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Purpose: Assess the importance of overall time (OT) and dose for biochemical failure (BF) after external-beam radiotherapy of prostate cancer in a retrospective analysis of a nine-institution database with 4839 patients., Patients and Methods: Relevant baseline factors (T stage, Gleason score, initial PSA) were available for 4338 men. Cox models were used to estimate the effects of dose and OT corrected for baseline factors, treatment year, institution and interactions, and differences in post-treatment PSA-measurement intervals. After exclusion of very short and long intervals, patient numbers were 1445 events/3426 at risk (endpoint all BFs), and 1177 events/3354 at risk (endpoint exclusion of BFs that were likely distant failures). Separate analyses were carried out by risk group for men who received <70 Gy and > or = 70 Gy., Results: Neither dose nor OT was significant when the analysis was restricted to doses <70 Gy, while for patients treated to 70 Gy or higher there were significant influences of both dose and OT on outcome in low- and intermediate-risk patients. These effects were quantified as a relative increase after 5 years followup of 6% in BFs for a 1-week increase in OT, a relative decrease of 15% in BFs for a 6-Gy increase in dose, and a dose equivalent of proliferation of 0.24 Gy/day. As the dose per fraction was nearly constant, the data contain no information on the alpha/beta ratio., Conclusion: The results show that OT and dose are significant determinants of outcome of radiotherapy in low- and intermediate-risk patients treated to 70 Gy or higher, and suggest that meaningful improvements in outcome may be targeted by modest increases in total dose and decreases in OT., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To evaluate acute and long-term urinary morbidity after permanent prostate brachytherapy at a single tertiary care center. To minimize the risk of long-term urinary morbidity, it is important for clinicians to be able to distinguish acute urinary side effects after prostate brachytherapy from longer-term treatment-related urinary complications., Methods: The medical records of 351 consecutive patients who underwent prostate brachytherapy at the MD Anderson Cancer Center between 1998 and 2006 were analyzed. To evaluate the short-term urinary side effects, the Expanded Prostate Cancer Index Composite questionnaire was administered at baseline and at 1, 4, 8, and 12 months. Long-term urinary complications were scored using a modified Radiation Therapy Oncology Group scale., Results: All 4 urinary subdomain scores evaluating acute urinary side effects after treatment (bother, function, incontinence, and irritation or obstruction) had returned to baseline levels by 8 months after implantation. At 5 years, the cumulative risks of late urinary complications by grade were 8.6% for grade 1 complications, 6.5% for grade 2, 1.7% for grade 3%, and 0.5% for grade 4. The most common grade 2 late urinary complications were urethral stricture (4 patients), incontinence requiring daily pads (3 patients), and intermittent hematuria (3 patients). Grade 3 complications were urinary retention requiring self-catheterization (2 patients) and severe frequency with dysuria (2 patients). The only grade 4 event was severe hemorrhagic cystitis., Conclusions: Short-term urinary side effects after prostate brachytherapy are common, follow a predictable course, and typically resolve within 1 year. Conservative management of short-term urinary side effects is recommended to minimize the risk of long-term urinary complications.

Purpose: To evaluate the dose changes to the target and critical structures from rotational setup errors in prostate cancer patients treated with proton therapy., Methods and Materials: A total of 70 plans were analyzed for 10 patients treated with parallel-opposed proton beams to a dose of 7,600 (60)Co-cGy-equivalent (CcGE) in 200 CcGE fractions to the clinical target volume (i.e., prostate and proximal seminal vesicles). Rotational setup errors of +3 degrees , -3 degrees , +5 degrees , and -5 degrees (to simulate pelvic tilt) were generated by adjusting the gantry. Horizontal couch shifts of +3 degrees and -3 degrees (to simulate longitudinal setup variability) were also generated. Verification plans were recomputed, keeping the same treatment parameters as the control., Results: All changes shown are for 38 fractions. The mean clinical target volume dose was 7,780 CcGE. The mean change in the clinical target volume dose in the worse case scenario for all shifts was 2 CcGE (absolute range in worst case scenario, 7,729-7,848 CcGE). The mean changes in the critical organ dose in the worst case scenario was 6 CcGE (bladder), 18 CcGE (rectum), 36 CcGE (anterior rectal wall), and 141 CcGE (femoral heads) for all plans. In general, the percentage of change in the worse case scenario for all shifts to the critical structures was <5%. Deviations in the absolute percentage of volume of organ receiving 45 and 70 Gy for the bladder and rectum were <2% for all plans., Conclusion: Patient rotational movements of 3 degrees and 5 degrees and horizontal couch shifts of 3 degrees in prostate proton planning did not confer clinically significant dose changes to the target volumes or critical structures.

