Urinary 6beta-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals.

6beta-Hydroxycortisol (6beta-OHF) urinary excretion has, for a long time, been considered a marker of drug induction and, more recently, of drug inhibition in humans and in laboratory animals, but its specificity is still under debate. In this work, we review 277 papers devoted to 6beta-OHF urinary excretion. We have evaluated factors that could modify 6beta-OHF excretion and, thus, could explain contradictory results. We have examined the effect of the analytical techniques on physiological values. Intra- and inter-individual variability and the effect of circadian rhythms on urinary excretion of 6beta-OHF as well as cortisol and 17-hydroxycorticosteroids have been evaluated. We also give an overview of drugs that induce, inhibit or have no effect on 6beta-OHF. For inducing and inhibiting drugs, we calculated the ranges of variation of 6beta-OHF excretion from the results indicated in the different papers. This work was done for well-known inducers, such as anticonvulsants, but also for other inducing or inhibiting drugs found in the literature. The time-course of variation in 6beta-OHF excretion when different drugs are co-administered was also investigated. The potential relationship between cytochrome P(450) 3A4 (CYP3A4) polymorphism and 6beta-OHF excretion was studied. Finally, the interest of 6beta-OHF urinary excretion was compared with that of other tests proposed to measure CYP3A4 activity. This review demonstrates that 6beta-OHF urinary excretion is a good test to evaluate drug-metabolising enzyme inducing or inhibiting properties of drugs when the subjects are their own controls, but this test is not reliable enough to measure actual CYP3A4 activity.

Pretest probability assessment for selective rest sestamibi scans in stable chest pain patients.

The objective of this study was to determine whether pretest probability assessments permit more selective testing of chest pain patients with technetium-99m sestamibi scanning. Pretest probabilities of cardiac ischemia were measured both objectively (Acute Cardiac Ischemia Time-Insensitive Predictive Instrument [ACI-TIPI]) and subjectively (physician's estimate of the probability of unstable angina). Two groups were defined: patients whose postsestamibi scan led to a "downgrade" of the intensity of monitoring and those that resulted in no change in monitoring intensity. Sixty-five patients met study criteria; 25 had a disposition downgrade and 40 had no change. Pretest ACI-TIPI scores were similar in the two groups (29% +/- 18% versus 27% +/- 11%, mean +/- standard deviation; P = .95) as were the physician's assessment of unstable angina (39% +/- 22% versus 40% +/- 24%; P = .75). Objective or subjective pretest probabilities are not significantly different in patients who are likely to have their disposition altered by sestamibi scanning.

Combined low-dose-rate brachytherapy and external beam radiation for cervical cancer: experience over ten years.

Cervical cancer was treated with a combination of external beam and intracavitary radiation during a 10-year period at Wayne State University. Data were collected for 216 patients treated radically with external beam radiation (EBRT) and low-dose-rate brachytherapy for cervical cancer between 1980 and 1991 at Wayne State University. Patient distribution by stage was IB, 20.8%; IIA, 7.4%; IIB, 26.9%; IIIA, 1.8%; IIIB, 40.7%; and IVA, 2.3 %. Survival curves were constructed using Kaplan-Meier methods and differences between groups were tested for significance using the log-rank test. Multivariate analysis was done using the Cox proportional hazards model. With a median follow-up of 114 months, actuarial disease-free survival for all patients was 60% at 5 years and 55% at 10 years. Actuarial 5-year survival for Stage IB was 79%; for Stage II, 59%; and for Stage III, 53%. There were 14/216 (6%) of patients with severe late complications. On univariate analysis, race was found to be statistically significant, with Caucasian patients having better survival than African American (P = 0.03). The survival for patients treated in shorter overall times was significantly higher (P<0.001), especially with treatment completion in under 58 days. The stepwise Cox multivariate analysis provided the following significant results: race (African American vs. Caucasian; P = 0.04, RR = 1.6), Stage (II vs. I, P = 0.004, RR = 2.6), Stage (III vs. I; P = 0.004, RR = 2.5), and overall treatment time (P = 0.006, RR = 1.62). Rates of local control, survival, and complications among women treated with combined external beam and intracavitary radiation for cervix cancer were similar to those of prior retrospective studies.

