Evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for adjuvant radiotherapy in breast cancer.

BACKGROUND: The European Society of Medical Oncology (ESMO) has suggested using the ESMO-Magnitude of Clinical Benefit Scale (MCBS) to grade the magnitude of clinical benefit of cancer therapies. This approach has not been applied to radiation therapy (RT) yet. We applied the ESMO-MCBS to experiences describing the use of RT to assess (1) the 'scoreability' of the data, (2) evaluate the reasonableness of the grades for clinical benefit and (3) identify potential shortcomings in the current version of the ESMO-MCBS in its applicability to RT. MATERIALS AND METHODS: We applied the ESMO-MCBS v1.1 to a selection of studies in radiotherapy that had been identified as references in the development of American Society for Radiation Oncology (ASTRO) evidence-based guidelines on whole breast radiation. Of the 112 cited references, we identified a subset of 16 studies that are amenable to grading using the ESMO-MCBS. RESULTS: Of the 16 studies reviewed, 3/16 were scoreable with the ESMO tool. Six of 16 studies could not be scored because of shortcomings in the ESMO-MCBS v1.1: (1) in 'non-inferiority studies', there is no credit for improved patient convenience, reduced patient burden or improved cosmesis; (2) in 'superiority studies' evaluating local control as a primary endpoint, there is no credit for the clinical benefit such as reduced need for further interventions. In 7/16 studies, methodological deficiencies in the conduct and reporting were identified. CONCLUSIONS: This study represents a first step in determining the utility of the ESMO-MCBS in the evaluation of clinical benefit in radiotherapy. Important shortcomings were identified that would need to be addressed in developing a version of the ESMO-MCBS that can be robustly applied to radiotherapy treatments. Optimization of the ESMO-MCBS instrument will proceed to enable assessment of value in radiotherapy.

Glass vials for small volume parenterals: influence of drug and manufacturing processes on glass delamination.

PURPOSE: Studies were initiated to examine the effect of formulation and process variables on the delamination process and also the influence of the glass manufacturing process, supplier, and glass surface treatment. METHODS: Stress testing was performed by exposing filled vials to multiple sterilization cycles followed by accelerated stability testing. Delamination incidence was determined by visual examination, light obscuration (HIAC), and microscopical methods. The inner surface of vials from each supplier and lot were also examined by scanning electron microscopy. RESULTS: Vials sourced from Supplier A had smooth surfaces as demonstrated by SEM examination, whereas vials sourced from Suppliers B and C displayed extensive surface imperfections such as pitting and/or deposits. These imperfections were localized to the vial wall, adjacent to the vial bottom, and increased with sulfate treatment. Delamination incidence increased in those vial lots with increased surface imperfections. Thus, vials sourced from Supplier A had the lowest frequency of delamination. Sulfate treatment and high pH increased delamination incidence to as high as 100%. CONCLUSION: These results demonstrate the importance of the surface morphology created during the vial forming process. Given the diferences observed, final vial selection should include extensive microscopical and product stress testing studies on multiple vial lots.

Spectrum-analysis and neural networks for imaging to detect and treat prostate cancer.

Conventional B-mode ultrasound currently is the standard means of imaging the prostate for guiding prostate biopsies and planning brachytherapy to treat prostate cancer. Yet B-mode images do not adequately display cancerous lesions of the prostate. Ultrasonic tissue-type imaging based on spectrum analysis of radiofrequency (rf) echo signals has shown promise for overcoming the limitations of B-mode imaging for visualizing prostate tumors. This method of tissue-type imaging utilizes nonlinear classifiers, such as neural networks, to classify tissue based on values of spectral parameter and clinical variables. Two- and three-dimensional images based on these methods demonstrate potential for guiding prostate biopsies and targeting radiotherapy of prostate cancer. Two-dimensional images are being generated in real time in ultrasound scanners used for real-time biopsy guidance and have been incorporated into commercial dosimetry software used for brachytherapy planning. Three-dimensional renderings show promise for depicting locations and volumes of cancer foci for disease evaluation to assist staging and treatment planning, and potentially for registration or fusion with CT images for targeting external-beam radiotherapy.

