted and was refractory to the usual treatments of genital support and diuretics. Three weeks postoperatively daily decongestive therapy was started, consisting of MLD, lower extremity stretching exercises and overlapping circumferential compressive wrappings to the scrotum that transmitted low pressure compression (20 to 30 mm Hg). MLD was initiated in the inguinal region, moving cephalad, with the goal of transferring lymph from the edematous tissues to nonedematous cutaneous sites. Nonelastic compressive wrappings were applied after each session of MLD and worn continuously between treatments. Each daily therapy session of MLD lasted 3 to 4 hours. Between therapy sessions the patient was also instructed to wear tight briefs or an athletic supporter continuously. After several days of therapy the genital lymphedema and pain improved considerably, and after 2 weeks of treatment it had resolved completely. The patient was able to return to normal activities of daily living without sequelae. He was instructed to continue to wear tight supportive undergarments at home for 2 weeks. At 3 months postoperatively he was doing well, with no residual genital edema, and with excellent urinary control and an undetectable serum prostate specific antigen. DISCUSSION

Clinicopathologic Implications of hMSH2 Gene Expression

Human mismatch repair (MMR) genes encode highly conserved interacting proteins that correct replication errors predisposing to hereditary gastrointestinal and genitourinary malignancies. We previously investigated expression of the prototype MMR gene hMSH2 in normal, benign prostatic hyperplasia and malignant prostate tissues (Velasco et al, Cancer 94:690-699, 2002). An association was detected between reduced hMSH2 staining and favorable outcome as determined by undetectable serum prostate specific antigen (PSA) after radical prostatectomy. We now investigate the association between clinicopathological variables and hMSH2 expression or microsatellite instability (MSI). A statistically significant association was found between tumors exhibiting MSI (MSI+ tumors) and lower preoperative serum PSA values, smaller tumor volumes and lower frequency of surgical specimens with extracapsular extension of tumor. No statistically significant association (P value less than or equal to 0.05) was found between hMSH2 staining and these clinicopathologic variables. Based on our analysis, we conclude that MMR deficiency has important clinicopathologic implications in prostate cancer. Furthermore, specific MMR genes may have different effects on prostate cancer biology.

Prostate carcinoma with testicular or penile metastases. Clinical, pathologic, and immunohistochemical features.

Despite the proximity, prostate carcinoma seldom metastasizes to the penis or testis. In the current study, the authors retrospectively examined the clinical history of 12 patients with prostate carcinoma and testicular or penile metastases. Pathologic review and immunohistochemical staining were performed on tumors from eight of these patients. Patients with prostate carcinoma and testicular or penile metastasis responded to androgen ablative therapy (median duration, 33 months). They were predisposed to developing persistent or recurrent urinary symptoms and visceral metastases. Six of 9 evaluable patients had elevated serum carcinoembryonic antigen levels (> 6 ng/mL), whereas 2 of 10 patients had low or undetectable serum prostate specific antigen levels (< 4 ng/mL). In seven of the eight patients for whom specimens were available, the tumors were found to contain histologic features that were compatible with a diagnosis of ductal or endometrioid adenocarcinoma of the prostate. Patients with prostate carcinoma and testicular or penile metastases have unique clinical and pathologic characteristics. Many of these patients' tumors are compatible with a subtype of prostate carcinoma known as ductal adenocarcinoma. Further studies need to be performed to elucidate the biologic basis of the various histologic subtypes of prostate carcinoma.

Nadir prostate-specific antigen as a predictor of progression to androgen-independent prostate cancer

Objectives. To determine the value of the before and after treatment level of prostate-specific antigen (PSA) to predict the time to androgen-independent progression (AIP) in patients with advanced prostate cancer who received androgen-deprivation therapy (ADT) at the time of recurrence or progression. Methods. The records of 153 patients with advanced or metastatic prostate cancer who were treated with ADT were retrospectively reviewed. Fifty-six percent of the patients were initially treated with ADT. In the remainder, ADT was started at progression and/or failure. AIP was defined as two consecutive elevations of serum PSA above the nadir value by any threshold. Kaplan-Meier and multiple logistic regression analyses were used to determine the potential predictors of AIP. Results. The median duration of the PSA response was 24 months. The most important predictors of the time to AIP were the initial Gleason grade and the nadir PSA level after the initiation of ADT. The odds ratio of having a response greater than 24 months was 15-times higher in patients achieving an undetectable serum PSA level versus those who did not. For each point increase in the Gleason sum, patients had a five times higher chance of progressing to AIP in 24 months or less. Conclusions. The ability to achieve an undetectable nadir PSA level and the initial Gleason grade are significant predictors of the time to AIP in men treated with ADT for metastatic and advanced prostate cancer.