Anesthetic methods for reduction of acute shoulder dislocations: a prospective randomized study comparing intraarticular lidocaine with intravenous analgesia and sedation.

A prospective, randomized, nonblinded clinical trial was undertaken to evaluate whether local intraarticular lidocaine injection (IAL) is equally effective in facilitating reduction of acute anterior shoulder dislocations (AASD) as intravenous analgesia/sedation (IVAS). The setting was an urban, Level 1, trauma center. Patients enrolled presented to the emergency department (ED) with radiographically confirmed AASD and were randomized either to the IVAS group or the IAL group. Ease of reduction and pain associated with reduction were measured subjectively using a 10-point scale. There were 49 patients entered into the study, 20 in the IVAS group and 29 in the IAL group. There was no statistically significant difference between mean +/- SD pain scores of 3.32+/-2.39 in the IVAS group and 4.90+/-2.34 in the IAL group (P = .18), or mean +/- SD ease of reduction scores of 3.32+/-2.36 in the IVAS group and 4.45+/-2.46 in the IAL group (P = .12). Although IVAS tended to have a higher success rate (20 of 20) than IAL (25 of 29) in this study, Kaplan-Meier estimates for delayed time-events curves applying the log-rank test showed that this difference was not statistically significant overall (P = .16). However, with reduction rate evaluated as a function of time delay in seeking treatment, patients presenting 5.5 hours after dislocation were more likely to fail treatment with IAL (P = .00001). Additionally, half of the patients in the IAL group who had experience with IVAS did not favor IAL. Emergency physicians should be aware of IAL as an alternative technique that may be considered in patients when there are reasons to avoid systemic analgesia or sedation.

Resting sestamibi imaging for the prognosis of low-risk chest pain.

OBJECTIVE: To assess the prognostic value of resting Tc-99m sestamibi scanning for adverse cardiac events (ACEs) in ED chest pain patients with a low probability of acute cardiac ischemia (ACI). METHODS: Sixty-nine consenting, hemodynamically stable patients with chest pain and a nondiagnostic electrocardiogram received an injection of 25 mCi of sestamibi during or within two hours of active pain. Scans were interpreted locally by a nuclear cardiologist or radiologist. Interrater reliability was assessed. ACEs of myocardial infarction (MI), death, or revascularization were assessed during the index hospitalization and over a one-year follow-up period. RESULTS: For ACEs, rest scanning with sestamibi had a sensitivity of 71% (95% CI = 0.33 to 0.97), a specificity of 92% (95% CI = 0.82 to 0.97), and an accuracy of 90% (95% CI = 0.87 to 0.99). The positive predictive value was 50% (95% CI = 0.19 to 0.82) and the negative predictive value was 97% (95% CI = 0.87 to 0.98). Sestamibi scanning was highly discriminating, with 62% of patients with positive scans but only 3% with negative scans having ACEs (p<0.001, log rank test). CONCLUSION: In patients with low-risk chest pain, sestamibi scanning has good specificity and moderate sensitivity for ACEs over a 12-month period.

External beam radiotherapy for painful osseous metastases: pooled data dose response analysis.

PURPOSE: Although the effectiveness of external beam irradiation in palliation of pain from osseous metastases is well established, the optimal fractionation schedule has not been determined. Clinical studies to date have failed to demonstrate an advantage for higher doses. To further address this issue, we conducted a pooled dose response analysis using data from published Phase III clinical trials. METHODS AND MATERIALS: Complete response (CR) was used as an endpoint because it was felt to be least susceptible to inconsistencies in assessment.The biological effective dose (BED) was calculated for each schedule using the linear-quadratic model and an alpha/beta of 10. Using SAS version 6.12, the data were fitted using a weighted linear regression, a logistic model, and the spline technique. Finally, BED was categorized, and odds ratios for each level were calculated. RESULTS: CR was assessed early and late in 383 and 1,007 patients, respectively. Linear regression on the early-response data yielded a poor fit and a nonsignificant dose coefficient. With the late-response data, there was an excellent fit (R-square = 0.842) and a highly significant dose coefficient (p = 0.0002). Fitting early CR to a logistic model, we could not establish a significant dose response relationship. However, with the late-response data there was an excellent fit and the dose coefficient was significantly different from zero (0.017 +/- 0.00524; p = 0.0012). Application of the spline technique or removal of an outlier resulted in an improved fit (p = 0.048 and p = 0.0001, respectively). Using BED of < 14.4 Gy as a reference level, the odds ratios for late CR were 2.29-3.32 (BED of 19.5-51.4 Gy, respectively). CONCLUSION: Our results demonstrate a clear dose-response for pain relief. Further testing of high intensity regiments is warranted.