Which patients with newly diagnosed prostate cancer need a radionuclide bone scan? An analysis based on 631 patients.

PURPOSE: Although radionuclide bone scans are frequently recommended as part of the staging evaluation for newly diagnosed prostate cancer, most scans are negative for metastases. We hypothesized that Gleason score, prostate-specific antigen (PSA), and clinical stage could predict for a positive bone scan (BS), and that a low-risk group of patients could be identified in whom BS might be omitted. METHODS: All patients who had both pathologic review of their prostate cancer biopsies and radionuclide BS at our institution between 1/90 and 5/96 were studied. Gleason score, PSA, and clinical stage (AJCC, 4th edition) were evaluated by univariate and multivariate analyses for their ability to predict a positive BS. Groups analyzed were Gleason of 2-6 vs. 7 vs. 8-10; PSA of 0-15 vs. greater than 15-50 vs. greater than 50; and clinical stage of T1a-T2b vs. T2c-T4. Univariate analysis using chi(2) and multivariate analysis using logistic regression were performed. RESULTS: Of the 631 consecutive patients, 88 (14%) had positive BS. Multivariate analysis (64 excluded due to missing PSA and/or clinical stage) showed Gleason score, PSA, and clinical stage to be significant independent predictors for positive BS (p < 0.002, p < 0.001, p < 0.001, respectively). The odds ratios were 5.25 (confidence interval [CI], 3.43-8.04) for PSA > 50 vs. 0-15; 2.25 (CI, 1.43-3.54) for Gleason of 8-10 vs. 2-6; 2.15 (CI, 1.54-2.99) for clinical stage T2c-T4 vs. T2b or less. Three of 308 (1%) had a positive BS in patients with Gleason 2-7, PSA of 50 or less, and clinical stage of T2b or less. In the subset of the same risk group with PSA of 15 or less, all 237 had negative bone scans. In patients with PSA greater than 50, 49/99(49.5%) had positive BS. CONCLUSION: Gleason score, PSA, and clinical stage were independent predictors for a positive radionuclide BS in newly diagnosed prostate cancer patients. PSA is the major predictor for positive BS. About one-half of the patients analyzed were in the low-risk group (Gleason 2-7, PSA < or = 50, clinical stage < or = T2b) and elimination of BS in these patients would result in considerable economic savings.

Factors predicting for postimplantation urinary retention after permanent prostate brachytherapy.

PURPOSE: Urinary retention requiring catheterization is a known complication among prostate cancer patients treated with permanent interstitial radioactive seed implantation. However, the factors associated with this complication are not well known. This study was conducted to determine these factors. METHODS AND MATERIALS: Ninety-one consecutive prostate cancer patients treated with permanent interstitial implantation at our institution from 1996 to 1999 were evaluated. All patients underwent pre-implant ultrasound and postimplant CT volume studies. Isotopes used were (125)I (54 patients) or (103)Pd (37 patients). Twenty-three patients were treated with a combination of 45 Gy of external beam radiation therapy as well as seed implantation, of which only 3 patients were treated with (125)I. Mean pretreatment prostate ultrasound volume was 35.4 cc (range, 10.0-70.2 cc). The mean planning ultrasound target volume (PUTV) was 39.6 cc (range, 16.1-74.5 cc), whereas the mean posttreatment CT target volume was 55.0 cc (range, 20.2-116 cc). Patient records were reviewed to determine which patients required urinary catheterization for relief of urinary obstruction. The following factors were analyzed as predictors for urinary retention: clinical stage; Gleason score; prostate-specific antigen; external beam radiation therapy; hormone therapy; pre-implant urinary symptoms (asymptomatic/nocturia x 1 vs. more significant urinary symptoms); pretreatment ultrasound prostate volume; PUTV; PUTV within the 125%, 150%, 200%, 250%, 300% isodose lines; postimplant CT volume within the 125%, 150%, 200%, 250%, 300% isodose lines; D90; D80; D50; ratio of post-CT volume to the PUTV; the absolute change in volume between the CT volume and PUTV; number of needles used; activity per seed; and the total activity of the implant. Statistical analyses using logistic regression and chi2 were performed. RESULTS: Eleven of 91 (12%) became obstructed. Significant factors predicting for urinary retention were the total number of needles used (p < 0.038); the pretreatment ultrasound prostate volume (p < 0.048); the PUTV (p < 0.02); and the posttreatment CT volume (p < 0.021). Two of 51 patients (3.9%) requiring 33 or fewer needles (median) experienced obstruction vs. 9 of 40 (22.5%) requiring more than 33 (p < 0.007). If the pretreatment ultrasound prostate volume was 35 cc or less (median), 3 of 43 (7%) vs. 8 of 36 (22%) with a volume greater than 35 cc experienced obstruction (p < 0.051). CONCLUSION: The number of needles required (perhaps related to trauma to the prostate) and the prostate volumes were significant factors predicting for urinary retention after permanent prostate seed implantation.