Cryoablation for clinically localized prostate cancer using an argon-based system: complication rates and biochemical recurrence.

To determine the complication rates and biochemical recurrence after cryoablation of the prostate, using an argon gas-based system, in patients with localized prostate cancer. Between October 1997 and June 1999, 35 patients underwent cryoablation of the prostate (19 after radiation therapy failure and 16 as a primary treatment for localized prostate cancer). All patients had biopsy-confirmed prostate cancer with no seminal vesicle invasion, negative bone scans and a negative lymph node dissection. Patients received 3 months of combined hormonal therapy before cryosurgery. One surgeon performed all the procedures. Biochemical recurrence was defined by an increase in prostate specific antigen (PSA) of >/= 0.2 ng/mL above the PSA nadir. The complications were rectal pain (26%), urinary infection (3%), scrotal oedema (12%), haematuria (6%) and incontinence (6%). Complication rates were higher in those patients who failed after radiation therapy than in those who did not receive radiation (incontinence 11% vs 0%, rectal pain 37% vs 12%) but the difference was not statistically significant. Twenty-two patients (63%) had an undetectable serum PSA nadir (< 0.1 ng/mL) after cryotherapy and 30 (84%) patients had a PSA value of < 1.0 ng/mL. After a mean follow-up of 8.3 months (range 0.2-18), nine patients had biochemical recurrence. The biochemical recurrence-free survival (BRFS) was 70% at 9 months. Patients who had an undetectable PSA nadir had a statistically higher BRSF at 9 months than did patients who had a detectable PSA nadir (89% vs 55%, respectively, P = 0.03). Similarly, patients with a preoperative serum PSA level of < 10 ng/mL had a statistically higher BRFS than patients who had a PSA level of > 10 ng/mL (86% vs 42% at 9 months, P < 0.001). A PSA level before cryotherapy of < 10 ng/mL and an undetectable PSA nadir after cryotherapy were associated with the highest BRFS. Cryoablation of the prostate, with low morbidity, seems to be a viable option in managing patients by salvage therapy after radiation therapy and for the primary treatment of clinically localized prostate cancer.

Salvage cryotherapy for recurrent prostate cancer after radiation therapy: the Columbia experience

Objectives. Cryotherapy of the prostate represents a potential treatment for localized recurrent prostate cancer after radiation therapy. We report our experience and evaluate the predictive factors for prostate-specific antigen (PSA) recurrence. Methods. Between October 1994 and April 1999, 43 patients underwent salvage cryoablation. All patients had biopsy-proven recurrent prostate cancer without seminal vesicle invasion, negative bone scans, and negative lymph node dissection. Patients had received 3 months of combined hormonal therapy before cryosurgery. Biochemical recurrence-free survival (bRFS) was defined as a PSA value less than 0.1 ng/mL. Results. Complications included incontinence (9%), obstruction (5%), urethral stricture (5%), rectal pain (26%), urinary infection (9%), scrotal edema (12%), and hematuria (5%). The mean follow-up was 21.9 months (range 1.2 to 54). Twenty-six patients (60%) reached a serum PSA nadir less than 0.1 ng/mL, 16 (37%) had a PSA less than 4 ng/mL, and 1 (3%) had a PSA less than 10 ng/mL. The bRFS rate was 79% at 6 months and 66% at 12 months. The bRFS rate was higher for patients who had an undetectable postcryotherapy PSA than for patients who did not reach a PSA less than 0.1 ng/mL (73% versus 30%, P = 0.0076). Using multivariate analysis, a PSA nadir greater than 0.1 ng/mL was an independent predictor of PSA recurrence. Conclusions. Current salvage cryotherapy of the prostate can result in undetectable serum PSA levels with low morbidity. Our data support the current safety and efficacy profile. We believe that cryotherapy is a viable option in the treatment of patients who have biopsy-proven local failure after radiation therapy for prostate cancer. Further refinements in technique and equipment may enhance cryosurgical results.