Antihistaminic and anticholinergic activity of barberry fruit (Berberis vulgaris) in the guinea-pig ileum.

Barberry (Berberis vulgaris) is a well known medicinal plant in Iran and has also been used as food. The antihistaminic and anticholinergic activity of aqueous extract of barberry fruits were investigated on isolated guinea-pig ileum, and dose response curves of histamine and acetylcholine with and without extract were plotted. The pA2 values for antihistaminic activity of extract and dexchlorpheniramine were calculated (extract; pA2 +/- S.E.M. = 4.50 +/- 0.01[-log C (g/l)]; dexchlorpheniramine; pA2 +/- S.E.M. = 9.36 +/- 0.14[-log C (M)]) and compared with each other. The pA2 values for anticholinergic activity of extract and atropine were also calculated (extract, pA2 +/- S.E.M. = 4.37 +/- 0.03[-log C (g/l)]; atropine, pA2 +/- S.E.M. = 8.99 +/- 0.13[-log C (M)]) and compared. The results indicated antihistaminic and anticholinergic activity of extract that seems to be of the competitive type.

Permanent 125iodine implants for recurrent malignant gliomas.

PURPOSE: To determine the efficacy and toxicity of permanent 125iodine implants for recurrent malignant gliomas. METHODS AND MATERIALS: Between January 1989 and January:, 59 patients with histologically confirmed recurrent malignant gliomas (22 nonglioblastoma malignant gliomas, 37 glioblastoma multiforme at the time of implant) received a permanent 125iodine implant. Patients ranged in age from 13-74 years. The median ages for the overall group, nonglioblastoma (nonGBM), and glioblastoma (GBM) groups was 47 years, 39 years, and 53 years, respectively. RESULTS: With a median follow-up of 40 months, the median survival for the 59 total patients is 1.34 years; nonGBM 2.04 years, GBM 0.9 years. Factors predictive for poor prognosis were GBM histology, age 60 years or more, target volume 17 cc or more, and/or tumor location within the corpus callosum or thalamus. Reoperations have been performed in 24 (40%) patients; 15 (25%) for tumor progression; 3 (5%) for radiation necrosis; 2 (3%) for skull necrosis/infection, and 4 (7%) for other reasons (Ommaya reservoir insertion, catheter removal, hematoma evacuation). CONCLUSION: Permanent 125iodine implants in selected patients with recurrent malignant gliomas are associated with reasonable long-term survival and a low risk of complications. Given the low incidence of radiation necrosis, future plans are to increase dose rate and/or total dose delivered with the permanent implant.

The influence of race on the efficacy of curative radiation therapy for carcinoma of the prostate.

The purpose of this study was to examine the effect of race on the outcome of patients treated curatively with external beam irradiation for carcinoma of the prostate. The study was performed between January 1980 and December 1993 of 1,529 men with prostate cancer. Similar percentages of Caucasian men (CM) and African-American men (AAM) had localized disease (stages T1 and T2) and advanced stage disease (stage T3). There was no difference in crude survival by race (P = .13). At 5 years, crude survival by race was 75% for CM and 73% for AAM. At 10 years, the crude survivals, were 50% and 40%, respectively. Disease-specific survival rates were equivalent for AAM and CM (P = .66). The 5-year disease-specific survival was 83% for CM and 85% for AAM. At 10 years, the disease-specific survival was 65% for CM and 69% for AAM. There was no difference in disease-specific survival by race when stage-for-stage comparisons were made. Among those patients referred for curative radiation therapy, AAM and CM had a similar age, stage, and grade distribution. This study demonstrated that there was no difference in disease-specific survival between CM and AAM treated curatively with radiation for prostate cancer.

Nutritional and zinc status of head and neck cancer patients: an interpretive review.

