Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy

BACKGROUND: Salvage radical prostatectomy is a treatment option for patients with recurrent cancer following radiation therapy. This study was conducted to identify predictors of survival for patients treated with salvage radical prostatectomy. METHODS: The authors studied 86 prostate carcinoma patients who underwent salvage radical prostatectomy for locally persistent or recurrent prostate carcinoma at Mayo Clinic between 1967 and 1996. The mean interval from radiation therapy to biopsy-proven recurrence was 3.7 years (range, 6 months to 17 years). Patient age at surgery ranged from 51 to 78 years (median, 66 years). The mean follow-up after surgery was 5.8 years (range, 1.0-15.2 years). Cox proportional hazards models were used to identify clinical and pathologic factors associated with distant metastasis free survival and cancer specific survival. RESULTS: Actuarial distant metastasis free survival, cancer specific survival, and overall survival were 83%, 91%, and 85% at 5 years and 69%, 64%, and 54% at 10 years, respectively. In multivariate analysis, radical prostatectomy Gleason score and DNA ploidy were independent predictors of distant metastasis free survival and cancer specific survival. CONCLUSIONS: Postirradiation Gleason score and DNA ploidy were highly predictive of the clinical outcomes of patients treated by salvage radical prostatectomy after radiation therapy.     

Predictors of pathological stage before neoadjuvant androgen withdrawal therapy and radical prostatectomy. The Canadian Urologic Oncology Group

PURPOSE: This prospective randomized trial was used to compare predictive factors for organ confined margin negative status after radical prostatectomy with and without a 3-month course of neoadjuvant androgen withdrawal therapy. MATERIALS AND METHODS: A total of 213 patients with localized adenocarcinoma of the prostate were randomized to radical prostatectomy with or without a 3-month course of 300 mg. neoadjuvant cyproterone acetate daily. Multivariate logistic regression analysis was used to determine significant predictors of organ confined margin negative status after radical prostatectomy in both groups. Parameters evaluated included baseline prostate specific antigen (PSA 4 or less, 4.1 to 10, greater than 10 ng./ml.), clinical stage (T2c versus T2b or less), biopsy Gleason score and percentage of surface area of biopsies involved with cancer. The multivariate analysis was repeated with PSA density and the natural logarithm of PSA to optimize the model. RESULTS: In the radical prostatectomy alone arm a model incorporating only PSA density was the best predictor of organ confined margin negative status. In the neoadjuvant androgen withdrawal therapy arm a model incorporating biopsy Gleason score, PSA density and clinical stage was the best predictor. CONCLUSIONS: The conventional predictors of pathology at radical prostatectomy, biopsy Gleason score, PSA density and clinical stage retain significance as predictors in patients treated with a 3-month course of neoadjuvant androgen withdrawal therapy before radical prostatectomy.     

Intrathecal clonidine alleviates allodynia in neuropathic rats: interaction with spinal muscarinic and nicotinic receptors

PURPOSE: There has been a significant shift toward multimodality therapy to try to eradicate extracapsular disease better in patients with locally advanced prostate cancer. We assess the feasibility and complications of initial cryotherapy followed by radical prostatectomy, and evaluate the frequency and location of viable benign and malignant prostate tissue and positive surgical margins after this treatment combination. MATERIALS AND METHODS: A total of 12 patients with clinical stage T3 cancer or clinical stages T1c to T2, Gleason score 8 to 10 cancer on the initial biopsy were treated with initial cryotherapy followed by open surgical exploration 2 to 8 days later. If pelvic lymph nodes were negative, radical prostatectomy was performed. Prostate specific antigen was measured approximately every 3 months postoperatively, and complications were assessed by retrospective chart review and a quality of life survey. RESULTS: Radical prostatectomy was aborted in 5 patients with positive pelvic lymph nodes. Of the 7 patients who underwent prostatectomy 4 had no residual prostate cancer in the specimen (pathological stage pT0 disease). All 7 of these patients had focal areas of viable normal prostate glands. Only 1 of the 7 patients had a positive surgical margin and biochemical failure (mean followup 22.6 months). The main complications of cryotherapy followed by radical prostatectomy were urinary incontinence and impotence. CONCLUSIONS: Neoadjuvant cryotherapy achieved complete tumor destruction in 4 of 7 patients with locally advanced prostate cancer. Cryotherapy followed by radical prostatectomy was associated with substantial morbidity, mainly in terms of urinary incontinence.     

Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide-induced production of interleukin-1 and tumour necrosis factor alpha in mice

PURPOSE: To evaluate whether transient androgen deprivation improves outcome in patients irradiated after radical prostatectomy for locally advanced disease, persistent or rising postoperative prostate specific antigen (PSA), or local recurrence. METHODS AND MATERIALS: Records of 105 consecutive patients who were treated with pelvic irradiation after radical retropubic prostatectomy between August 1985 and December 1995 were reviewed. Seventy-four patients received radiation alone (mean follow up: 4.6 years), and 31 received transient androgen blockade with a gonadotropin-releasing hormone agonist (4) androgen receptor blocker (1) or both (24) beginning 2 months prior to irradiation (mean follow-up 3.0 years) for a mean duration of 6 months. Two of these patients were excluded from further analysis because they received hormonal therapy for more than 1 year. Patients received a prostatic fossa dose of 60-70 Gy at 2 Gy per fraction; 48 patients also received pelvic nodal irradiation to a median dose of 50 Gy. Survival, freedom from clinical relapse (FFCR), and freedom from biochemical relapse (FFBR) were evaluated by the Kaplan-Meier method. Biochemical relapse was defined as two consecutive PSA measurements exceeding 0.07 ng/ml. RESULTS: At 5 years after irradiation, actuarial survival for all patients was 92%, FFCR was 77%, and FFBR was 34%. FFBR was significantly better among patients who received transient androgen blockade before and during radiotherapy than among those treated with radiation alone (56 vs. 27% at 5 years, p = 0.004). FFCR was also superior for the combined treatment group (100 vs. 70% at 5 years, p = 0.014). Potential clinical prognostic factors before irradiation did not differ significantly between treatment groups, including tumor stage, summed Gleason histologic score, lymph node status, indication for treatment, and PSA levels before surgery or subsequent treatment. Multivariate analysis revealed that transient androgen deprivation was the only significant predictor for biochemical failure. CONCLUSION: This retrospective study of irradiation after radical prostatectomy suggests that transient androgen blockade and irradiation may improve freedom from early biochemical and clinically evident relapse compared to radiotherapy alone, although more prolonged follow-up will be needed to assess durability of impact upon clinical recurrence and survival rates.     

Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer

PURPOSE: During radical prostatectomy for prostate cancer tumor at the surgical margin is a relatively frequent finding. We summarize the literature on the incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy. MATERIALS AND METHODS: The literature was reviewed for data on positive margins during radical prostatectomy for prostate cancer. RESULTS: Positive surgical margins may result from artifacts induced by tissue processing, incising inadvertently into the prostate or incising into extraprostatic tumor that has extended beyond the limits of resection. Patients with 10 ng./ml. or greater preoperative prostate specific antigen, biopsy Gleason score 7, multiple positive biopsies, or clinical stage T2b, T2c or T3 cancer have a higher risk of positive margins. Preoperative endorectal magnetic resonance imaging may be useful in staging a select group of patients. Neoadjuvant androgen deprivation reduces the incidence of positive margins but does not appear to delay progression or improve survival. The surgical approach, retropubic or perineal, may influence the location and etiology of positive margins. In general, nerve and bladder neck sparing procedures do not compromise tumor removal in appropriately selected patients. Positive margins increase the risk of progression and correlate with decreased cancer specific and overall survival. There is no consensus on the management of positive margins. External beam radiation and androgen deprivation may be administered as adjuvant therapy or at the time of recurrence. CONCLUSIONS: Tumor at the specimen edge is an adverse prognostic factor. With appropriate patient selection and meticulous surgical technique some positive margins can be prevented. Controlled prospective randomized studies of postoperative therapy are needed before definitive recommendations can be made for treating positive margins.     