DIGITAL RECTAL EXAMINATION AND IMAGING STUDIES ARE UNNECESSARY IN MEN WITH UNDETECTABLE PROSTATE SPECIFIC ANTIGEN FOLLOWING RADICAL PROSTATECTOMY

We determine the probability of local or distant recurrence following radical prostatectomy in men with an undetectable prostate specific antigen (PSA) level. The clinical course of 1,916 consecutive men followed during a 14-year period after radical prostatectomy was reviewed. Average followup plus or minus standard deviation is 5.5+/-3.5 years, and 326 men (17%) have been followed for more than 10 years. In total this population of men has been followed for 10,540 patient-years. Of 1,916 men 56 (2.9%) had local recurrence an average of 6.1+/-2.7 years (range 1 to 12) after surgery. No man had local recurrence with an undetectable serum PSA. Mean serum PSA at the time of local recurrence was 5.8 ng./ml. Of the 56 men 13 (25%) who had local disease recurrence had an undetectable serum PSA at 5 years of followup but had progression to biochemical and local disease recurrence later. Of 1,916 men 118 had distant metastases with a mean serum PSA of 28.6 ng./ml. No man has had distant metastasis with an undetectable serum PSA. Disease can recur after radical prostatectomy even after an extended biochemical disease-free interval. None of the 1,916 men followed for an average of greater than 5 years after surgery had local recurrence or distant metastasis with an undetectable serum PSA. Based on these observations, we recommend no further evaluation, that is digital rectal examination or imaging studies, in men with an undetectable PSA following radical prostatectomy.

Clinically unsuspected and undetected (clinical stage t0) prostate cancer diagnosed on random needle biopsy

Objectives. To describe the findings in 4 patients who underwent radical prostatectomy for clinically undetected and unsuspected prostate cancer detected on random needle biopsy. Methods. We reviewed the Mayo Clinic Radical Prostatectomy Prostate Cancer Database of 5793 prostatectomies from 1987 to 1997, and identified 4 patients who had prostate cancer detected on random needle biopsy of the prostate with serum prostate-specific antigen (PSA) less than 4 ng/mL and normal digital rectal examination. Each had requested biopsy despite the absence of clinical suspicion of cancer; 3 had normal transrectal ultrasound, and the fourth had a benign hypoechoic lesion contralateral to the cancer. Results. Mean patient age at diagnosis was 65.5 years (range 61 to 67). Mean PSA was 2.4 ng/mL (range 2 to 2.9). Mean tumor volume was 3 cc (range 0.04 to 11.2). Mean Gleason grade at prostatectomy was 5.75 (range 5 to 7). Prostate cancer was Stage T2a in 1 patient (25%), T2c in 2 (50%), and T3a (25%) in 1. Three tumors were DNA diploid, and one was aneuploid. All patients were alive without evidence of cancer at a mean follow-up of 43 months (range 25 to 53) with undetectable serum PSA concentration. Conclusions. Our findings indicate that clinically unsuspected and undetected (clinical Stage T0) prostate cancer may be clinically significant. Patient insistence on biopsy reflects increasing concern among the public about prostate cancer. Current clinical thresholds for biopsy detection will fail for some patients with clinically significant prostate cancer.

Recombinant vaccinia-PSA (PROSTVAC) can induce a prostate-specific immune response in androgen-modulated human prostate cancer

Objectives. Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo. Methods. A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction. Results. Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline. Conclusions. Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.

RADIATION THERAPY FOR THE MANAGEMENT OF BIOPSY PROVED LOCAL RECURRENCE AFTER RADICAL PROSTATECTOMY

Purpose We determine which clinical characteristics correlate with a successful outcome following external beam radiation for the management of biopsy proved, locally recurrent prostate cancer after radical prostatectomy. Materials and Methods The clinical records of 34 patients who were treated at our institution with external beam radiation for biopsy proved local disease recurrence after radical prostatectomy were reviewed. Mean followup was 77.9 months after radical prostatectomy and 38.3 months after radiotherapy. Preoperative, postoperative and pathological characteristics were examined for the ability to predict failure following radiotherapy. Results Of the 34 patients 9 (26%) exhibited persistently low and stable serum prostate specific antigen (PSA) (less than 0.5 ng./ml.), while 7 (21%) had an undetectable serum PSA (less than 0.1 ng./ml.) during followup. These 16 patients were considered to be successfully treated by radiation and in the remaining 18 (53%) radiation was considered to have failed. The likelihood of successful treatment at 3 years after radiotherapy for all patients was 48%. Preoperative PSA, PSA at first elevation, postoperative PSA velocity and pathological stage were not significant predictors of a successful outcome following radiation treatment. Patients with a serum PSA of 4 ng./ml. or less before receiving radiotherapy and those with a prostatectomy specimen Gleason score of 7 or less were significantly more likely to be successfully treated by radiotherapy. Conclusions Radiation therapy is a viable treatment option for select patients with biopsy proved local disease recurrence following radical prostatectomy. The chance of achieving and maintaining a persistently low and stable or undetectable serum PSA is likely in those patients with a prostatectomy specimen Gleason score of 7 or less and a pre-radiation PSA of 4.0 ng./ml. or less. More effective treatment regimens are needed for those patients in whom radical prostatectomy fails.