Intraoperative preplanning for transperineal ultrasound-guided permanent prostate brachytherapy.

PURPOSE: To describe our approach to intraoperative preplanning (INTRA-OP) for prostate implants and compare it to our standard method using a pre-implant volume study (STAND). METHODS AND MATERIALS: Twenty patients (10 STAND, 10 INTRA-OP) were evaluated. Time required for each step of the INTRA-OP procedure was recorded. Overall procedure times and operating room times were obtained for all sessions. Postimplant dosimetry was CT-based. RESULTS: Mean times required for each stage of the INTRA-OP procedure were as follows: Pre-implant TRUS/prostate stabilization, 26 min; image transfer, 4 min; volume outlining, 8 min; plan generation, 18 min; initial needle loading, 17 min; seed implantation, 57 min. Mean time for the implantation session was 150 min for the INTRA-OP and 120 min for the STAND groups (p = 0.002). However, this difference is negated if the preplanning volume study is included. In addition, there was a trend toward a shorter time for the INTRA-OP patients when evaluating mean total operating room times (200 min vs. 220 min; p = 0.07). The mean postimplant %D80 for the INTRA-OP patients was 104. 8% vs. 116.2% for the STAND group (p = 0.1). The corresponding %D90 values were 85.3% and 94.6%, respectively (p = 0.08). CONCLUSION: Intraoperative preplanning increased the time required for the implantation session, but appeared to decrease overall operating room time. The overall convenience of the procedure makes intraoperative preplanning an attractive technique for transperineal ultrasound-guided prostate brachytherapy.

Dosimetric and volumetric criteria for selecting a source activity and a source type ((125)I or (103)Pd) in the presence of irregular seed placement in permanent prostate implants.

PURPOSE: The dosimetric merit of a permanent prostate implant relies on two factors: the quality of the plan itself, and the fidelity of its implementation. The former factor depends on source type and on source strength, while the latter is a combination of skill and experience. The purpose of this study is to offer criteria by which to select a source type ((125)I or (103)Pd) and activity. METHODS AND MATERIALS: Given a prescription dose and potential seed positions along needles, treatment plans were designed for a number of seed types and activities, specifically for (125)I with activities ranging from 0.3 to 0.7 mCi, and for (103)Pd with activities in the range of 0.8 to 1.6 mCi. To avoid human planner bias, an automated computerized planning system based on integer programming was used to obtain optimal seed configurations for each seed type and activity. To simulate the effect of seed-placement inaccuracies, random seed-displacement "errors" were generated for all plans. The displacement errors were assumed to be uniformly distributed within a cube with side equal to 2sigma. The resulting treatment plans were assessed using two volumetric and two dosimetric indices. RESULTS: For (125)I implants a coverage index (CI) of 98.5% or higher can be achieved for all activities (CI is the fraction of the target volume receiving the prescribed or larger dose). The external volume index (EI) (i.e., the amount of healthy tissue, as percentage of the target volume, receiving the prescribed or larger dose) increases from 13.9% to 20% as the activity increases from 0.3 to 0.7 mCi. For implants using (103)Pd, the external volume index increases from 10. 2% to 13.9% whenever CI exceeds 98.5%. Volumetric and dosimetric indices (coverage index, external volume index, D90, and D80) are all sensitive to seed displacement, although the activity dependence of these indices is more pronounced for (125)I than for (103)Pd implants. CONCLUSIONS: For both isotopes, the lower activities studied systematically result in lower EIs. If seeds can be placed within approximately 0.5 cm of their intended position (103)Pd should be preferred because its EI is lower than that of (125)I. For all activities the coverage indices and D90 are within the required range. If seed placement uncertainties are larger than 0.5 cm, (125)I provides slightly better target coverage; however, in terms of external volume (healthy tissue) covered, (103)Pd is superior to (125)I.