Comparison of radical prostatectomy and iodine 125 interstitial radiotherapy for the treatment of clinically localized prostate cancer: a 7-year biochemical (PSA) progression analysis

OBJECTIVES: To evaluate the relative efficacy of brachytherapy to radical prostatectomy, we compared biochemical progression rates from a published series of men who underwent iodine 125 (125I) interstitial radiotherapy for localized prostate cancer to a similar group of men who underwent anatomic radical prostatectomy using appropriate end points. METHODS: Seventy-six men who underwent anatomic radical prostatectomy between 1988 and 1990 were carefully matched for Gleason score and clinical stage to a recently reported contemporary series of patients treated at another institution with 125I brachytherapy without adjuvant treatment. The definition of biochemical progression was a serum PSA level greater than 0.2 ng/mL after anatomic radical prostatectomy and greater than 0.5 ng/mL for brachytherapy-treated patients. RESULTS: The 7-year actuarial PSA progression-free survival following anatomic radical prostatectomy was 97.8% (95% confidence interval [CI], 85.6% to 99.7%) for this group of men selected to match the brachytherapy group, compared to 79% (95% CI not published) for men treated with 125I interstitial radiotherapy. CONCLUSIONS: Using comparative end points for biochemical-free progression, failure rates may be higher following 125I interstitial radiotherapy compared to anatomic radical prostatectomy. These data provide a better comparison of biochemical progression than previously published studies and emphasize the need for caution in interpreting the relative efficacy of brachytherapy in controlling localized prostate cancer.     

HpSS: a new silver staining method for Helicobacter pylori

Fifty-seven patients with clinically localized prostate cancer were treated by radical prostatectomy or external radiation therapy following pelvic lymphadenectomy. Comparing the outcome of radiotherapy with that of prostatectomy in 42 T2 patients without lymph node metastasis, the 5-year cause-specific survival did not differ between the radical prostatectomy group (n = 31) and radiotherapy group (n = 11). The 5-year disease-free survival of the prostatectomy group, however, was superior to that of radiotherapy group (p = 0.01). To cure patients with T2 prostate cancer, therefore, it is supposed that radical prostatectomy should be performed. To improve the treatment outcome after radiotherapy, stereotactic radiosurgery for prostate cancer has been attempted in our institution. Phantom experiments using a linear accelerator demonstrated a round dose distribution, and high reproducibility of prostate positioning was confirmed by CT when a thermoplastic immobilization device was used to fix the pelvis. In one patient with localized prostate cancer treated by radiosurgery, acute complication has not been recognized during the 5 week follow-up. Radiosurgery may be available to treat clinically localized prostate cancer.     

Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostate carcinoma: effect of early adjuvant radiation therapy on biochemical control

BACKGROUND: The authors evaluated the effect of postoperative radiation therapy on freedom from biochemical failure (bNED) in men with prostate carcinoma who had pathologic seminal vesicle invasion after radical prostatectomy and negative pelvic lymph node dissection (pT3cN0). METHODS: Between 1989 and 1995, 375 men underwent radical prostatectomy at Thomas Jefferson University Hospital. Fifty-three men (13%) had pT3cN0 prostate carcinoma and were the subject of this analysis. Men in whom prostate specific antigen (PSA) could not be detected were deemed free of biochemical failure. RESULTS: Of the 53 men with pT3cN0 prostate carcinoma, 18 had an elevated PSA immediately after surgery and received salvage radiation therapy (RT). The 3-year bNED rate for this group was only 38%. At 3 months, PSA could not be detected in the other 35 men. Fifteen of those 35 men underwent early adjuvant RT, and the other 20 were observed for biochemical failure. The 3-year bNED rate for the 15 patients treated with immediate adjuvant RT was 86%, compared with 48% for the 20 men who were observed (P = 0.01). CONCLUSIONS: These data suggest that early adjuvant RT for men with pT3cN0 prostate carcinoma and no detectable PSA postoperatively reduces the likelihood of future biochemical failure. Men with pT3cN0 prostate carcinoma and a persistently elevated postoperative PSA level are less likely to benefit from RT and should be considered for systemic therapy.     