In this review, we provide evidence based on our studies, for zinc deficiency and cell mediated immune disorders, and the effects of protein and zinc status on clinical morbidities in patients with head and neck cancer. We investigated subjects with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. Patients with metastatic disease and with severe co-morbidity were excluded. Nutritional assessment included dietary history, body composition, and prognostic nutritional index (PNI) determination. Zinc status was determined by zinc assay in plasma, lymphocytes, and granulocytes. Pretreatment zinc status and nutritional status were correlated with clinical outcomes in 47 patients. Assessment of immune functions included production of TH1 and TH2 cytokines, T cell subpopulations and cutaneous delayed hypersensitivity reaction to common antigens. At baseline approximately 50% of our subjects were zinc-deficient based on cellular zinc criteria and had decreased production of TH1 cytokines but not TH2 cytokines, decreased NK cell lytic activity and decreased proportion of CD4+ CD45RA+ cells in the peripheral blood. The tumor size and overall stage of the disease correlated with baseline zinc status but not with PNI, alcohol intake, or smoking. Zinc deficiency was associated with increased unplanned hospitalizations. The disease-free interval was highest for the group which had both zinc sufficient and nutrition sufficient status. Zinc deficiency and cell mediated immune dysfunctions were frequently present in patients with head and neck cancer when seen initially. Zinc deficiency resulted in an imbalance of TH1 and TH2 functions. Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations. These observations have broad implications in the management of patients with head and neck cancer.

Evaluation and risk stratification of patients with chest pain in the emergency department. Predictors of life-threatening events.

While assessing chest pain in the emergency department, physicians must first estimate the probability of acute ischemic states in the patient. This first estimate is based on the patient's history, physical examination, and electrocardiogram. Patients who meet the threshold for acute cardiac ischemia are further evaluated to confirm or exclude this diagnosis, while other life-threatening factors are excluded.

Effects of zinc and nutritional status on clinical outcomes in head and neck cancer.

The head and neck cancer patient often presents with both protein malnutrition and trace element deficiencies. Zinc has been found to be deficient in many head and neck cancer patients. In this study, pretreatment zinc status and nutritional status (measured by the Prognostic Nutritional Index [PNI]) were correlated with clinical outcomes in 47 patients. The patients were followed-up for a median of 52 mo from the time of enrollment. Our results showed that the tumor size and overall stage correlated significantly to zinc status whereas no such correlation was seen with PNI, alcohol intake, or smoking in our subjects. The results also showed that impaired zinc status was associated with an increased number of treatment morbidities, unplanned hospitalizations, and treatment delays (P < 0.05). Nutritional status was not associated with any studied outcome variable. The disease-free interval was highest for the group which had both zinc-sufficient and nutrition-sufficient status. Although our data do not prove conclusively, they do suggest that impaired zinc status at presentation may contribute to treatment morbidity, and that for an optimal mean disease-free interval, a sufficient zinc and nutritional status is required.

Radiation therapy for endometrial cancer in patients treated for postoperative recurrence.

PURPOSE: To retrospectively evaluate the outcome and risk factors in patients treated with radiation for endometrial cancer at time of recurrence. MATERIALS AND METHODS: Three hundred ninety-nine women were treated with radiation therapy for endometrial cancer at KCI/WSU from January 1980 to December 1994. Of these, 26 patients treated primarily with surgery received radiation therapy at the time of recurrence. Median time to recurrence after surgery was 8 months, with all recurrences occurring within 24 months. Twenty-four patients had recurrences in the vaginal cuff, vagina, or pelvis. These patients received external-beam radiation to the pelvis (45.00-50.40 Gy) and periaortic lymph nodes (45.00-50.00 Gy), along with a boost given by external-beam radiation or brachytherapy (16.00-30.00 Gy). Mean follow-up was 15 months (range 1-85 months). RESULTS: The 2-year survival was 50% and median survival was 16 months (survival range 1-85 months). Of 26 patients, 54% (14) failed locally following radiation therapy. Factors indicative of poor survival included histology (sarcoma, poorly differentiated adenocarcinoma), grade, and lymph node positivity. Histological differentiation influenced local control; lymphovascular space invasion was of borderline significance with regard to local control. CONCLUSION: Local control and survival for surgically treated endometrial cancer patients who receive radiation at the time of recurrence are poor, with the exception of those patients with recurrent disease limited to the vagina. Early detection of recurrence may improve outcome. Pathologic risk factors may identify those patients at risk for extrapelvic recurrence. Alternative treatment modalities need to be developed for this high-risk group of patients.

