Stage D2 Disease Research Articles

A primer for the student joining the adult cardiac surgery service tomorrow: Primer 1 of 7

A primer for the student joining the adult cardiac surgery service tomorrow: Primer 1 of 7

Favorable outcome of intraoperative radiotherapy to the primary site in patients with metastatic prostate cancer.

The aim of this study was to determine whether local radiotherapy to the prostate by intraoperative radiotherapy (IORT) increases the overall and cancer-specific survival rates of patients with metastatic prostate cancer. Between 1993 and 2000, 102 patients with prostate cancer were treated with a combination of (a) IORT of the prostate (25 or 30Gy per fraction); (b) external beam radiotherapy of the prostate (30Gy in 10 fractions), starting approximately 1week post-operatively; and (c) endocrine treatment. Of these, 16 patients had stage D1 disease (D1 IORT group), 32 had stage D2 disease without visceral metastasis (D2 IORT group), and 38 had stage D2 disease without visceral metastasis and did not receive local therapy (D2 control group). Overall and cancer-specific survival rates were compared. The 5- and 10-year cancer-specific survival rates were 75.9 and 52.7%, respectively, in the (D1+D2) IORT group and 45.8 and 33.5%, respectively, in the D2 control group, with cancer-specific survival being significantly longer in the D2 IORT than in the D2 control group (P=0.030). Univariate and multivariate reduced-rank regression analyses showed that extent of skeletal disease Grade 4 and non-regional lymph node metastasis were significantly prognostic of poorer cancer-specific survival (P<0.001 each). Local radiotherapy to the prostate by IORT in patients with metastatic prostate cancer may contribute to better survival, especially in patients without extent of skeletal disease Grade 4 or non-regional lymph node metastasis.

Prediction of survival by immunohistochemical stains (IHC) in stage D2 prostate cancer patients (pts): The importance of pTEN overexpression

e16019 Background: Several signal transduction pathways,important for apoptosis and angiogenesis were idendified and their expression and correlation with survival was studied by IHC in archival prostate cancer biopsies. All pts has androgen deprivation for stage D2 disease and were followed at 3 month intervals. Methods: In an IRB approved study,42 pts had adequate tissue preserved between 1992 and 2006 and their charts were reviewed retrospectively.IHC stains to detect tumor expression of S6(ribosomal),p70s6,pTEN,AKT-1,BCL-1(Cyclin D1),VEGF,c-KIT,PDGFR-alpha and PDGFR-beta were performed by US Labs(Irvine,CA).All results were independently evaluated by two pathologists.Immunoreactivity was scored using a semiquantitative system combining intensity of staining(0–3+) and percentage of cells staining positive(0–3+).The total score was obtained by adding the scores for indensity and the percentage of positive cells,then averaging the resuts obtained by each reader.For the purpose of this study, stain intensity of 0–1+ was considered negative and the intensity of 2–3+ was considered positive.A Cox regression survival model for each stain was developed with variables known to predict survival :Gleason score,Hemoglobin(Hgb),Alkaline Phosphatase(Alk Phos),Prostate Specific Antigen(PSA),Lactate Dehydrogenase(LDH) levels. Results: The median values were: age 70yrs(56–92),Gleason score 8(6–10), LDH 171 IU/L(97–350),Hgb 12.9gm/dl (6.8–16.3), PSA 188ng/ml(2–5677),Alk Phos 139U/L(60–1756),survival 851 days(163- 6102).In univariate analysis,VEGF staining was predictive of survival (p&lt;0.037) but not in multivariate analysis.The pTEN staining correlated with survival (p&lt;0.0367) and a hazard ratio of 0.040 in multivariate analysis. Conclusions: In this small sample of pts, overexpression of S6,p70s6,AKT-1,BCL-1,VEGF,c-KIT,PDGFR-alpha and PDGFR-beta by IHC staining did not predict survival independently.The pTEN staining,however was strong predictor of survival in the multivariate analysis. No significant financial relationships to disclose.

