Ronald D. Ennis

Intracoronary irradiation: Dose response for the prevention of restenosis in swine

PURPOSE Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that high-dose radiation (20 Gy), delivered via an intracoronary 192Ir source, causes focal medial fibrosis and markedly impairs the restenosis process after balloon angioplasty in swine. This study sought to delineate the dose-response characteristics of this effect. METHODS AND MATERIALS Forty juvenile swine underwent coronary angiography; a segment of the left coronary artery was chosen as a target for balloon injury. In 30 swine, a 2 cm ribbon of 192Ir was positioned at the target segment and 20, 15, or 10 Gy were delivered to the vessel wall (10 animals/dose). Subsequently, overdilatation balloon angioplasty was performed at the irradiated segment. In 10 control swine, overdilatation balloon angioplasty was performed without previous irradiation. Thirty-eight animals survived until sacrifice at 30 +/- 3 days. Histopathological analysis was performed by a pathologist in a blinded manner. The area of maximal luminal compromise within the target segment was analyzed via computer-assisted planimetry. RESULTS Neointimal area was decreased by 71.4% at 20 Gy and by 58.3% at 15 Gy compared with control animals (p < 0.05 for both). A stimulatory effect on smooth muscle cell proliferation was noted at 10 Gy, with a 123% increase in neointimal area compared with controls (p < 0.05). Mean percent area stenosis was also reduced by 63% at 20 Gy and by 74.8% at 15 Gy compared with controls (p < 0.05 for both). CONCLUSIONS Intracoronary irradiation prior to overstretch balloon angioplasty markedly reduces neointima formation; this effect is dose dependent, with evidence of a significant stimulatory effect at 10 Gy. The effective therapeutic dose range for the prevention of restenosis in this model begins at approximately 15 Gy delivered to the vessel wall.

Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma

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.

DOSIMETRIC CONSIDERATIONS FOR CATHETER-BASED BETA AND GAMMA EMITTERS IN THE THERAPY OF NEOINTIMAL HYPERPLASIA IN HUMAN CORONARY ARTERIES

PURPOSE Recent data indicate that intraluminal irradiation of coronary arteries following balloon angioplasty reduces proliferation of smooth muscle cells, neointima formation, and restenosis. We present calculations for various isotopes and geometries in an attempt to identify suitable source designs for such treatments. METHODS AND MATERIALS Analytical calculations of dose distributions and dose rates are presented for 192Ir, 125I, 103Pd, 32P, and 90Sr for use in intracoronary irradiation. The effects of source geometry and positioning accuracy are studied. RESULTS Accurate source centering, high dose rate, well-defined treatment volume, and radiation safety are all of concern; 15-20 Gy are required to a length of 2-3 cm of vessel wall (2-4 mm diameter). Dose must be confined to the region of the angioplasty, with reduced doses to normal tissues. Beta emitters have radiation safety advantages, but may not have suitable ranges for treating large diameter vessels. Gamma emitters deliver larger doses to normal tissues and to staff. Low energy x-ray emitters such as 125I and 103Pd reduce these risks but are not available at high enough activities. The feasibility of injecting a radioactive liquid directly into the angioplasty balloon is also explored. CONCLUSIONS Accurate source centering is found to be of great importance. If this can be accomplished, then high energy beta emitters such as 90Sr would be ideal sources. Otherwise, gamma emitters such as 192Ir may be optimal. A liquid beta source would have optimal geometry and dose distribution, but available sources, such as 32P are unsafe for use with available balloon catheters.

Prostate localization using transabdominal ultrasound imaging

PURPOSE Adding margin around a target is done in an attempt to ensure complete coverage of the target. The B-mode acquisition and targeting (BAT) system allows ultrasound imaging of the prostate in patients with a full bladder. This provides a setup tool for patients with localized prostate cancer that takes into account real-time prostate position and may make it possible to decrease tumor margins. Prostate localization using the conventional setup verification method and daily isocenter shifts recommended by the ultrasound imaging system (BAT) were compared and analyzed. METHODS AND MATERIALS Daily treatment isocenter shifts for patients with localized adenocarcinoma of the prostate, obtained from two different imaging modalities, electronic portal imaging (EPI) and BAT, were calculated. We studied the difference in patient setup error calculated using BAT contour alignment and measured from EPI; the reproducibility of BAT contour alignment; intrafraction prostate motion; and how the BAT imaging procedure itself affected the prostate position. Prostate motion relative to its position during simulation was calculated by subtracting the EPI-measured isocenter shifts from the corresponding BAT-defined isocenter shifts. BAT reproducibility was measured by taking a verification BAT image after the patient was moved according to the initial BAT-defined isocenter shifts. Intrafraction prostate motion was measured by repeating BAT imaging at the end of a treatment fraction. The BAT imaging effect on prostate position was studied by examining the effect of suprapubic pressure on seed position in patients after a seed implant. RESULTS The mean BAT isocenter shifts for prostate motion were 0.32 +/- 0.46 cm in the lateral, 0.31 +/- 0.73 cm in the superoinferior, and 0.32 +/- 0.56 cm in the AP directions. Isocenter shifts obtained from EPI measurements were significantly smaller, with a mean of 0.05 +/- 0.24 cm in the lateral, 0.01 +/- 0.11 cm in the superoinferior and -0.11 +/- 0.29 cm in the AP directions. This larger shift seen by BAT was due to prostate motion. For BAT reproducibility, the results showed that for BAT verification images, 90% of the lateral shifts were <0.2 cm, 93% of the superoinferior shifts were <0.3 cm, and 83% of the AP shifts were <0.2 cm. The mean isocenter shift (intrafraction localization error) during patient treatment fraction was 0.02 +/- 0.28 cm in the lateral, 0.04 +/- 0.48 cm in the superoinferior, and 0.0 +/- 0.32 cm in the AP direction. The BAT procedure itself induced an average motion of 1 mm in the AP and superoinferior directions. CONCLUSIONS Prostate patient setup verification on the basis of bony anatomy position does not reflect the actual prostate position. BAT ultrasound target alignment provides a real-time prostate localization system that may make it possible to measure prostate position variations and reduce margins.

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.

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.

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.

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.

Detection of circulating prostate carcinoma cells via an enhanced reverse transcriptase-polymerase chain reaction assay in patients with early stage prostate carcinoma†

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.

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.