Predicting the outcome of radiotherapy for prostate carcinoma: a model-building strategy.

BACKGROUND: Clinical research of prostate carcinoma could be enhanced by models that allow early and reliable prediction of outcome. In this study, the authors describe a model-building strategy and compare different models. METHODS: The sample population was comprised of 158 patients treated definitively with radiotherapy. Univariate and multivariate logistic regression analyses were conducted to identify prognostic factors and select the best predictive model. Variables included age, race, method of diagnosis (needle biopsy vs. transurethral resection of the prostate), stage, grade, pretreatment prostate specific antigen (PSA), in-treatment PSA (PSA(tx)), posttreatment PSA (PSA(post)), and nadir PSA. The following indices were used to compare discriminatory power: log-likelihood function, Akaike information criterion, the generalized coefficient of determination, and the area under the receiver operating characteristic curve. RESULTS: At last follow-up, 49 patients (31%) had recurrence of carcinoma. By univariate analysis, the failure rate was significantly higher in patients with advanced stage, higher grade, higher pretherapy PSA, and nadir PSA > 1 ng/mL (P < 0.0001). Pretherapy PSA was associated significantly with stage, age, and nadir PSA (P = 0.001, P = 0.001, and P = 0.001, respectively). All PSA measurements were significantly interrelated. Nadir PSA was the most predictive variable. Significant gains (P = 0.01) in predictive power were derived from inclusion of PSA(tx), but not PSA (post). Age, race, stage, grade, and method of diagnosis contributed predictive power in addition to that derived from PSA levels (P = 0.01, log-likelihood test). The authors' model of choice predicts outcome with an overall correctness, sensitivity, specificity, and false-negative rate of 81.8%, 87.2%, 79.6%, and 12.8%, respectively. CONCLUSIONS: Applying the strategy described, a model was selected that allowed accurate prediction of failure shortly after the completion of therapy.

Radiotherapeutic management of osseous metastases: a survey of current patterns of care.

PURPOSE: Radiotherapy plays a major role in the management of painful osseous metastases. This survey was conducted to study the current approaches to this clinical problem in the radiotherapy community. METHODS AND MATERIALS: A questionnaire was sent to 2500 members of the American Society for Therapeutic Radiology and Oncology. It consisted of 30 multiple-choice questions regarding four hypothetical clinical scenarios likely to be encountered in daily practice. Questions related to the technique of choice [local field (LF) vs. hemibody radiotherapy (HBI)], the use of systemic radionuclides (SR), fractionation schemes, dose, the integration of modalities, and the follow-up of these patients. The analysis is based on 817 (33%) responses received regarding 3268 cases. RESULTS: Local field is the most common form of therapy. Overall, LF was used, alone or in combination with other forms of therapy, in 54% and 74% of patients, respectively. LF was used more frequently in patients with breast cancer than in patients with prostate cancer (79% vs. 45%; p = 0.0001). Long fractionation schemes were used by 90% of physicians in 96% of cases. Short fractionation schemes were used by 7% of physicians in 4% of cases. This tendency was more pronounced in private practice than in the university or government/ multidisciplinary settings (p = 0.008) and in physicians starting their practice before 1982 (p = 0.05). The most common schedule was 30 Gy in 10 fractions, used by 77% of physicians in 64% of cases. HBI was used, alone or in combination with other forms of therapy, in 1% and 2% of patients, respectively. It was used more frequently in patients with prostate cancer than in patients with breast cancer (1.2% vs. 0.1%, respectively; p < 0.0001). SR were used alone or in combination with local-field irradiation in 21% and 40% of cases, respectively. SR were used more frequently in patients with prostate cancer than in those with breast cancer (28% vs. 0.2%, respectively;p < 0.00001). The most common radionuclide in use is Sr-89 (99%) at a dose of 4 mCi (73%) or 10.8 mCi (26%). CONCLUSIONS: Although LF remains the mainstay of therapy, our results demonstrate the emergence of a new pattern of practice: LF to the painful site in combination with SR for clinically occult metastases. Despite an ongoing academic debate regarding fractionation schemes, the vast majority of American practitioners advocate long schedules.

