PREDICTING EXTRACAPSULAR EXTENSION OF PROSTATE CANCER IN MEN TREATED WITH RADICAL PROSTATECTOMY: RESULTS FROM THE POPULATION BASED PROSTATE CANCER OUTCOMES STUDY

PURPOSE: We investigated whether clinical information routinely available in community practice could predict extracapsular extension of clinically localized prostate cancer in men undergoing radical prostatectomy. MATERIALS AND METHODS: We examined prostate cancer outcomes in a population based sample of 3,826 patients with primary prostate cancer in 6 regions of the United States covered by the Surveillance, Epidemiology, and End Results program. Stratified and weighted logistic regression was used to identify predictors of and probabilities for extracapsular extension of clinically localized tumors treated with radical prostatectomy. RESULTS: Nearly 47% of men undergoing radical prostatectomy had extraprostatic extension. The strongest predictors were elevated prostate specific antigen (PSA) greater than 20 versus less than 4 ng./ml. (odds ratio 5.88, 95% confidence interval 2.90 to 11.15), Gleason score greater than 8 versus less than 6 (1.73, 1.04 to 2.87) and age greater than 70 versus less than 50 years (1.91, 0.98 to 3.70). Ethnicity and region were not associated with increased risk of extraprostatic extension. A nomogram developed from our model predicts extracapsular extension ranging from 24% in men younger than 50 years with PSA less than 4 ng./ml. and a Gleason score of less than 7 to 85% in those 70 years old or older with PSA greater than 20 ng./ml. and a Gleason score of 8 or more. If prostatectomy were limited to patients with less than 60% probability of extraprostatic extension based on the nomogram, 95% of those with organ confined cancers would undergo definitive surgery and 18% of those with extracapsular extension would be spared the morbidity of surgery. CONCLUSIONS: In a population based analysis of prostate cancer practice patterns PSA, Gleason score and age are clinically useful predictors of extracapsular extension. Although extracapsular extension may be an imperfect predictor of cancer outcomes, our nomogram provides more realistic probabilities for extracapsular extension than those based on institutional series.     

THE USE OF PERCENT FREE PROSTATE SPECIFIC ANTIGEN FOR STAGING CLINICALLY LOCALIZED PROSTATE CANCER

Purpose

The free-to-total serum prostate specific antigen (PSA) ratio (percent free PSA) has been demonstrated to have clinical use for early detection of men with prostate cancer with total PSA levels between 4.0 and 10.0 ng./ml. Several studies evaluating the usefulness of percent free PSA for the staging of clinically localized prostate cancer have provided conflicting results. We further investigate the usefulness of percent free PSA for staging of clinically localized prostate cancer.

Materials and Methods

In 263 men with clinically localized prostate cancer who underwent radical prostatectomy total PSA and free PSA were measured preoperatively. Pathological stages were classified as organ confined in 134 cases, capsular penetration in 92, seminal vesicle involvement in 7, involvement of the surgical margins in 20 and lymph node involvement in 10.

Results

Percent free PSA was significantly different between men with organ confined versus nonorgan confined tumors (p <0.0001) and between those with favorable versus unfavorable pathology (p <0.0001). A cutoff of 12% free PSA provided a 72% positive predictive value and 52% negative predictive value for favorable pathology. A cutoff of 15% free PSA provided a 76% and 53% positive and negative predictive value, respectively, for organ confined disease.

Conclusions

These data demonstrate that the use of percent free PSA may be of additional value for the staging of clinically localized prostate cancer. The recommendations for cutoff levels of percent free PSA for detection and staging of localized prostate cancer are preliminary and can only be given for this particular assay. A large multicenter trial, controlling for age, stage and grade distribution, as well as for a uniform pathological evaluation and comparable total and free PSA assays, is required to elucidate this issue further.     

PRELIMINARY OUTCOMES FOLLOWING CRYOSURGICAL ABLATION OF THE PROSTATE IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CARCINOMA

Purpose

Cryosurgical ablation of the prostate is a novel therapeutic modality that induces cell lysis in the prostate by direct application of low temperatures. We have been conducting an ongoing prospective pilot study of the use of cryosurgical prostate ablation in treating patients with nonmetastatic prostate adenocarcinoma since January 1993. Results in 145 consecutive patients with mean 36 months and minimum 12 months of followup are presented.

Materials and Methods

Accrual was open to patients with clinical stages T1a to T3c prostate adenocarcinoma. Pelvic lymph node dissections were recommended but not required for patients with prostate specific antigen (PSA) greater than 15 ng./ml. before study entry. PSA changes, random prostate biopsy findings and morbidities after cryosurgical prostate ablation were recorded for each patient.