Clinical stage T3 prostate cancer: natural history, therapeutic choices and their results

Clinical stage T3 prostate cancer is ambiguous both in terms of its definition and its place in the natural history of the disease, and there is no consensus concerning its treatment. In a review of the literature, 148 articles were selected and analysed from the Medline database over a 14-year period (1983-1997). Single-agent therapy: Radiotherapy and radical prostatectomy: it is unlikely that these treatments can cure clinical stage T3 prostatic cancer, except perhaps for a small minority of patients actually presenting with overstaged pT2 disease or certain forms of low-grade pT3. Neither treatment appears to have any advantage over the other-Endocrine therapy: it has been proposed as exclusive treatment at this stage. Few studies have been reported. However, many authors consider this choice to be legitimate, because one-half of patients already have lymph node involvement. Combination therapy: Radiotherapy and endocrine therapy: recent studies comparing exclusive external beram radiotherapy with endocrine therapy show an advantage in favour of combination therapy. Total prostatectomy and endocrine therapy: neoadjuvant endocrine therapy does not provide any advantage. Adjuvant endocrine therapy improves local control and progression-free survival. Adjuvant radiotherapy and radical prostatectomy provides no advantage for T3. The choice of treatment for stage T3, N0, M0 obviously depends on the patient's general state and life expectancy. If the option of a curative treatment in a young subject can be reasonably considered, combination therapy should be preferred.     

Acute stroke: usefulness of early CT findings before thrombolytic therapy

PURPOSE: Three-dimensional conformal radiotherapy (3D-CRT) has been associated with a reduction in acute and late toxicity among patients treated for localized prostatic cancer. The purpose of this study is to assess the acute and late toxicity of 3D-CRT delivered to patients in the postprostatectomy setting and to analyze which factors predict for durable biochemical control in this group of patients. METHODS AND MATERIALS: Between 1988 and 1994, 42 patients were treated after prostatectomy with three-dimensional conformal radiotherapy. The median time from prostatectomy to radiotherapy was 11 months. Indications for treatment included a rising serum PSA level in 28 patients (65%) and positive surgical margins without a rising PSA level in 14 (35%). Twenty-five patients (60%) had pathologic stage T3 disease, and 32 (74%) had tumor at or close to the surgical margins. The median dose was 64.8 Gy, and the median follow-up time was 2 years. RESULTS: 3D-CRT in the postprostatectomy setting was well tolerated. Three patients (7%) experienced Grade II acute genitourinary toxicity and nine patients (21%) experienced Grade II acute gastrointestinal toxicity during treatment. No patient experienced Grade III or higher acute morbidity. The 2-year actuarial risk for Grade II late genitourinary and gastrointestinal late complications were 5 and 9%, respectively. In patients with existing incontinence, the incidence of worsening stress incontinence 6 months after treatment was 17%, which resolved within 12 months to its preradiotherapy level in four of six cases (66%). The overall 2-year postirradiation PSA relapse-free survival rate was 53%. The 2-year PSA relapse-free survival was 66% for patients with undetectable PSA levels in the immediate postoperative period compared to 26% for those with detectable levels of PSA after surgery (p < 0.006). Furthermore, for patients with preradiotherapy PSA levels of < or = 1.0 ng/ml, the 2-year PSA relapse-free survival was 74% compared to 17% of those with preradiotherapy PSA levels of > 1.0 ng/ml (p < 0.002). The resection margin status, presence of seminal vesicle involvement, Gleason score, and the preprostatectomy PSA level did not impact on PSA relapse-free survival. A Cox proportional hazards regression analysis demonstrated that a preradiotherapy PSA value of > 1 ng/ml (p < 0.002) was the most important covariate predicting for a rising PSA after radiotherapy. CONCLUSIONS: After prostatectomy, three-dimensional conformal radiotherapy is associated with minimal treatment-related morbidity. Patients with postprostatectomy, preradiotherapy PSA levels < or = 1.0 ng/ml, and those patients who had undetectable PSA levels in the immediate postoperative period are more likely to benefit from local adjuvant therapy.     