Microvessel density as a predictor of PSA recurrence after radical prostatectomy. A comparison of CD34 and CD31.

Whether prostate cancer recurrence can be predicted by microvessel density (MVD) measurements is controversial. One reason for the lack of agreement may be the differing antibodies used to determine MVD. We evaluated MVD using 2 different antibodies against endothelial cells, CD31 and CD34, on 102 patients who underwent radical prostatectomy without adjuvant hormonal therapy. The tumors from these cases were identified, and areas with the highest Gleason pattern were immunostained. Average MVD determined by CD31 (MVD/CD31) staining was significantly lower than that obtained by MVD/CD34 staining (60.1 vs 80.3). By using Kaplan-Meier analysis, prostate-specific antigen (PSA) recurrence was correlated with MVD/CD31 and MVD/CD34. MVD/CD34 and MVD/CD31 were associated strongly with PSA recurrence on a univariate level. However, only MVD/CD34 was an independent predictor of PSA failure. Therefore, some of the confusion about MVD value as a prognostic indicator may be due to the antibodies used.

PSA based review of adjuvant and salvage radiation therapy vs. observation in postoperative prostate cancer patients.

Because of the uncertainties regarding the efficacy of postoperative radiation therapy for early prostate cancer, treatment strategies following radical prostatectomy include: (1) observation alone in high-risk patients, (2) adjuvant radiation therapy (PSA undetectable) in high-risk patients, or (3) salvage radiation therapy for biochemical and clinical recurrence. Fifty-two patients treated with postoperative radiation therapy in either an adjuvant setting (13) or for salvage (39) were retrospectively reviewed. The actuarial biochemical disease-free survival (bNED) rates following radiation therapy were calculated using the life-table method. Univariate and multi variate analyses were used to define the clinical factors that predict biochemical failure following postoperative radiation therapy. In addition, the bNED survival rate for 36 high-risk surgery patients who were simply observed following prostatectomy was determined. The 3-year bNED survival rate for the adjuvant radiation group was 85% compared with 27% for salvage radiation and 43% for the observation group. These results are statistically significant. Factors that predict biochemical failure following postoperative radiation therapy include preoperative PSA level, pre-radiation therapy PSA level, and seminal vesicle involvement. At our institutions, adjuvant radiation therapy was a superior strategy compared with either observation alone or salvage radiation therapy for high-risk postoperative prostate cancer patients. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 29-36 (2000).

The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer.