There are a range of government food policies at national and international level. Overall, their aims are diverse but all will have an impact on women and thus impact on the developmental origins of adult disease through their role as mothers of future generations. The present paper describes the approach of the Food Standards Agency to help consumers choose, cook and eat healthy safe food by influencing individuals, products and the food environment. Examples of activity at the national, local and international level are used to demonstrate this approach.

This review of the literature on late rectal complications after prostate brachytherapy indicated that it is a highly effective treatment modality for patients with clinically localized prostate cancer but can cause chronic radiation proctitis. The most common manifestation of chronic radiation proctitis was anterior rectal wall bleeding, which often occurred within the first 2 years after brachytherapy. It is interesting to note that the rates of late rectal morbidity appear to have declined over time, which may reflect improvements in implantation techniques and imaging. Rectal biopsy as part of the workup to evaluate rectal bleeding can lead to rectal fistula and the need for colostomy, a rare but major complication. The authors recommend 1) screening colonoscopy before brachytherapy for patients who have not had a screening colonoscopy within the preceding 3 years to rule out colorectal malignancies and, thus, facilitate conservative management should rectal bleeding occur; 2) lifestyle modifications during treatment to limit exposure of the rectum to radiation; and 3) conservative management for rectal bleeding that occurs within 2 years after brachytherapy. Cancer 2009. (c) 2009 American Cancer Society.

Purpose: Many clinicians use Prostogram data to advise patients selecting prostate cancer therapy. We examined whether the Prostogram accurately predicted recurrence at 5 years in patients treated with (125)I brachytherapy at 1 tertiary cancer center., Materials and Methods: We retrospectively reviewed the records of 208 consecutive patients with prostate cancer treated with a permanent (125)I implant without neoadjuvant androgen deprivation therapy at 1 tertiary cancer center during 1998 to 2006. In each patient the Prostogram brachytherapy formula was used to calculate 5-year biochemical recurrence-free survival probability based on clinical stage, Gleason sum score, prostate specific antigen and the receipt or not of external beam radiotherapy. Recurrence was defined as clinical relapse, death from disease, posttreatment androgen deprivation therapy, secondary treatments administered before prostate specific antigen failure or biochemical recurrence based on the Kattan modification of the American Society for Therapeutic Radiology and Oncology definition of biochemical recurrence after external beam radiation therapy. Patients were divided into quartiles based on Prostogram predicted 5-year recurrence-free survival probability and mean probability was compared to the actual 5-year recurrence-free survival rate in each quartile. Harrell's concordance statistic was used to assess the predictive accuracy of the nomogram., Results: Actual 5-year biochemical recurrence-free survival rates were superior to Prostogram predicted probabilities, including 89% vs 80%, 87% vs 86%, 100% vs 89% and 100% vs 94% in quartiles 1 to 4, respectively. Harrell's concordance value was 0.487 (95% CI 0.369-0.605), indicating that the predictive accuracy of the nomogram in our patients was less than 50%., Conclusions: The Prostogram did not predict recurrence after permanent prostate brachytherapy in this series. Institutional variability requires that clinicians be cautious when using the Prostogram to counsel patients about the probability of success after permanent prostate brachytherapy.