Results

Overall actuarial rates at 42 months for maintaining PSA less than 0.3 and less than 1.0 were 59% and 66%, respectively. The overall actuarial progression-free rate at 60 months was 56%. Among 160 biopsies performed 16% showed some evidence of residual carcinoma. Overall crude rates of maintaining either a negative biopsy or PSA less than 0.3 at 6 and 24 months after cryosurgical prostate ablation were 87% and 73%, respectively. Significantly higher morbidities were seen in previously radiated patients undergoing cryosurgical prostate ablation compared to those with no prior radiation. Among nonradiated patients 85% experienced no significant morbidity after cryosurgical prostate ablation.

Conclusions

Although preliminary, short-term outcomes after cryosurgical prostate ablation appear to be comparable to identical outcomes reported for external beam radiotherapy. Based on these results cryosurgical prostate ablation appears to be an effective therapeutic alternative for treating patients with localized prostate adenocarcinoma.     

RESULTS OF EXTERNAL BEAM RADIOTHERAPY IN 448 PATIENTS WITH CLINICALLY LOCALIZED ADENOCARCINOMA OF THE PROSTATE

The results of external beam radiotherapy for clinically localized adenocarcinorna of the prostate in 448 patients treated in the period 1980–90 were reviewed. The average follow up was 4.9 years. The patients were aged 44–87 years (median 69 years) and all had histopathological evidence of adenocarcinoma by needle biopsy or transurethral resection of prostate. The histopathological grading was: 127 G₁; 154 G₂; 127 G₃; 12 G₄; 28 G_x. Clinical staging according to TNM (American Urological Association) was: 29 T₀ (A2); 4 T₁ (B1); 173 T₂ (B2); 176 T₃ (C1); 63 T₄ (C2); 3 T_x. Routine surgical pelvic lymph node staging was not performed but patients had radiological (computerized tomography scan or lymphogram) nodal staging: 350 N₀; 22 N₁; 12 N₂; 64 N_x. High energy linear accelerator external beam radiotherapy was given by multiple fields to total doses of 50–70 Gy (median 60 Gy). The majority of patients (307, 69%) was treated by a uniform policy under the care of one radiation oncologist (HM). The rates of local and distant failure at 5 years were 10% (s.e. = 2%) and 42% (s.e. = 3%), respectively. The late complication rate at 5 years was 25% (s.e. = 2%), comprising mild 16%, moderate 7% and severe 1.3%. The 5 year overall survival rate was 64% (s.e. = 2%) and the cancer-specific survival rate was 74% (s.e. = 3%). Both histological grade and clinical stage were strongly predictive of overall survival and distant failure. Only histological grade was predictive of local failure. Treatment with external beam radiotherapy for this common cancer resulted in survival and disease control rates that compare favourably with other published radiotherapy series and has been accompanied by acceptably low morbidity.     

CLASSIFICATION OF LOCALIZED UNTREATED PROSTATE CANCER BASED ON 791 MEN TREATED ONLY WITH RADICAL PROSTATECTOMY: COMMON GROUND FOR THERAPEUTIC TRIALS AND TNM SUBGROUPS

Purpose

We examined cancer volume, percent Gleason grade 4/5 cancer, cancer location (peripheral versus transition zone), capsular penetration and biochemical cure rates in men undergoing radical prostatectomy to determine differences among clinical stages T1c, T2a, T2b and T2c.

Materials and Methods

Detailed chart reviews confirmed the precise clinical stages assigned to 791 consecutive men treated only with radical prostatectomy. All prostates were examined prospectively by the Stanford technique of 3 mm. step sections. For biochemical cure rates a subset of 366 men were followed for a minimum of 5 years. Failure was defined as prostate specific antigen Tosoh [dagger] 0.07 ng./ml. or greater and rising. T1c was defined as impalpable cancer.[dagger] TOSOH Medics, Foster City, California.

Results

T1c and T2a stages had half as much cancer volume as T2b and T2c cancers, 10 versus 25% Gleason grade 4/5 and half as much capsular penetration (30 versus 61%). Biochemical cure rates were 70 and 72% for T1c and T2a compared to 37 and 27% for T2b and T2c, respectively. Of T1c cancers 25% were in the transition zone compared to 7.9 to 9.9% of T2a to c cancers.

Conclusions

T1c cancers are similar to T2a cancers in tumor volume and percent Gleason grade 4/5, the primary determinants of therapeutic failure. Minimal 5-year cure rates for T1c and T2a cancers are similar. Transition zone cancers are 2.5 times more common in T1c cancers than in palpable T2 tumors. T2a cancers like T1c cancers are highly favorable tumors and should be retained in TNM classifications. These data suggest that the 4 clinical stages of T1c to T2c can serve as a valid basis for comparing different therapeutic strategies.     