PURPOSE: Trials have demonstrated decreased relapse with perioperative methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy in patients with muscle invasive bladder cancer. We evaluated whether the benefit of chemotherapy correlates with its effects on distant or pelvic relapse. MATERIALS AND METHODS: We retrospectively evaluated the records of all 107 patients who underwent cystectomy for muscle invasive bladder cancer at our institution between 1988 and 1994. Factors predicting relapse were identified and used to group patients at high or low risk. The outcome in each group with and without M-VAC chemotherapy was then analyzed in terms of overall, metastatic and pelvic relapse. Univariate analysis was performed using the Kaplan-Meier method and log rank statistic, and multivariate analysis was done using the Cox proportional hazards model. Median survival was 29 months for patients free of disease. RESULTS: Pathological stage T3 or greater according to the American Joint Committee on Cancer, tumor greater than 3 cm. and creatinine greater than 1.5-fold normal were independent poor prognostic factors in patients treated with cystectomy only. Patients with any of these factors or metastatic involvement of the pelvic lymph nodes were considered at high risk. All 35 low risk patients were treated with cystectomy only and had an excellent outcome with a 3-year relapse-free survival plus or minus standard error of 93% +/- 5%. The 3-year rates in 52 and 20 high risk patients treated without and with chemotherapy, respectively, were 42% +/- 8% versus 57% +/- 13% for relapse-free survival (p = 0.17), 38% +/- 9% versus 8% +/- 8% for pelvic failure (p = 0.02) and 39% +/- 9% versus 38% +/- 13% for distant metastases (not significant). Multivariate analysis of patients who underwent pelvic lymphadenectomy revealed that perioperative chemotherapy improved relapse-free survival and pelvic control but not metastatic control (p = 0.03, 0.02 and 0.31, respectively). CONCLUSIONS: Low risk patients have excellent disease control when treated with cystectomy only. Those with high risk features are at substantial risk for pelvic failure (38% at 3 years) after cystectomy only. Perioperative M-VAC chemotherapy has a profound impact on pelvic but not on metastatic failure.

Which patients with newly diagnosed prostate cancer need a computed tomography scan of the abdomen and pelvis? An analysis based on 588 patients.

OBJECTIVES: Although a computed tomography (CT) scan of the abdomen and pelvis is often recommended as part of the staging evaluation for newly diagnosed prostate cancer, most scans are negative for metastases. We hypothesized that biopsy Gleason score, serum prostate-specific antigen (PSA) levels, and clinical stage could predict for a positive CT scan and that a low-risk group of patients could be identified in whom CT might be omitted. METHODS: All patients who had both pathologic review of their prostate cancer biopsies and abdominopelvic CT scans at our institution between January 1990 and May 1996 were studied. Gleason score, PSA, and stage were evaluated by univariate (chi-square) and multivariate (logistic regression) analyses for their ability to predict for a positive CT. RESULTS: Of 588 patients, 41 (7%) had a positive CT scan. Multivariate analysis showed Gleason score, PSA, and clinical stage to be significant independent predictors of a positive CT scan, all P <0.001. The odds ratios for a positive CT scan were 6.17 (95% confidence interval [CI] = 1.58 to 24) for Gleason score 8 to 10 versus 2 to 6; 2.25 (CI = 1.24 to 4) for PSA greater than 50 versus 0 to 15 ng/mL; 2.08 (CI = 1.70 to 3.21 ) for Stage T2c-T4 versus T2b or lower. All 244 patients with Gleason score 2 to 7, PSA 1 5 ng/mL or less, and clinical Stage T2b or less had negative CT scans. Of the other 174 patients with a Gleason score of 2 to 7, 8 (5%) had a positive CT scan. Of the 1 26 patients with a Gleason score of 8 to 10, 28 (22%) had a positive CT scan. CONCLUSIONS: Gleason score, PSA, and clinical stage were independent predictors for a positive CT scan of the abdomen and pelvis in patients with newly diagnosed prostate cancer. In this cost-conscious era, we can decrease expenditure by obviating the need for a CT scan in low-risk patients (clinical Stage T2b or less, Gleason score 2 to 7, and PSA 15 ng/mL or less). A CT scan should be considered in all other patients.

Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome.