Long-term outcome of patients treated with docetaxel for hormone-dependent prostate-specific antigen (PSA) progression after local therapy for prostate cancer

16030 Background: Mechanisms of chemotherapy resistance increase as cancer progresses, and a treatment approach that targets prostate tumors early, before hormonal therapy, may result in an improved outcome. A long-term outcomes analysis of our prior published study (treating patients for up to 8 months of docetaxel) was conducted to determine if the natural history of patients with PSA progression was altered by docetaxel. Methods: Twenty patients treated on our prior study were assessed for long-term follow up at a median of 9.4 years. All patients were followed until PSA progression (increase of 2 ng/mL over nadir) without the introduction of androgen ablation therapy, but may have received androgen ablation prior to radiographic progression (i.e., metastatic disease). One patient was excluded from the current analysis due to stage D1 disease pre-trial. Time to PSA progression, time to radiographic progression, and mortality were assessed. Comparisons were made between responders and non-responders to docetaxel (responders = PSA decrease ≥ 50%). Kaplan-Meier curves were constructed for the time to radiographic progression and mortality data. Results: Nineteen patients were treated on the original study with a mean time to PSA progression after local therapy of 3.3 years and a mean pre-trial PSA doubling time of 186 days. On docetaxel therapy, 8 (42%) of 19 patients demonstrated a decrease in PSA by ≥ 50% for at least 4 weeks. The median time to PSA progression after trial end was 57.5 vs. 20.0 days among PSA responders and non-responders respectively. The median time to radiographic progression from diagnosis of prostate cancer was 56.5 (95% CI: 27.7 to 99.8) vs. 45.3 months (95% CI: 40.3 to 82.5) among PSA responders and non-responders respectively. There were 4 deaths in the follow up period. Conclusions: Although treatment with docetaxel did not appear to alter overall progression in this small study, the trend towards longer time to disease progression in PSA responders suggests activity, and warrants larger studies of chemotherapy in this patient population. No significant financial relationships to disclose.

Is the flare phenomenon clinically significant?

Objectives: The existing luteinizing hormone–releasing hormone (LHRH) analogs have been the preferred method of inducing androgen deprivation for prostate cancer for over a decade. These agents are well known to cause a surge in serum testosterone levels during the first week of therapy. However, there are wide discrepancies in reports of the frequency and severity of acute clinical progression or clinical flare that might result from the testosterone surge. Also, there is not a clear consensus as to whether antiandrogens should be routinely given to all patients during the first month of LHRH therapy to prevent flare responses. Methods: Clinical trials involving LHRH analog therapy for prostate cancer were reviewed, and the frequency of clinical flare responses noted. Particular attention was given to the kinds of clinical problems associated with the flare response. The use of LHRH analog therapy in treatment of patients with prostate cancer for indications other than overt metastatic disease is discussed, because this is becoming a much more common use of these agents. This article analyzes 2 placebo-controlled, double-blind trials testing the effectiveness of existing antiandrogens in ameliorating flare responses. Results: The use of LHRH analogs for patients with stage D2 disease can be associated with clinical flare in approximately 10% of D2 patients. In addition to bone pain, cord compression, and bladder outlet obstruction, another potentially severe side effect is cardiovascular risk arising presumably from hypercoagulability associated with a rapid increase in tumor burden. In clinical series involving D2 patients, the frequency of clinical flare greatly varies, probably because of the level of scrutiny of the investigator and/or the prostate-cancer tumor burden present at the initiation of therapy. Concomitant antiandrogen therapy reduces, but does not totally eliminate, the flare responses in patients at high risk for flare. Treating prostate cancer in the D0 stage or in the neoadjuvant setting will result in biochemical evidence of testosterone surge, but these patients are at very little risk for clinical flare responses. Conclusions: There is a wide variation in the reported frequency of clinical flare responses from LHRH analogs during the initial treatment of patients with stage D2 disease. The risk-to-benefit ratio, especially in patients with symptomatic bone metastasis, would dictate routine use of antiandrogen therapy for the first month of LHRH analog treatment. For patients at risk for cord compression, other means of ablating testosterone might be considered, such as ketoconazole, orchiectomy, or LHRH antagonists. Clinical flare responses, as opposed to biochemical flare responses, are very rare during LHRH analog therapy for stage D0 disease and/or in the setting of neoadjuvant hormonal therapy.