Reduced space hidden Markov model training

OBJECTIVE: To analyze trends in the clinical stage and pathologic outcome of patients with prostate cancer who underwent radical prostatectomy at a large referral practice during the prostate-specific antigen (PSA) testing era. MATERIAL AND METHODS: Between January 1987 and June 1995, 5,568 patients with prostate cancer (4,774 with clinically localized disease of stage T2c or less) underwent pelvic lymphadenectomy and radical retropubic prostatectomy at our institution. Patient age, preoperative serum PSA level, clinical stage, pathologic stage, Gleason score, and tumor ploidy were assessed. Outcome was based on clinical and PSA (increases in PSA level of 0.2 ng/mL or more) progression-free survival. RESULTS: Patient age (65 to 63 years old; P<0.001) and serum PSA level (median, 8.4 to 6.8 ng/mL; P<0.001) decreased during the study period. The percentage of patients with clinical stage T1c prostate cancer increased from 2.1% in 1987 to 36.4% in 1995 (P<0.001), and clinical stage T3 cancer decreased from 25.3% to 6.5% (P<0.001). Nondiploid tumors decreased from 38.3% to 24.6% (P<0.001), and the proportion of patients with pathologically organ-confined disease increased from 54.9% to 74.3% (P<0.001). More cT1c than cT2 tumors were diploid (80% versus 72%; P<0.001), had a Gleason score of 7 or less (75% versus 65%; P<0.001), and were confined to the prostate (75% versus 57%; P<0.001). Five-year progression-free survival was 85% and 76% for patients with clinical stage T1c and T2, respectively (P<0.001). CONCLUSION: Since the advent of PSA testing, patients referred to our institution for radical prostatectomy have shown a significant migration to lower-stage, less-nondiploid, more often organ-confined prostate cancer at the time of initial assessment. Cancer-free survival associated with PSA-detected cancer (cT1c) is superior to that with palpable tumors (cT2). Whether these trends translate into improved long-term cancer-specific survival remains to be confirmed with longer follow-up.     

Effects of 17 beta estradiol on the metabolism of labelled arachidonic acid in uteri isolated from intact and ovariectomized rats. Influence of a restricted diet

Of the 69 patients with clinical stage C prostate cancer under 75 years old and with good performance status between 1986 and 1995, 29 underwent radical prostatectomy combined with endocrine therapy, 21 underwent radiation therapy combined with endocrine therapy and remaining 19 patients were treated by endocrine therapy alone. The median followup was 44 months (range 4 to 122). Radical prostatectomy resulted in progression-free rates of 79% and 61% at 5 and 10 years, respectively. Progression-free rates were lower in patients with lymph node metastasis or positive surgical margins. In patients with clinical stage T3a-c and well or moderately differentiated tumor, radical prostatectomy resulted in a progression-free rate of 100% at 5 years. However, in patients with clinical stage T4a or poorly differentiated tumor, radiation therapy resulted in a better progression-free rate than radical prostatectomy. These findings suggest that patients with clinical stage T3a-c and well or moderately differentiated tumor will benefit from radical prostatectomy combined with endocrine therapy and that radiation therapy well be effective for advanced diseases.     

Adjuvant treatment after radical prostatectomy in prostatic carcinoma (pT3 or pTxN+): prognostic factors and results

Adjuvant therapy after radical prostatectomy should ideally be limited to those patients at greatest risk for cancer recurrence, but identification of these patients remains a challenge. The local control rate in a group of 7494 patients undergoing radical prostatectomy for patients with pT2a disease of 76% is not different to pN+ disease of 80%. 95% of the pT3 patients were pN+ .90% of them received adjuvant treatment but only few patients with organ-confined cancer. A prognostic scoring system was created using the regression coefficients from the Cox multivariate model to classify patients with pathologically organ-confined prostate cancer according to risk of progression. Although tumor volume has traditionally been regarded as the most important prognostic factor in patients with localized prostate cancer, a recent multivariate analysis has shown that tumor volume is not an independent predictor. Moreover, accurate measurement of tumor volume is extremely difficult. Preoperative serum PSA levels, clinical stage, pathological grade and stage, and deoxyribonucleic acid (DNA) ploidy were evaluated by multivariate analysis to determine relative value in predicting treatment failure. Patients with the lowest score had a 92% progression free survival rate at 5 years, compared to only 39% of those with the highest scores. Patients believed to be at higher risk for cancer progression despite having organ confined disease might be targeted for adjuvant therapy and closer surveillance, while those at low risk may be followed less often.     