Purpose: To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and identify predictors of improved disease-free survival., Methods and Materials: Eleven institutions combined data on 2,693 patients treated with permanent interstitial BT monotherapy for T1-T2 prostate cancer. Of these patients, 1,831 (68%) were treated with I-125 (median dose, 144 Gy) and 862 (32%) were treated with Pd-103 (median dose, 130 Gy). Criteria for inclusion were: available pre-BT PSA, BT > or =5 years before data submission, BT between 1988-1998, and no androgen deprivation before failure. The median follow-up was 63 months., Results: Among patients where the I-125 dose to 90% of the prostate (D90) was > or =130 Gy, the 8-year PSA relapse-free survival (PRFS) was 93% compared with 76% for those with lower D90 dose levels (p < 0.001). A multivariable analysis identified tumor stage (p = 0.002), Gleason score (p < 0.001), pretreatment PSA level (p < 0.001), treatment year (p = 0.001), and the isotope used (p = 0.004) as pretreatment and treatment variables associated with PRFS. When restricted to patients with available postimplantation dosimetric information, D90 emerged as a significant predictor of biochemical outcome (p = 0.01), and isotope was not significant. The 8-year PRFS was 92%, 86%, 79%, and 67%, respectively, for patients with PSA nadir values of 0-0.49, 0.5-0.99, 1.0-1.99, and >2.0 ng/mL (p < 0.001). Among patients free of biochemical relapse at 8 years, the median nadir level was 0.1 ng/mL, and 90% of these patients achieved a nadir PSA level <0.6 ng/mL., Conclusions: Outcome after permanent BT for prostatic cancer relates to tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < or =0.5 ng/mL was particularly associated with durable long-term PSA disease-free survival. The only controllable factor to impact on long-term outcome was the D90 which is a reflection of implant quality.

Objectives: To determine whether nadir prostate-specific antigen (PSA) levels within 12 months (nadir PSA12) after completion of radiotherapy (RT) can be used as an early marker of recurrence risk., Methods: A total of 4839 patients were treated with RT and without hormonal therapy from 1986 to 1995 for Stage T1-T2 prostate cancer at nine institutions. Of these 4839 patients, 4833, with a median follow-up of 6.3 years, met the criteria for analysis. The study endpoints included freedom from PSA failure, initiation of androgen deprivation, or documented local or distant failure (PSA-DFS); freedom from clinically apparent distant metastasis (DMFS); and overall survival (OS)., Results: Patients with a nadir PSA12 of 2.0 ng/mL or less had an 8-year PSA-DFS, DMFS, and OS rate of 55%, 95%, and 73%, respectively, compared with 40%, 88%, and 69%, respectively, for patients with a nadir PSA12 of more than 2.0 ng/mL. Multivariate analysis confirmed that a nadir PSA12 of greater than 2 ng/mL was an independent predictor of PSA-DFS, DMFS, and OS. Classification and regression tree analysis identified the nadir PSA12 levels after RT associated with PSA-DFS, DMFS, and OS. Nadir PSA12, combined with the pretreatment PSA level, identified patients at particularly high risk of distant metastasis., Conclusions: The results of this large, multi-institutional study have demonstrated that nadir PSA12 is predictive of clinical outcomes for patients with localized prostate cancer after RT. A high pretreatment PSA level and high nadir PSA12 will identify patients at particularly high risk who might benefit from early adjuvant therapy.