The role of diethylstilbestrol in the treatment of prostate cancer

Objectives: Diethylstilbestrol administration was a classic form of androgen deprivation therapy (ADT) that gradually fell out of favor because of its cardiovascular toxicity, economic disinterest on the part of manufacturers, and the emergence of novel therapeutic agents with a superior safety profile. The cost of contemporary agents and the efficacy of diethylstilbestrol (DES) have perpetuated the evaluation of this agent, especially in the circumstance of early hormone-refractory (clinical stage D2.5) disease. The objective of this study is to evaluate the status of DES-based therapies, and assess their efficacy and toxicity as a viable form of ADT. Methods: Current research from single-institution and group studies, as well as basic scientific investigations related to DES, were assessed with regard to the population studied, dosage, criteria for response, response rate, duration of response, and toxicity. Results: Contemporary basic research has demonstrated a direct apoptotic effect of DES on prostate cancer cells. There is also evidence to support the ability of DES to suppress testosterone production at extratesticular sites and inhibit dihydroepiandrosterone sulfate serum levels. Contemporary cooperative group trials for stage D2 disease incorporating a DES arm have demonstrated therapeutic efficacy and equivalence to orchiectomy, which is marred by significant cardiovascular toxicity. In smaller single-institution studies (n = 17 to 38) of patients with D2.5 disease, an average response rate of 55% is noted with a mean time to clinical progression of 6.4 months (2 to 18). Cardiovascular toxicity occurred in 10% to 30% of patients, with events including deep vein thrombosis, myocardial infarction, and transient ischemic attack. Edema and gynecomastia was also noted. Strategies to reduce thromboembolic events, such as dose reduction or the use of warfarin sodium were unsuccessful, whereas the use of low-dose aspirin (100 mg daily) resulted in only 1 of 38 vascular events. Conclusions: In contemporary studies of DES as an agent for ADT in D2.5 patients, a reasonable response rate (40% to 60%) of modest duration (5 to 8 months) is noted. Cardiovascular complications still persist, requiring the development of safe, effective antithrombolic therapy to take advantage of this phenomenon.

Circulating neuroendocrine markers in patients with prostate carcinoma

Circulating neuroendocrine markers were measured in patients with prostate carcinoma (PC), prostatic intraepithelial neoplasia (PIN), and benign prostatic hypertrophy (BPH) with the goal to: 1) evaluate the differences in the expression of these markers in patients with benign, premalignant, and primary or metastatic PC; 2) evaluate their prognostic significance; 3) compare values in patients with hormone-naive and hormone-refractory disease; and 4) assess changes after androgen deprivation or chemotherapy. Serum neuron specific enolase (NSE) (immunoradiometric assay) and plasma chromogranin A (CgA) (enzyme-linked immunoadsorbent assay) were evaluated in 141 patients with BPH, 54 patients with PIN, and 159 patients with PC; 119 patients were bearing hormone-naive disease and 40 were bearing hormone-refractory disease. CgA was monitored in 31 patients submitted to androgen deprivation and in 24 patients receiving chemotherapy. Supranormal CgA was observed more frequently in patients with American Urologic Association (AUA) Stage D2 disease (45.5%) compared with those with Stage D1 disease (33.3%), Stage C disease (16.7%), Stage A/B disease (18.8%), PIN (25.9%), and BPH (17.0%) (P < 0.02). Supranormal NSE did not change in any of the patient subgroups. Elevated CgA was observed in 36.0% of patients with metastases who had hormone-naive disease and in 45.0% of patients with hormone-refractory disease (P value not significant). Supranormal NSE and CgA values were predictors for poor prognosis in patients with hormone-refractory disease. Elevated baseline CgA values decreased > 50% in 1 of 12 patients who received luteinizing hormone-releasing hormone analogs and in 2 of 12 patients who underwent chemotherapy. CgA appears to reflect the neuroendocrine activity of PC better than NSE. Elevated CgA values correlate with poor prognosis and are scarcely influenced by either endocrine therapy or chemotherapy.