OBJECTIVES: Angiogenesis is believed to play an important role in tumor progression and metastasis. Previous studies have suggested that the microvessel density (MVD) of prostate tumors may be of prognostic value. This study investigated the reliability of assessing MVD in radical prostatectomy specimens and its value as an independent prognostic indicator in men with clinically localized prostate cancer. METHODS: One hundred radical prostatectomy specimens from 1993 to 1995 were randomly selected for this study. Thirteen cases were excluded because the patients had undergone neoadjuvant hormonal therapy or tissue blocks were unavailable. The median follow-up time was 36 months. Tumor blocks were immunostained using the endothelial-specific antibody CD31. MVD was counted in areas with the greatest microvessel immunostaining, which were designated "hot spots." MVD was analyzed for associations with clinical and pathologic factors. In a subset of 60 cases, the same observer repeated the counts three times. RESULTS: Intraobserver reliability for MVD counting was excellent (reliability coefficient 0.82), demonstrating that this method could be reproduced by a single observer. MVD was not associated with Gleason sum, tumor stage, surgical margin status, or seminal vesicle invasion. Of the 87 patients, 20 (23%) had a prostate-specific antigen (PSA) failure during a 36-month median follow-up time. As expected, Gleason sum and tumor stage were strong predictors of PSA failure, with risk ratios of 2.1 and 2.3, respectively. In contrast, MVD was not associated with PSA failure. CONCLUSIONS: MVD, as determined by CD31, can be reliably measured by a single observer, but it is not a useful prognostic indicator for men with clinically localized prostate cancer.

Changes in biochemical disease-free survival rates as a result of adoption of the consensus conference definition in patients with clinically localized prostate cancer treated with external-beam radiotherapy.

PURPOSE: The optimal definition of biochemical recurrence of prostate cancer after definitive radiotherapy remains elusive. Different institutions have developed their own definitions, and a consensus conference (CC) sponsored by the American Society for Therapeutic Radiology and Oncology has recently proposed another definition. This study compares the definition previously used at our institution with the definition proposed by the CC. METHODS: Two hundred and eight patients were treated for localized prostate cancer with conformal external-beam radiotherapy between 1989-1993 at our institution and followed for at least 24 months. Patients were categorized as failures according to our institutional definition and the CC definition. Our definition (CPMC) required two increases in serum prostate specific antigen (PSA) over at least a 3-month period with a final value of at least 1 ng/ml or a single value resulting in clinical intervention. The CC definition required three consecutive increases in PSA. This was modified to also consider those patients with one or two increases leading to clinical intervention as failures. Differences in the failure rates between the two definitions were evaluated and factors influencing these differences were explored. In an additional analysis, CC was modified such that patients with one or two PSA increases were censored at the time of the PSA prior to the increases (CC-II), rather than at the last PSA (CC). The median follow-up time was 31 months. RESULTS: There were 36 fewer failures according to CC (n = 96) compared with CPMC (n = 132) (p < 0.001). Twenty cases called failures by CPMC subsequently had a decrease in PSA ("false failures"). The other 16 patients have had two increases in PSA, but are awaiting their next follow-up visit to obtain a third PSA ("pending failures"). Analysis of factors predicting "pending failures" showed Gleason score to be the sole predictor of this change in status in multivariate analysis (p = 0.03) with patients with lower-grade tumors being more likely to change status (Gleason 2-6: 15% vs. Gleason 7-10: 1%). On the other hand, "false failures," compared to true failures, had a lower mean PSA nadir (1.7 ng/ml vs. 7.0 ng/ml, p < 0.001) and significantly smaller mean increases in PSA (1st increase: 0.6 ng/ml vs. 3.4 ng/ml, p = 0.006; 2nd increase: 0.4 ng/ml vs. 4.8 ng/ml, p = 0.002). In 85% (17 of 20) of these patients, at least one of the increases was < or = 0.3 ng/ml compared with 44% (42 of 96) of the true failures (p = 0.0008). CC-II resulted in a small decrease in BDFS rates compared with CC, but did not affect the overall difference between CC and CPMC. A modified definition that defines failure as two consecutive increases in PSA over 3 months, with a final value greater than 1.0 ng/ml and each increase being at least 0.3 ng/ml, or three consecutive increases would result in a "false" failure rate of only 3% (3 of 99) and identify 56% (54 of 96) of the true failures after only two PSA increases. CONCLUSION: The CPMC definition of two PSA increases can falsely identify patients as failures, particularly if the increases in PSA are small (i.e., < or = 0.3 ng/ml). The CC definition requiring three increases in PSA can falsely identify patients as disease-free when the time to failure is long relative to the follow-up time. We propose a that a definition that combines aspects of both definitions (two consecutive increases in PSA over 3 months, with a final value greater than 1.0 ng/ml and each increase being at least 0.3 ng/ml, or three consecutive increases) may be a better definition of biochemical failure.