Histological Presence of Viable Prostatic Glands on Routine Biopsy Following Cryosurgical Ablation of the Prostate

Cryosurgical ablation of the prostate has recently received much attention as a therapeutic alternative for the treatment of localized prostatic adenocarcinoma. Biopsies after treatment reveal a variety of dysplastic changes as well as unaltered prostatic glandular epithelial elements. Prostate specific antigen (PSA) remains undetectable in the majority of men. However, in some PSA increases without demonstrable local recurrence. A total of 383 patients underwent 447 procedures between June 1990 and January 1994. Of 358 biopsies performed at our institution, 317 (2,075 cores) were available for review. Each core was examined for unaltered prostatic glandular epithelial elements and then scored for the percentage of epithelial glandular involvement according to a scale of: 0-no, 0.5-less than 10%, 1-10 to 25%, 2-25 to 50%, 3-50 to 75% and 4-76 to 100% unaltered prostatic glandular epithelial elements. Of 317 biopsies 158 (49.8%) contained no unaltered prostatic glandular epithelial elements, while 185 (58.3%) and 206 (65%) had 1 core containing 10% and 10 to 25%, respectively, of such elements. Of 262 cases (82.6%) with a mean of 10% unaltered prostatic glandular epithelial elements per core 22 (8.4%) were positive for residual carcinoma. Among 55 cases with more normal epithelium per core 24 (43.6%) were positive for residual carcinoma. Patients with a positive biopsy had a median PSA of 2.02 ng./ml. (average gland/core score 0.54). Median PSA for men with negative biopsies was 0.2 ng./ml. (gland/core score 0.124). Cryosurgical ablation of the prostate has the ability to ablate prostatic tissue completely, thus rendering it free of glandular elements as determined by biopsy. Increasing PSA can indicate residual glandular elements. Increases in unaltered prostatic glandular epithelial elements with time are not paralleled by increased rates of local disease recurrence. undetectable serum PSA has a low risk of residual unaltered prostatic glandular epithelial elements and localized carcinoma. Results as measured by unaltered prostatic glandular epithelial elements and PSA improve with the surgical experience.

Cryosurgical Treatment of Localized Prostate Cancer (Stages T1 to T4): Preliminary Results

Purpose We determined the posttreatment biopsy results, prostate specific antigen (PSA) levels and complications associated with cryosurgical ablation of the prostate performed for localized prostate cancer. Materials and Methods Within 18 months 102 patients underwent cryosurgery as definitive therapy for localized prostate cancer. Mean patient age was 68 years and 57 percent had advanced local disease (stage T3 or T4). Mean preoperative PSA was 21.8 ng./ml. Results PSA was undetectable at 6 months in 48 percent of patients who received no androgen deprivation therapy following cryosurgery. Of 91 patients with postoperative biopsies 77 percent had no evidence of cancer but 71 percent had benign epithelial elements. The complication rate (excluding impotence) was 51 percent. Biopsy and PSA results improved with experience and changes in technique, that is double freezing, more lateral placement of cryoprobes and more aggressive freezing beyond the prostatic capsule. The most recent cohort of 77 patients had a detectable PSA rate of 23 percent and a positive post-cryosurgical biopsy rate of 11 percent. The most common serious complication encountered was bladder outflow obstruction requiring transurethral resection in 23 percent of the patients. Impotence occurred in 84 percent of patients potent preoperatively. Conclusions Cryosurgical ablation of the prostate can result in negative posttreatment biopsies and undetectable serum PSA levels. However, it is associated with significant side effects and the long-term durability of the procedure is unknown.