Biochemical response to testicular androgen ablation among patients with prostate cancer for whom flutamide and/or finasteride therapy failed

Objectives. To evaluate the response of testicular androgen ablation in patients with advanced prostate cancer with a biochemical recurrence after finasteride or combined finasteride and flutamide therapy. Methods. Eighteen hormone naı̈ve men with advanced prostate cancer (10 with detectable prostate-specific antigen [PSA] levels after radical prostatectomy, 4 with rising PSA levels after definitive radiation therapy, and 4 with Stage D2 disease) were treated with finasteride (5 mg/day) alone or in combination with flutamide (250 mg three times a day). All men experienced an initial reduction in serum PSA, but later had treatment failure with two consecutive rising PSA measurements. All men were then treated with testicular androgen ablation (bilateral orchiectomy in 15 and luteinizing hormone-releasing hormone analogue in 3). Results. Overall, serum PSA declined by more than 80% in 15 (83%) of 18 and to undetectable levels in 14 (78%) of 18. With a median ± semi-interquartile range follow-up of 22 ± 14.5 months from the initiation of hormone therapy, 12 (67%) of 18 currently have undetectable PSA levels. Two men having rising serum PSA levels above 100 ng/mL and 1 man has died from complications of metastatic prostate cancer. Conclusions. Testicular androgen ablation effectively lowers serum PSA levels in most men with advanced prostate cancer who have experienced a biochemical recurrence despite initial response and subsequent relapse on finasteride or combined finasteride and flutamide therapy.

A worse prognosis for men with testicular atrophy at therapeutic orchiectomy for prostate carcinoma.

The significance of testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma has not been examined even though pretreatment hypogonadism has been associated with poor prognosis during chemical androgen ablation for these tumors. Survival after therapeutic orchiectomy was determined for 78 men with prostate carcinoma and related to the histologic severity of testicular atrophy. Included in analysis were the presence or absence of prior radiation therapy, tumor grade and stage at diagnosis, host age, obesity, and smoking habits. Among 35 men who underwent therapeutic orchiectomy for progressive disease after primary radiation therapy to the prostate bed, the 25 men with testicular atrophy had worse 5-year, tumor specific, postorchiectomy survival than the 10 men without testicular atrophy (30% vs. 89%) (P=0.02). These 25 men had tumors of more advanced stage and greater undifferentiation at the time of diagnosis an average of 45 months before orchiectomy, but neither characteristic was related to postorchiectomy survival. Among 25 men with Stage D2 disease (American Urologic Association staging system) with orchiectomy as the primary treatment, the 7 men with testicular atrophy more often had undifferentiated tumors and had lower 2-year tumor specific survival than the 18 men without atrophy (43% vs. 72% ) (P > 0.10). Testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma is associated with poor postorchiectomy prognosis in men with prior prostate bed radiation therapy and perhaps in men without prior radiation. The association may reflect a high frequency of inherently more aggressive tumors (often relatively nonandrogen-dependent) among those tumors that are progressing in hypogonadal men.