Biologic classification as an alternative to anatomic staging for clinically localized prostate cancer: a proposal based on patients treated with external beam radiotherapy.

OBJECTIVES: The prognostic significance of clinical stage in patients with prostate cancer who are treated with external beam radiotherapy is unclear. This study evaluates multiple pretreatment factors, including clinical stage, to determine which are the best prognostic factors, and develops a classification system based on these factors. METHODS: All 249 evaluable patients with clinically localized adenocarcinoma of the prostate treated with definitive conformal external beam radiotherapy without androgen deprivation at our institution between 1989 and 1993 were analyzed. Clinical stage, serum PSA level, Gleason score, race, and history of transurethral resection of the prostate (TURP) were evaluated for their ability to predict biochemical disease-free survival (BDFS). Factors predictive of BDFS were then used to construct a classification system. The classification system was then analyzed for its ability to predict BDFS, distant metastases, local recurrence, and clinical disease free survival in univariate and multivariate analyses. Median follow-up was 27 months. RESULTS: Gleason score and PSA predicted BDFS in multivariate analysis (both P <0.0001), whereas clinical stage, race, and history of a TURP did not. These two biologic factors were combined into a four-level classification system. This classification system was analyzed together with Gleason score and PSA and was found to be the only predictor of BDFS on multivariate analysis (P <0.0001). In addition, this classification system was the only predictor of distant metastases in multivariate analysis (P <0.0001). CONCLUSIONS: The classification system derived herein based on the biologic factors of Gleason score and serum PSA levels is the sole predictor of distant metastases and biochemical recurrence for patients treated with definitive conformal external beam radiotherapy for clinically localized prostate cancer. This classification system may be useful when comparing competing therapies and stratifying patients in clinical trials, but requires validation from other institutions and other therapies prior to its widespread use.

Re-examining the role of prostate-specific antigen density in predicting outcome for clinically localized prostate cancer.

OBJECTIVES: To evaluate the prognostic significance of prostate-specific antigen density (PSAD) in clinically localized prostate cancer and determine whether this index is independent of or superior to prostate-specific antigen (PSA) in predicting outcome of patients treated with external beam radiotherapy. METHODS: Between January 1989 and December 1993, 175 evaluable patients with clinically localized prostate cancer received definitive radiotherapy using computed tomography (CT)-guided conformal techniques. PSAD was defined as the ratio of the pretreatment serum PSA to the prostate volume measured from CT treatment planning scans by one investigator. All PSA values were determined using the Hybritech assay. Biochemical failure was defined as two consecutive elevations in PSA separated by at least 3 months and a final PSA value greater than 1 ng/mL. RESULTS: Multivariate analysis including PSA and Gleason score revealed both to be statistically significant predictors of biochemical disease-free survival (P = 0.048 and P < 0.001, respectively). PSAD did not achieve significance on regression analysis. A direct multivariate analysis including PSA and PSAD required dichotomization in order to reduce high correlation. This analysis demonstrated a relative risk (RR) for failure of 1.27 (NS) for high PSA versus low PSA compared with a RR of 1.20 (NS) for high PSAD versus low PSAD. A regression model containing all three variables indicated only the Gleason score as significant in predicting biochemical failure. CONCLUSIONS: These data do not suggest that PSAD is either an independent prognostic factor or a stronger discriminant of outcome than PSA in patients with clinically localized prostate cancer treated with definitive external beam radiotherapy. Larger patient numbers with longer follow-up data, use of a clinical end point, or an analysis restricted to the appropriate subgroup may demonstrate the utility of PSAD in the future.