Pathological staging and biochemical recurrence after neoadjuvant androgen deprivation therapy in combination with radical prostatectomy in clinically localized prostate cancer: results of a phase II study

OBJECTIVES: To assess the pathological staging and biochemical progression-free survival (assessed using serum prostate-specific antigen level) of patients with clinically localized prostate cancer using neoadjuvant androgen deprivation therapy (ADT) in combination with radical retropubic prostatectomy (RRP). PATIENTS AND METHODS: A prospective study was carried out on 69 patients with localized prostate cancer who were enrolled in a trial of 3 months of ADT followed by RRP (group 1). These patients were compared with 72 patients matched for age and clinical stage who declined ADT therapy and had RRP concurrently (group 2). Assignment to the individual treatment groups was thus determined by the patient's preference and not the physician's selection. Pathological staging and biochemical progression-free recurrence were compared between the groups. RESULTS: The rate of organ-confined (pT2) tumours was 74% in group 1 and 49% in group 2 (P < 0.01), and the rate of margin-negative tumours was 87% in group 1 and 64% in group 2 (P < 0.01). Within a median follow-up of 35 months, there was no significant difference in biochemical failure between the groups (P = 0.37). Patients with pT2 disease, regardless of treatment, had similar biochemical failure rates. In the patients with margin-positive disease, there was a significantly higher biochemical failure rate in group 1 (P = 0.02). CONCLUSIONS: The rates of organ- and specimen-confined disease were higher among the patients treated with ADT. The preliminary follow-up suggested that patients with pT2 disease after ADT have a biochemical progression-free recurrence rate similar to pT2 patients treated with RRP alone. Additionally, high biochemical failure rates in patients with margin-positive disease after ADT may identify a subset of more biologically aggressive tumours in need of early adjuvant treatment.     

Invasive prostatic carcinoma with or without positive tumor margins after radical prostatectomy--an indication for adjuvant radiotherapy?

Radiation therapy (RT) following radical prostatectomy (RP) in locally progressed prostate carcinoma has become increasingly important in the last few years as both adjuvant therapy and treatment for a PSA increase in local recurrence of disease. The background for this is the knowledge gained by using PSA that up to 50% of the patients with pathologically confirmed pT3/4 tumors are systemically and/or locally progressive after 3-5 years if only surgical or radiation therapy was performed. A number of retrospective studies substantiated a significantly higher local tumor control by RT after RR. This holds true for adjuvant therapy as well as with a PSA increase from the "zero" range, whereby it must be taken into consideration that a certain percentage of treated patients among those with histologically proven local recurrence actually do not need further therapy. Lengthening the survival time has, however, not yet been proven. With an increase in the PSA from the "zero range" after RP, there are indications that systemic metastatic spread already occurs with values higher than 2.5-4 ng/ml and the RT no longer has any curative intention. A total of three prospective randomized studies on the question of adjuvant radiation therapy are presently being conducted. There are only very little, although interesting, data on the question of radiation therapy in combination with simultaneous systemic hormonal therapy (HT).     

Long-term results of preoperative radiation therapy alone for stage T3 and T4 rectal cancer