Incidence of Lymph Node Metastasis and its Impact on Long‐term Prognosis in Clinically Localized Prostate Cancer

Pelvic lymph node dissection (PLND) is an important staging method for men with clinically localized prostate cancer. We report our experience with staging PLND and the impact of lymph node metastasis on long-term prognosis. One hundred forty-eight consecutive patients who underwent staging PLND for clinically localized prostate cancer were retrospectively studied. Patients were evaluated for the presence and number of lymph node metastases, treatment (prostatectomy vs. radiotherapy), and endocrine therapy, and analyzed with respect to disease progression and survival. The mean follow-up period was 52.9 months (range, 2.3 to 165.8 months). Thirty-two patients (21.6%) had pelvic lymph node metastases, the incidence of which markedly decreased from 32.3% in 1982 to 1987 to 6.7% in 1994 to 1997. The intervals to disease progression and cancer death were significantly shorter in patients with positive lymph nodes (P < 0.001). In stage D1 disease, patients who underwent a radical prostatectomy tended to be free of progression longer than those receiving radiotherapy or conservative therapy (P = 0.0546). Other factors, such as early endocrine therapy, the extent of lymph node involvement and the Gleason score of the primary tumor did not predict disease progression or survival. These data suggest a decreasing trend in the incidence of lymph node metastasis in the PSA era. Although longer disease-free intervals were observed in radical prostatectomy-treated patients, the impact of an aggressive approach to stage D1 disease awaits further studies.

Effect of laparoscopic pelvic lymph node dissection on the natural history of D1 (T1-3, N1-3, MO) prostate cancer

Reports of abdominal wall tumor implantation after laparoscopic procedures have raised questions regarding the safety of laparoscopic surgery when applied to patients with malignancies. Our objective was to determine if laparoscopic pelvic lymph node dissection (LPLND) had a negative effect on tumor behavior and clinical outcome in men with Stage T1-3, N1-3, M0 (D1) prostate cancer. Fifty-two men were retrospectively identified at four institutions who had pelvic nodes positive for metastatic prostate adenocarcinoma at LPLND and at least 1 year of follow-up. Operative and clinical records were reviewed to determine morbidity, adjuvant treatment, onset of hormone-resistant disease, and survival. During a mean follow-up of 3.1 years, there were no cases of trocar site tumor implantation. There were four perioperative complications, including enterotomy, epigastric vessel injury, abscess, and symptomatic lymphocele formation. There were three deaths from prostate cancer (5.8%) occurring 3 to 4 years after LPLND. For the 45 men treated with early androgen ablation, the 5-year biochemical prostate-specific antigen and clinical progression free rates were 45% and 55%, respectively. Abdominal wall tumor implantation after LPLND for prostate cancer was not demonstrated, even in patients who developed hormone-resistant disease. LPLND in men with Stage D1 disease did not alter short-term disease progression. Longer follow-up in a larger cohort is necessary to determine if LPLND will have an impact on the 5 and 10-year disease progression and survival rates for patients with Stage D1 prostate cancer.

Stage D1 (T1-3, N1-3, M0) Prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy

Objectives There is no consensus on the management of Stage D1 prostate cancer. The literature suggests that radical prostatectomy, as compared with pelvic lymphadenectomy (PLND) alone, may extend survival. Despite evidence that lymph node tumor burden influences cancer survival, few groups of researchers have controlled for this variable when comparing management strategies. We performed a study that was case-controlled for nodal tumor burden to determine if a survival advantage exists for radical prostatectomy. Methods Of 168 men with Stage D1 disease diagnosed between 1983 and 1995, 127 underwent pelvic lymphadenectomy and radical retropubic prostatectomy (PLND/RRP) and 41 underwent PLND alone. Clinical charts were reviewed for follow-up, and lymph node tumor burden was assessed by volume of nodal metastases and the percentage of positive nodes sampled. Adjuvant treatment was based on the surgeon's preference and clinical situation. Nineteen patients from each group were matched for age, PSA, Gleason score, clinical stage, follow-up, and nodal tumor burden. Results Comparison of the non-case-controlled PLND/RRP and PLND groups showed no differences in age, prostate-specific antigen level, Gleason score, clinical stage, or follow-up. The nodal tumor burden was greater for the PLND group (P = 0.001). The 10-year cancer-specific survival rates for the PLND/RRP and PLND groups were statistically different (P = 0.006). In the case-controlled group, the results were similar for cancer-specific survival at 10 years (56% and 34%, respectively; P = 0.09). Conclusions These data suggest that in Stage D1 prostate cancer, a trend toward a statistical difference in survival may exist for radical prostatectomy as compared with conservative treatment. Further case-controlled and prospective randomized studies are needed to verify these results.

Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate

Objectives. Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide. Methods. Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride 5, mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first second nadir PSA values. Results. The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 ± 38.2 ng/mL at baseline and 7.8 ± 2.7 and 4.7 ± 2.2 ng/mL at the first and second PSA nadir values, respectively ( P = 0.034). Mean percent decline in PSA value from baseline was 87.0 ± 3.1% with flutamide alone and 94.0 ± 1.9% with both flutamide and finasteride ( P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 ± 14.7% of baseline ( P = 0.0001), DHEA fell a mean of 32.4 ± 4.6% ( P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 ± 6% ( P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 ± 4.7% ( P = 0.0009). Conclusions. Finasteride and flutamide were safe and well tolerated at AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.

The Value of Serum Carboxyterminal Propeptide of Type 1 Procollagen in Predicting Bone Metastases in Prostate Cancer

Purpose Carboxyterminal propeptide of type 1 procollagen (P1CP) is believed to be a marker of new bone formation. We investigated the possible application of serum P1CP as a biochemical marker for bone metastases in patients with prostate cancer. Materials and Methods Prostate specific antigen (PSA), prostatic acid phosphatase (PAP), P1CP and alkaline phosphatase were measured in 136 serum samples from 79 patients with untreated prostate cancer, 29 with stage D2 disease in remission and 28 with progressive stage D2 carcinoma. Results Serum P1CP and alkaline phosphatase were significantly elevated in untreated patients with a positive bone scan (278.9 +/− 61.9 ng./ml. and 826.5 +/− 176.3 international units per l., respectively) compared to those with a negative bone scan (104.2 +/− 4.2 and 200.8 +/− 9.1, respectively, p <0.05). The areas under receiver operating characteristics curves were 0.86 for P1CP, 0.87 for alkaline phosphatase, 0.88 for PSA and 0.85 for PAP. The best accuracy rates for P1CP, alkaline phosphatase, PSA and PAP to predict bone lesions were 84, 87, 86 and 84%, respectively. P1CP provided a greater specificity and positive predictive value. These serum markers correlated significantly with the extent of disease on bone scan (p <0.05). The incidence of positive serum P1CP and alkaline phosphatase decreased significantly in response to endocrine therapy in patients with bone metastasis, and increased progressively in association with progression of the tumor (p <0.05) parallel to PSA and PAP. Conclusions These findings suggest that serum P1CP is a useful indicator for predicting bone metastases.

Prostate Specific Antigen Decreases After Withdrawal of Antiandrogen Therapy with Bicalutamide or Flutamide in Patients Receiving Combined Androgen Blockade

Purpose We determined whether decreases in prostate specific antigen (PSA) would occur after withdrawal of double-blinded antiandrogen therapy with flutamide or bicalutamide for clinical progression or increasing PSA concentration in patients receiving combined androgen blockade for advanced prostate cancer. Materials and Methods PSA concentrations were determined weekly for at least 6 weeks and then every other week for 6 weeks in 22 patients with stage D2 prostate cancer. All patients were withdrawn from antiandrogen therapy (8 flutamide and 14 bicalutamide) due to progression or an increasing PSA concentration. Objective response was evaluated before antiandrogen withdrawal and at week 12. Results In 4 of 8 patients (50%) withdrawn from flutamide and 4 of 14 (29%) withdrawn from bicalutamide serum PSA concentrations decreased by 50% or more. PSA responses after withdrawal of flutamide therapy occurred within the first few days, whereas those after withdrawal of bicalutamide therapy occurred within 4 to 8 weeks. Of 4 patients assessed for objective response 2 had stable disease and 2 had progression. A PSA response was observed in the 2 patients with stable disease but not the 2 with progression. Conclusions For patients with stage D2 prostate cancer and disease progression or an increasing PSA concentration, withdrawal of antiandrogen therapy with bicalutamide or flutamide may result in a PSA response. The time to PSA response is longer with bicalutamide than with flutamide. The clinical significance of the antiandrogen withdrawal phenomenon is unknown.