Detection of circulating prostate carcinoma cells via an enhanced reverse transcriptase-polymerase chain reaction assay in patients with early stage prostate carcinoma. Independence from other pretreatment characteristics.

BACKGROUND: Circulating prostate cells can be detected in the venous blood of patients with clinically localized prostate carcinoma by applying reverse transcriptase-polymerase chain reaction (RT-PCR) techniques using primers specific for the prostate specific antigen (PSA) gene. This study evaluates whether the detection of circulating cells correlates with established prognostic factors, treatment, and pathologic stage. METHODS: Two hundred and twenty-seven patients with clinically localized adenocarcinoma of the prostate had an RT-PCR assay performed as part of their staging evaluation. No treatment decisions were made on the basis of the RT-PCR results. Of these, 156 patients were treated with radical prostatectomy (RP) and 71 with radical external beam radiotherapy (EBRT). Forty-eight patients were treated with hormonal therapy prior to RP (n = 39) or EBRT (n = 9). The prognostic factors analyzed for their relationship to RT-PCR were clinical stage, pretreatment serum PSA levels, Gleason score of the biopsy specimen, and Gleason score of the surgical specimen. An analysis of the relationship between treatment and RT-PCR results was also performed. Multivariate logistic regression analysis of predictors of RT-PCR positivity was performed as well. In addition, univariate and multivariate analyses of predictors of pathologic stage, including RT-PCR, were performed. RESULTS: Sixty-one patients (26.9%) had a positive RT-PCR assay. There was no relationship between clinical stage, pretreatment PSA, biopsy Gleason score, or surgical Gleason score and RT-PCR positivity. In univariate analysis, patients treated with RP had a higher rate of RT-PCR positivity than patients treated with EBRT (P = 0.054). However, in multivariate logistic regression analysis no factor, including treatment with RP, was a significant predictor of RT-PCR positivity. RT-PCR and pretreatment PSA predicted pathologic stage in univariate and multivariate analyses (P < 0.0001 and P = 0.002, respectively). CONCLUSIONS: The detection of circulating prostate cells using RT-PCR occurs in approximately 25% of early stage prostate carcinoma patients and is independent of other established prognostic factors. In addition, a positive RT-PCR assay is a strong predictor of pathologic upstaging in patients with clinically organ-confined disease.

Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.

BACKGROUND: Radiation therapy (RT) to the pelvis has been associated with an increased risk of bladder carcinoma, as well as other malignancies. However, no controlled studies have previously explored the risk of second malignancies after RT for prostate carcinoma. METHODS: A retrospective cohort study was conducted utilizing data from the Surveillance, Epidemiology, and End Results Program (SEER) of the U. S. National Cancer Institute from 1973-1990. The standardized incidence ratio (SIR), adjusted for age, was calculated as an estimate of the relative risk (RR) of developing a second malignancy after prostate carcinoma for radiated and nonradiated prostate carcinoma patients separately. RESULTS: The cohort was comprised of 34,889 prostate carcinoma patients who had undergone RT, and 106,872 who had not. After 8 years, the risk of bladder carcinoma was elevated for the RT group (RR 1.5; 95% confidence interval [CI], 1.1-2.0) but not for the non-RT group (RR 1.0; 95% CI, 0.7-1.2). There was an elevated risk of bladder carcinoma for the RT group at 5-8 years as well (RR 1.3; 95% CI, 1.0-1.7). No elevations in risk were observed for rectal carcinoma, acute nonlymphocytic leukemia, or chronic lymphocytic leukemia for either RT patients or non-RT patients. CONCLUSIONS: The risk of bladder carcinoma is elevated several years after RT for prostate carcinoma, but this elevation is not dramatic. There is no increased risk of rectal carcinoma or leukemia after this type of radiation exposure.