Diagnostic testing of the emergency department patient with chest pain.

In evaluating patients with nondiagnostic initial clinical or electrocardiogram (ECG) findings for acute cardiac ischemia, continuous 12-lead ECG monitoring increases the detection of diagnostic ECG findings, including ST-segment elevation, in patients awaiting hospital admission. Rest scanning with technitium-99m sestamibi is able to risk stratify low-moderate risk patients into lower and higher risk groups for cardiac events. Caveats include the reduced sensitivity of scanning of patients who are pain free and the need for follow-up exercise scans for patients free of perfusion defects at rest. Cardiac markers, particularly the troponins, show great promise for the detection of a larger part of the spectrum of acute coronary syndromes in the emergency department, including patients with minimal myocardial damage and higher risk for short-term death and nonfatal acute myocardial infarction. Accelerated diagnostic protocols using serial testing with cardiac markers, ECGs and then provocative testing over a 14-hour period, are feasible, safe, and cost-effective.

Zinc deficiency in head and neck cancer patients.

BACKGROUND: Although a great deal of attention has been given to protein and calorie malnutrition in patients with head and neck cancer, zinc status has not been assessed properly in such patients in the past. METHODS: In this study we characterized zinc status by cellular zinc criteria and assessed several measures of protein and calorie malnutrition in patients with head and neck cancer. We determined prognostic nutritional index (PNI) based on serum albumin, serum transferrin, triceps skin fold measures, and delayed hypersensitivity, as proposed by Buzby et al. In this study, the baseline zinc status and PNI of 60 head and neck cancer patients were correlated with the tumor size and overall stage of the disease. RESULTS: Our results showed that the tumor size and overall stage correlated significantly to zinc status whereas no correlation was seen with PNI, alcohol intake, or smoking in our study subjects. CONCLUSION: We conclude that zinc status is a better indicator of tumor burden and stage of the disease in head and neck cancer patients than the patients' overall nutritional status.

Therapeutic irradiation for patients with an elevated post-prostatectomy prostate specific antigen level.

PURPOSE: This study was initiated to determine the efficacy of post-prostatectomy therapeutic radiation for patients with elevated prostate specific antigen (PSA). MATERIALS AND METHODS: A total of 47 patients received 66 Gy. therapeutic irradiation to the prostate bed for a PSA level greater than 0 ng./ml. postoperatively. Univariate and multivariate survival analyses were performed to identify prognostic variables. RESULTS: At a median followup of 36 months (range 18 to 48) 83 and 33% of the patients with PSA 2 ng./ml. or less and 2 ng./ml. or greater, respectively, had no evidence of disease (p = 0.001). Pathological stage and a complete biochemical response (PSA less than 0.05 ng./ml.) were also significant prognostic variables. CONCLUSIONS: Therapeutic irradiation for patients with elevated PSA postoperatively is highly effective. At a median followup of 36 months 64% of the patients remain disease-free.

Enhancement of prostate tumor volume definition with intravesical contrast: a three-dimensional dosimetric evaluation.

PURPOSE: To assess the impact of intravesical contrast during computed tomography (CT) simulation on prostate tumor volume definition and dose distribution. METHODS AND MATERIALS: Sixteen patients with localized adenocarcinoma of the prostate underwent CT-based virtual simulation in preparation for definitive radiotherapy. Patients were immobilized with a foam cradle and an initial CT was performed after oral but without intravesical contrast (noncontrast scan). A second scan was performed following administration of intravesical contrast (contrast scan). Beam apertures were designed on the noncontrast scans and digitized into the contrast scan file. Beam apertures were also designed on the contrast scans. Isodose plans were generated for several beam apertures and arrangements. RESULTS: There was enhanced visualization of the prostate at the cephalad portion of the field for 15 of the 16 cases. The mean differences between the noncontrast and contrast volumes was significant (p = 0.0001). The mean percent underdosage to the prostate ranged from 3.9% to 18.6%, depending upon the target volume and beam arrangement. CONCLUSION: This study demonstrates the necessity of using intravesical contrast for defining the location of the prostate during CT simulation. The underestimation of the extent of the prostate when omitting intravesical contrast leads to significant underdosage. The value of intravesical contrast is most evident when small (prostate only) conformal fields are used.