C-erbB-2 oncoprotein: a potential biomarker of advanced prostate cancer.

Overexpression of the c-erbB-2 oncogene has been implicated in the development and/or prognosis of several human carcinomas, including that of the prostate. Recently, c-erbB-2 protein was found to be released in the circulation. The present study was undertaken to study the significance of serum c-erbB-2 protein determination in men with prostate cancer. Serum c-erbB-2 protein determination was performed via immunoradiometric assay using two monoclonal antibodies that react with the extracellular domain of the protein. The study population consisted of 71 untreated prostate cancer patients. Of those, 33 with stage D2 disease entered a follow-up study. As control, serum c-erbB-2 protein levels were determined in 92 patients with benign prostatic hypertrophy. In addition, elevations of c-erbB-2 protein were examined in patients with various disease statuses: clinically well controlled (28 patients), disease progression (24 patients), and end-stage disease (17 patients). Elevation of serum c-erbB-2 protein level was observed in patients in advanced stages, such as stage D2 disease (30%), disease progression (42%), and end-stage disease (82.4%). In the follow-up study, patients with an elevated c-erbB-2 level had a significantly shorter interval to disease progression than did those with a normal level. The results suggest that c-erbB-2 can be used as a biomarker to identify a malignant subgroup in prostate cancer.

Chromosomal Anomalies in Stage D1 Prostate Adenocarcinoma Primary Tumors and Lymph Node Metastases Detected by Fluorescence in Situ Hybridization

We determined if characteristic chromosomal anomalies exist within the primary tumors and lymph node metastases in patients with stage D1 prostate cancer, and compared the patterns of chromosomal alterations between primary tumors and nodal metastases. Fluorescence in situ hybridization analysis using peri-centromeric probes for chromosomes 6, 7, 8, 17, X and Y was performed on 5 mu. sections from paraffin embedded tissue blocks obtained from 23 consecutive patients who underwent radical prostatectomy and bilateral pelvic lymphadenectomy in 1990 for stage D1 prostate cancer. The dominant focus of primary tumor was compared to matched nodal metastases in 12 cases. Five of 12 primary tumor foci (41.7%) had similar chromosomal gains and the same fluorescence in situ hybridization ploidy result as the corresponding nodal metastases. Chromosomes 7 and X (73.2% of cases) were most frequently gained in the primary tumors, and chromosomes X and Y (81.2% of cases) were most frequently gained in the metastases. No primary tumor or metastasis demonstrated chromosomal loss. Three of 19 primary tumors (15.7%) were diploid, while 16 of 19 (84.3%) were nondiploid. Chromosomal aneusomy was inversely correlated with increasing Gleason summary score. These data indicate that the dominant primary tumor foci may not give rise to nodal metastases, gains of chromosomes 7, X and Y may be associated with metastatic behavior, and patients with stage D1 disease have a greater rate of aneuploidy than those with lower stage cancer.

Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: A pilot study

Objectives To affirm the feasibility of using intermittent androgen suppression in patients with hormonenaive prostate cancer. Methods Leuprolide and flutamide were administered for 9 to 12 months and then discontinued until prostate specific antigen (PSA) levels reached a threshold value determined by the baseline PSA value. This constituted one cycle of treatment. Androgen suppression was then administered intermittently as described until there was evidence of androgen independence. Results Twenty-two patients with PSA failure after primary therapy with surgery and/or radiation and untreated early or Stage D2 disease were treated. Twenty-one patients completed androgen suppression during cycle 1, with a median time to PSA nadir of 3.5 months (range, 2 to 12). Fifteen patients completed cycle 1 with a median time off treatment of 6 months (range, 2 to 19) or 38% (range, 17% to 64%) of a treatment cycle. Six patients continued off treatment during cycle 1 for 1 + to 31 + months. During cycle 2, 12 patients achieved a PSA nadir in a median time of 3.5 months. Two patients completed cycle 2 with a median time off treatment of 10 months (51%). Median follow-up for all patients is 26 months (range, 10 to 51). While off treatment, all patients reported a reduction of symptoms associated with androgen suppression. Conclusions Intermittent androgen suppression is a feasible alternative to continuous androgen suppression for treatment of prostate cancer, and quality of life is improved while off treatment.

Immunoassay and immunohistology studies of chromogranin A as a neuroendocrine marker in patients with carcinoma of the prostate

Objectives. Neuroendocrine differentiation in carcinoma of the prostate is characterized by the expression of neuroendocrine cell products such as chromogranin A (CgA). We studied serum levels and tissue staining for CgA in prostate cancer to assess their clinical value. Methods. In 82 patients with prostate cancer, serum specimens were obtained at diagnosis and studied by both CgA and prostate-specific antigen (PSA) immunoassays. In 43 additional patients with prostate cancer, paraffin-embedded tissue from core biopsies or transurethral resections and serum samples were studied, respectively, by immunohistology and immunoassay for CgA. Results. In serum samples from the 82 patients in whom CgA and PSA levels were measured, 26 of 82 (32%) had an elevated CgA (greater than 200 ng/mL), and 36 of 82 (44%) had an elevated PSA (greater than 4.0 ng/mL). Of the patients with Stage D2 cancer, 11 of 18 (61%) had an elevated CgA and 6 of 18 (33%) had an elevated PSA. Four of 5 patients with local recurrence had an elevated CgA, but only 1 patient had an elevated PSA. Of the 43 patients in whom serum and tissue CgA studies were performed, 12 (28%) had elevated serum CgA, and 15 of the 43 (35%) had CgA staining in their prostate tissue. Of the 14 of these patients with D2 disease (distant metastases), 9 (64%) had elevated serum levels of CgA and 6 (43%) had positive staining in their prostate tissue. Of the 9 patients with Stage D2 disease and elevated serum CgA, 6 had a normal serum PSA. Conclusions. Our studies complement those of others and indicate that CgA has potential as a clinically useful serum and tumor marker for prostate cancer. Serum CgA measurements can identify some patients with advanced disease who do not have elevated serum PSA. However, further studies in larger groups of patients are needed to define the clinical value of CgA as a marker for prostate cancer.

A clinical study of radial prostatectomy

The objective of this study is to evaluate the efficacy of radical prostatectomy for patients with organ-confined prostate cancer. From 1990 to 1994, a total of 50 patients with prostate cancer underwent radical retropubic prostatectomy. Eleven patients were in state A2, 34 in stage B and 5 in stage C according to clinical stage. Extended disease was observed pathologically in 45%, and 59% of patients in clinical stages A2 and B, respectively. Preoperative serum PSA levels were closely correlated with pathological extension of the disease. The disease-free rates for organ-confined disease, extended disease without lymph node metastasis and stage D1 disease were 75% (3 years), 82% (2 years) and 80% (3 years), respectively. Four patients had rectal injuries, and three of these underwent temporary colostomy diversion. Two patients had bladder neck contracture and received internal urethrotomy. Urinary incontinence improved in 60% of patients during the first 6 post-operative and in 90% of patients within 12 post-operative months. Urinary incontinence tended to improve earlier in patients with nerve-sparing than those without it. The erectile capacity in nerve sparing patients recovered good. Our results indicate that radical prostatectomy is a safe and temporarily satisfactory treatment for the patient with organ-confined prostate cancer.