LONG-TERM TREATMENT RELATED COMPLICATIONS OF BRACHYTHERAPY FOR EARLY PROSTATE CANCER: A SURVEY OF PATIENTS PREVIOUSLY TREATED

PURPOSE: We determined long-term symptoms in patients after brachytherapy (radioactive seed implantation) for early (nonmetastatic) prostate cancer. MATERIALS AND METHODS: We performed a cross-sectional survey of 105 (80% of those contacted) men treated at least 2 years 9 months (median 5.2 years) previously with brachytherapy alone (72 patients) or brachytherapy plus external beam radiation therapy (33) at a pioneering referral center for ultrasound guided brachytherapy. RESULTS: Median patient age was 70 years at treatment and 75 years when surveyed. Bowel symptoms were uncommon (range 4% to 9%) unless patient had also received external beam radiation therapy. Urinary incontinence occurred in 45% of men, although leakage of more than a few drops, daily leakage and wearing absorptive pads occurred in 11%, 11% and 16%, respectively. Men who underwent documented transurethral prostatic resection were much more likely to report incontinence (83% versus 39%, p = 0.005) and those who underwent implantation less than 5 years earlier were less likely (33% versus 53%, respectively, p = 0.04). Complete impotence was common (50%) but impaired erections were more so (73%). Patients who received combined radiation treatment had more frequent erectile dysfunction. CONCLUSIONS: Long-term bowel symptoms are infrequent after brachytherapy alone. Urinary incontinence is common, although usually only a few drops and not daily. Erectile dysfunction, prevalent in populations of older men, was found in most men. However, because our study design precluded documenting baseline symptoms before treatment and subsequent clinical interventions, the contribution of factors other than brachytherapy is unclear. The morbidity of patients receiving more recent brachytherapy may be less.     

SECOND PRIMARY MALIGNANCIES IN T1-3N0 PROSTATE CANCER PATIENTS TREATED WITH RADIATION THERAPY WITH 10-YEAR FOLLOWUP

Purpose

The risk of patients with prostate cancer to have second primary malignancies is unclear. Population and autopsy based studies have shown no increased risk, which is at variance with several institutional analyses. A retrospective review was performed with comparison to expected cancer data from the Connecticut Tumor Registry.

Materials and Methods

Records of a cohort of prostate cancer patients treated with staging pelvic lymphadenectomy and definitive radiotherapy between November 1, 1974 and July 7, 1987 were reviewed. Median potential followup from date of diagnosis was 10.9 years.

Results

Of the 164 patients 150 (91.5%) had followup to death or to August 1995, with data available in part on 4 of the remaining patients. In 43 patients 51 second primary malignancies developed. Increased frequency of lymphomas, and kidney, bladder and rectal lesions (all p <0.001) was observed concurrently with diagnosis of prostate cancer, although this may be due to bias since full staging for the prostate cancer may have led to their diagnosis. An increased frequency of renal lesions in the 1 to 4-year followup period (p = 0.032) also was observed. Two sarcomas and a leukemia were putatively radiation induced but their frequency was not significantly different from the comparison baseline.

Conclusions

Much of the apparent increase in second primary malignancies associated with prostate cancer noted by some authors may be attributed to bias in the staging process. Renal cancers may occur more frequently in patients with prostate cancer but the distribution of these lesions is inconsistent with a field defect mechanism of cancer induction.     

COMPARISON OF HELICAL COMPUTERIZED TOMOGRAPHY, POSITRON EMISSION TOMOGRAPHY AND MONOCLONAL ANTIBODY SCANS FOR EVALUATION OF LYMPH NODE METASTASES IN PATIENTS WITH PROSTATE SPECIFIC ANTIGEN RELAPSE AFTER TREATMENT FOR LOCALIZED PROSTATE CANCER

PURPOSE: We compare the detection of metastatic disease by helical computerized tomography (CT), positron emission tomography (PET) with F-18 fluorodeoxyglucose and monoclonal antibody scan with 111indium capromab pendetide in patients with an elevated prostate specific antigen (PSA) after treatment for localized prostate cancer. MATERIALS AND METHODS: A total of 45 patients with an elevated PSA (median 3.8 ng./ml.) were studied following definitive local therapy with radical prostatectomy in 33, radiation therapy in 9 and cryosurgery in 3. CT of the abdomen and pelvis, and whole body PET were performed in all patients, of whom 21 also underwent monoclonal antibody scan. Lymph nodes 1 cm. in diameter or greater on CT were considered abnormal and were sampled by fine needle aspiration in 12 patients. RESULTS: PET and CT were positive for distant disease in 50% of 22 patients with PSA greater than 4, and in 4 and 17%, respectively, of 23 with PSA less than 4 ng./ml. The detection rate for metastatic disease was similar for CT and PET, and higher overall than that for monoclonal antibody scan. Monoclonal antibody scan was true positive in only 1 of 6 patients, while PET was true positive in 6 of 9 with CT guided fine needle aspiration proved metastases. CONCLUSIONS: CT and PET each detected evidence of metastatic disease in 50% of all patients with a high PSA or PSA velocity (greater than 4 ng./ml. or greater than 0.2 ng./ml. per month, respectively). Both techniques are limited for detecting metastatic disease in patients with a low PSA or PSA velocity. Our data suggest that monoclonal antibody scan has a lower detection rate than CT or PET.     