The Incidence of Prostate Cancer Progression with Undetectable Serum Prostate Specific Antigen in a Series of 394 Radical Prostatectomies

The Incidence of Prostate Cancer Progression with Undetectable Serum Prostate Specific Antigen in a Series of 394 Radical Prostatectomies

The Incidence of Prostate Cancer Progression with Undetectable Serum Prostate Specific Antigen in a Series of 394 Radical Prostatectomies

Purpose Serum prostate specific antigen (PSA) has been reported to be a sensitive indicator of recurrent carcinoma after radical prostatectomy but it is not absolute. Disease progression with undetectable PSA levels has been described but the incidence of this phenomenon is unknown. Materials and Methods We retrospectively analyzed the records of 394 consecutive men who underwent radical prostatectomy between 1980 and 1991 to characterize the incidence of recurrent carcinoma despite undetectable serum PSA levels. Results Of the 394 men 133 had documented evidence of disease recurrence, 3 (2.3 percent) despite undetectable serum PSA levels (2 had local and systemic evidence of disease progression). Histological dedifferentiation characterized these recurrences. Conclusions Although a post-prostatectomy detectable serum PSA level precedes clinical evidence of disease progression by years, rare patients (2.3 percent in our series) in whom recurrent disease is characterized by marked histological dedifferentiation will remain negative for PSA.

Can aggressive prostatic carcinomas be identified and can their natural history be altered by treatment?

The factors that determine tumor aggressiveness are multifactorial: age, stage, and grade. Even a well differentiated tumor in a young patient may be aggressive someday because of genetic drift and tumor heterogeneity. In a recent review of 826 favorably selected cases managed with conservative therapy, metastatic disease had developed in 19% with grade I tumors, 42% with grade II, and 74% with grade III at 10 years. Recognizing that < 20% of men present with grade I disease, most prostate cancers are a threat to life in men who are going to live longer than 10 years. On the other hand, some tumors at presentation are too far advanced to cure. To improve the accuracy of preoperative staging in identifying these cases, we have developed nomograms based upon clinical stage, grade, and serum prostate-specific antigen (PSA). Traditionally, patients with high-grade tumors (Gleason 8-10) were never considered candidates for radical prostatectomy because of their poor expectancy for long-term survival. However, with improvements in the staging of prostate cancer and with a reduction in the morbidity of radical prostatectomy, a subset of these patients are potential candidates for curative therapy. We have recently studied the clinical outcome of 72 men with Gleason scores of 8-10 on needle biopsies who presented with clinically localized disease (9 T1c, 22 T2a, 17 T2b, 13 T2c, and 11 T3a). Of the 63 men who underwent radical prostatectomy, 46 (68%) had negative lymph nodes; nine did not undergo surgery because of positive lymph nodes identified from frozen section. The actuarial likelihood of an undetectable serum PSA at 5 years was 43% for men with negative lymph nodes and 45% for men with organ-confined disease. Thus, with proper evaluation, some men with even the most aggressive tumors can be cured by surgery if their pelvic lymph nodes are negative.

Clearance of serum PSA after open surgery for benign prostatic hypertrophy, radical cystectomy, and radical prostatectomy

To study the clearance of serum prostate-specific antigen (PSA) after several types of prostatic tissue ablation. Serum PSA levels were measured (YANG Proscheck ultrasensitive assay) just before surgery, immediately after specimen removal, then twice weekly for 5 weeks or until it was undetectable (< 0.05 ng/ml) in patients undergoing radical cystoprostatectomy for bladder cancer (n = 10), or radical prostatectomy for T1 T2 prostate cancer (n = 18) and daily for 6 days after open surgery for benign prostatic hypertrophy (BPH) (n = 10). Open enucleation for BPH: the immediately postoperative PSA level was 6 times its preoperative value. It decreased following a monoexponential curve with a very short half-life of 0.55 +/- 0.39 days, range (0.14-1.3), reaching a value lower than the preoperative level in all cases, except one by day 3. After radical cystoprostatectomy: the decrease of serum PSA is monoexponential with a half life of 1.92 +/- 1.2 days (0.57-4.24) reaching undetectable level (< 0.05 ng/ml) in all patients by day 21. After radical prostatectomy: 11/18 patients (61%) showed a one-component exponential decrease in PSA with a half-life of 2.5 +/- 1.33 days (range 0.97-4.6 days), and 7/18 showed a two-component exponential decrease with a first half-life of 0.94 +/- 0.8 days and a second of 7.62 +/- 6.35 days); 100% of the patients reached undetectable serum PSA by day 28 in the first group compared to 14.2% of the patients with a two component exponential decrease (P < 0.01). There was no difference between these groups as far as preoperative PSA levels and specimen pathology were concerned. Serum clearance of PSA after extirpative prostatic surgery is closely related to the type and indication of procedure used. Radical cystoprostatectomy is probably the best model in which to study the pharmacokinetics of PSA.