BACKGROUND: There has been a resurgence of interest in the use of preoperative radiation therapy, with or without chemotherapy, for locally advanced rectal cancer. The purpose of this study was to analyse the time course and pattern of failure for 74 patients with clinical stage T3 or T4 (cT3-4) rectal cancer treated with preoperative radiation therapy for whom long-term follow-up was available. METHODS: Seventy-four patients with cT3-4 rectal cancer received a median of 45.0 Gy radiation alone followed by surgery 4-8 weeks later. Median follow-up was 90 months; two-thirds of patients were followed for at least 60 months. RESULTS: Following radiation therapy the pathological stage was 4 per cent pT0, 26 per cent pT1-2 and 70 per cent pT3-4. Thirty-two per cent had involved lymph nodes. The actuarial 5-year rates of local control, freedom from distant metastasis and disease-specific survival were 80, 64 and 73 per cent respectively. The corresponding 10-year rates were 73, 51 and 50 per cent. Median times to detection of local and distant recurrence were 34 and 24 months respectively. Eighty per cent of local recurrences were detected within 54 months; 80 per cent of distant recurrences were detected within 57 months. CONCLUSION: In this analysis, the time to detection of both local and distant recurrences following preoperative radiation therapy for advanced rectal cancer was surprisingly long. Almost 5 years (57 months) of follow-up were required to detect 80 per cent of all failures. The 5-year local control rate of 80 per cent compares favourably with that achieved by more aggressive chemoradiation regimens for fixed cancers; however, the high distant failure rate with radiation therapy alone suggests that adjuvant systemic therapy should be investigated.     

The role of cyclic guanylate monophosphate in nitric oxide-induced injury to rat small intestinal epithelial cells

PURPOSE: Biostatistical models predicting the risk of recurrence after radical prostatectomy for clinically localized prostate cancer are necessary. Identifying these high risk patients shortly after surgery, while tumor burden is minimal, makes them candidates for possible adjuvant therapy and/or investigational phase II clinical trials. This study builds on previously proposed models that predict the likelihood of early recurrence after radical prostatectomy. MATERIALS AND METHODS: In our analysis we evaluate age, race, prostatic acid phosphatase and nuclear grade with the established prognostic variables of pretreatment prostate specific antigen, postoperative Gleason sum and pathological stage. RESULTS: After multivariable Cox regression analysis using only statistically significant variables that predicted recurrence we developed an equation that calculates the relative risk of recurrence (Rr) as: Rr = exp[(0.51 x Race) + (0.12 x PSAST) + (0.25 x Postop Gleason sum) + (0.89 x Organ Conf.). These cases are then categorized into 3 distinct risk groups of relative risk of recurrence of low (< 10.0), intermediate (10.0 to 30.0) and high (> 30.0). Kaplan-Meier survival analysis of these 3 risk groups reveals that each category has significantly different risks of recurrence (p < 0.05). This model is validated with an independent cohort of radical prostatectomy patients treated at a different medical center by multiple primary surgeons. CONCLUSIONS: This model suggests that race, preoperative prostate specific antigen, postoperative Gleason sum and pathological stage are important independent prognosticators of recurrence after radical prostatectomy for clinically localized prostate cancer. Race should be considered in future models that attempt to predict the likelihood of recurrence after surgery.     

Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy

PURPOSE: Prostate-specific antigen (PSA) is extensively used in case selection and outcome evaluation after treatment of clinically localized prostate cancer. Careful case selection can have a profound impact on pathologic findings and ultimate outcome. In addition, salvage treatment is frequently initiated at the time of biochemical relapse rather than clinical recurrence. Consequently, patterns of failure can be significantly altered compared to previous times when PSA was not available. To better understand the impact of PSA on pathologic findings, outcome, and salvage treatment, we reviewed our experience in the PSA era with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. METHODS AND MATERIALS: Between 1987 and 1993, 423 cases could be identified with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. The distribution of cases by pretreatment PSA levels was as follows: < or = 4 ng/ml (18%), 4-10 ng/ml (42%), 10-20 ng/ml (21%), > 20 ng/ml (14%), and unknown (5%). The median pretreatment PSA level for the entire group was 8.0 ng/ml. Sixteen patients received adjuvant or neoadjuvant androgen suppression and 13 received postoperative radiotherapy. Only 31 patients (7%) had pathologically positive pelvic lymph nodes. The overall margin involvement rate was 46%. Fifty-three percent of patients had surgical Gleason scores > or = 7, and 65% had extracapsular extension. The median follow-up time was 41 months. RESULTS: The projected overall survival at 7 years after surgery was 90%. The 5-year clinical relapse-free survival rate was 84%. At 5 years, the local control and distant failure rates were 92% and 91%, respectively. Biochemical relapse was defined as a detectable or rising PSA level after prostatectomy. The 5-year biochemical relapse-free survival (bRFS) rate was 59%. The 5-year RFS was 88% in patients with preoperative PSA levels < or = 4, 62% for 4-10, 48% for 10-20, and 31% for > 20. Combining the two independent preoperative variables, iPSA and biopsy GS (bGS), two risks groups were defined: low risk [initial PSA (iPSA) levels < or = 10.0 and bGS < or = 6] and high risk (iPSA levels > 10.0 ng/ml or bGS > or = 7). The 5-year bRFS rate for the low-risk cases was 81% vs. 40% for high-risk cases (p < 0.001). On multivariate analysis, three factors independently predicted biochemical relapse: iPSA levels (p = 0.005), Gleason score from the surgical specimen (sGS) (p = 0.002), and positive surgical margins (p < or = 0.001). The 5-year bRFS rates for margin positive vs. margin negative patients were 37% vs. 78%, respectively. The 5-year bRFS rates for GS > or = 7 vs. GS > or = 6 were 42% vs. 80%, respectively. All clinical relapses were accompanied by a rise in PSA. In patients who manifested biochemical failure followed by a clinical failure, the median interval between the PSA rise and clinical failure was 19 months (range 7-71). Margin involvement was the only independent predictor of local failure (p = 0.019). The 5-year local failure-free survival for negative margin cases was 96% vs. 87% for positive margin cases (p = 0.012). Lymph node (LN) involvement and high-risk group were the two independent predictors of distant failure. The 5-year distant failure-free survival for negative LN cases was 94% vs. 67% for positive LN cases (p < 0.001). The 5-year distant failure-free survival for low-risk cases was 97% vs. 85% for high-risk cases (p = 0.005). For the 124 patients failing biochemically, 85 were observed and 39 were treated either with radiation or androgen deprivation. With a median follow-up of 32 months, the clinical disease relapse-free survival was 79% for the treated patients vs. only 32% for the patients observed (p < 0.001). CONCLUSION: Pretreatment PSA is the most potent clinical factor independently predicting biochemical relapse, thereby allowing markedly better case selection. Achieving negative margins, even in relatively advanced disease, provides excellent lon     

Prostate-specific antigen doubling times are similar in patients with recurrence after radical prostatectomy or radiotherapy: a novel analysis

PURPOSE: Some investigators have analyzed the rate of growth of prostate cancer that has recurred after definitive radiotherapy or radical prostatectomy using serum prostate-specific antigen (PSA) doubling times (DT). We examined all PSA values in recurrent patients to determine the pattern and rate of increase in PSA after radiation therapy and radical prostatectomy. PATIENTS AND METHODS: Charts of 96 recurrent radical prostatectomy patients (mean age, 62.8 years; range, 47 to 76) and 42 recurrent radiation therapy patients (mean age, 67.2 years; range, 52 to 83) were reviewed. All available PSA values between the date of operation/radiation treatment and last follow-up evaluation or the initiation of second-line therapy are included. Rate of PSA DT was not assumed to be constant over time; it was instead allowed to vary. We use a piecewise linear random-coefficients model in time for log (PSA), which allowed different mean models for both treatments. RESULTS: The PSA DT in the first year after radiation therapy was--1.17 years, which reflects the continuous decline in PSA in the average patients during the first year after radiotherapy despite eventual biochemical progression. In contrast, the PSA DT in the radical prostatectomy group was 0.66 in the first year. In year 2, after radiation therapy, the PSA DT was lengthy at 1.82 years, significantly longer (P = .0025) than in the radical prostatectomy group (0.76 years). After year 2, there were no significant differences between the two groups (P > .05). CONCLUSION: A piecewise linear random-coefficients model enables interval analysis of PSA DT. While the PSA DT after radiation therapy and radical prostatectomy are different in the first 2 years, the rate of increase in PSA appears to be similar in the two groups after year 2, which suggests the rate of growth of cancers that recur after radiation therapy and radical prostatectomy is similar.