VALIDITY OF THE PROSTATE SPECIFIC ANTIGEN TEST FOR PROSTATE CANCER SCREENING: FOLLOWUP STUDY WITH A BANK OF 21,000 SERA IN FINLAND

PURPOSE: We investigate the validity of prostate specific antigen (PSA) as a screening test for prostate cancer. MATERIALS AND METHODS: A registry of serum samples drawn from 1968 to 1976 from 21,387 men was linked to the Finnish Cancer Registry. During followup from 1968 to 1991, 104 prostate cancers were identified. A matched case control design with incidence density sampling and nested in the serum sample bank was applied, and PSA was assessed. RESULTS: The estimated sensitivity of the test was 44% and specificity 94% at a cutoff of 4.0 microg./l. in the total material. The sensitivity had improved to 86% in patients diagnosed in 5 years after the sample drawing. The test had a better sensitivity (93%) and specificity (96%) in men younger than 65 years at the time of the sample drawing compared to those older. The sensitivity further improved to 100% with a cutoff of 2.5 microg./l. CONCLUSIONS: PSA is a valid screening test for prostate cancer, which compares favorably with mammography for breast cancer. However, until an effect on mortality has been shown, routine screening cannot be recommended.     

() INDIUM-CAPROMAB PENDETIDE IN THE EVALUATION OF PATIENTS WITH RESIDUAL OR RECURRENT PROSTATE CANCER AFTER RADICAL PROSTATECTOMY

Purpose

Standard diagnostic methods are limited for detecting distant metastases in patients with prostate cancer in whom the only evidence of disease after radical prostatectomy is a detectable prostate specific antigen (PSA) level. We evaluated the role of immunoscintigraphy with the radiolabeled monoclonal antibody,¹¹¹ indium (¹¹¹) In)-capromab pendetide, to differentiate between local and distant recurrence in this patient population.

Materials and Methods

We enrolled 183 men who had undergone radical prostatectomy in whom PSA later increased. Gamma camera images were acquired twice after infusion of a single dose of¹¹¹ In-capromab pendetide.

Results

Immunoscintigraphy revealed disease in 108 of 181 patients (60%) with interpretable scans. The antibody was localized most frequently to the prostatic fossa (34% of the cases), abdominal lymph nodes (23%) and pelvic lymph nodes (22%). Of the 181 men the scan localized the antibody outside the prostatic fossa in 42%. Half of the positive localizations in the fossa were confirmed by biopsy.

Conclusions

These findings suggest that immunoscintigraphy with¹¹¹ In-capromab pendetide can assist in determining the extent of disease in patients who have increasing PSA after prostatectomy.     

ASSESSMENT OF SEXTANT BIOPSY OF THE PROSTATE FOR DETECTING CANCER PRIOR TO THERAPY IN PATIENTS CLINICALLY DIAGNOSED AS BENIGN PROSTATIC HYPERPLASIA

Pathological results and perioperative morbidity were compared in 199 patients who had undergone prostatectomy and/or biopsy in order to determine the extent to which systematic biopsy is effective for detecting prostate cancer prior to therapy in patients clinically diagnosed as having benign prostatic hyperplasia. Seventeen (8.5%) cancers were detected in 199 patients following surgery and/or biopsy. Digitally-guided biopsy as a means of detecting prostate cancer was found to be just as effective as ultrasound-guided biopsy. Seven (12.5%) cancers were detected in 56 patients who had undergone biopsy and transurethral resection. Preprostatec to my biopsy detected only two of three patients with stage TIb disease. All four stage TIa and one stage TIb failed to be diagnosed. Of 90 patients who had biopsy prior to surgery other than TURP, seven (7.8%) cancers were found. Four of these were advanced. The incidence of postoperative fever > 38.0 °C and duration of postoperative pyuria did not differ significantly between groups with or without biopsy. Preoperative biopsy did not contribute to perioperative morbidity. Tumors detected by systematic biopsy are usually large and clinically significant. Positive biopsy results are often diagnostic, but the pathological features of a tumor together with clinical parameters should be considered to reduce the chance of overdiagnosing an insignificant tumor. Sextant biopsy would be most applicable to patients scheduled for any type of therapy other than TURP especially in those with markedly elevated serum PSA levels. This procedure may be beneficial particularly for younger patients with long life expectancy who will benefit from definitive therapy.