Background: The posttreatment prostate-specific antigen (PSA) bounce phenomenon has been recognized in at least 20% of all patients treated with radiation. The purpose of the current report was to determine if there was a difference in biochemical and clinical control between the bounce and nonbounce (NB) patients using pooled data on 4839 patients with T1-2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions between 1986 and 1995., Methods: The median follow-up was 6.3 years. A posttreatment PSA bounce was defined by a minimal rise of 0.4 ng/mL over a 6-month follow-up period, followed by a drop in PSA level of any magnitude. Endpoints included no biochemical evidence of disease (bNED) failure (BF) (ASTRO definition), distant failure (DF), cause-specific failure (CSF), and overall survival (OS). Patients were stratified by pretreatment PSA, Gleason score, T stage, age, dose, and risk group., Results: In all, 978 (20%) patients experienced at least 1 posttreatment PSA bounce. Within 3 subgroups (risk group, pretreatment PSA, and age), statistically significant differences of remaining bounce-free were observed on univariate analysis. Patients < 70 years had a 72% chance of remaining bounce-free at 5 years compared with 75% for older patients (P = .04). The NB patients had 72% bNED control at 10 years compared with 58% for the bounce patients. The effect of a bounce remained statistically significant on multivariate analysis (P < .0001). No statistically significant difference in DF, CSF, or OS was observed., Conclusions: Patients treated with external beam radiation therapy alone who experience a posttreatment PSA bounce have increased risk of BF. However, this did not translate into a difference in clinical failure with the available follow-up in the current study., ((c) 2006 American Cancer Society.)

Purpose: To assess prostate-specific antigen (PSA) failure definitions for patients with Stage T1-T2 prostate cancer treated by permanent prostate brachytherapy., Methods and Materials: A total of 2,693 patients treated with radioisotopic implant as solitary treatment for T1-T2 prostatic adenocarcinoma were studied. All patients had a pretreatment PSA, were treated at least 5 years before analysis, 1988 to 1998, and did not receive hormonal therapy before recurrence. Multiple PSA failure definitions were tested for their ability to predict clinical failure., Results: Definitions which determined failure by a certain increment of PSA rise above the lowest PSA level to date (nadir + x ng/mL) were more sensitive and specific than failure definitions based on PSA doubling time or a certain number of PSA rises. The sensitivity and specificity for the nadir + 2 definition were 72% and 83%, vs. 51% and 81% for 3 PSA rises. The surgical type definitions (PSA exceeding an absolute value) could match this sensitivity and specificity but only when failure was defined as exceeding a PSA level in the 1-3 ng/mL range and only when patients were allowed adequate time to nadir. When failure definitions were compared by time varying covariate regression analysis, nadir + 2 ng/mL retained the best fit., Conclusions: For patients treated by permanent radioisotopic implant for prostate cancer, the definition nadir + 2 ng/mL provides the best surrogate for failure throughout the entire follow-up period, similar to patients treated by external beam radiotherapy. Therefore, the same PSA failure definition could be used for both modalities. For brachytherapy patients with long-term follow-up, at least 6 years, defining failure as exceeding an absolute PSA level in the 0.5 ng/mL range may be reasonable.

Purpose: The aim of this study was to investigate effect of increasing dose on risk groups for clinical failure (CF: local failure or distant failure or hormone ablation or PSA>or=25 ng/ml) in patients with T1-T2 prostate cancer treated with external beam radiotherapy., Methods and Materials: Patients (n=4,537) were partitioned into nonoverlapping dose ranges, each narrow enough that dose was not a predictor of CF, and risk groups for CF were determined using recursive partitioning analysis (RPA). The same technique was applied to the highest of these dose ranges (70-76 Gy, 1,136 patients) to compare risk groups for CF in this dose range with the conventional risk-group classification., Results: Cutpoints defining low-risk groups in each dose range shifted to higher initial PSA levels and Gleason scores with increasing dose. Risk groups for CF in the dose range 70-76 Gy were not consistent with conventional risk groups., Conclusions: The conventional classification of risk groups was derived in the early PSA era, when total doses<70 Gy were common, and it is inconsistent with risk groups for patients treated to doses>70 Gy. Risk-group classifications must be continuously re-examined whenever the trend is toward increasing total dose.

Objectives: To identify predictive factors for locoregional recurrence (LR), distant metastasis (DM), and overall survival (OS) in patients treated with chemoradiation and surgery for rectal cancer., Methods: Between 1989 and 2001, 470 patients with rectal cancer were treated with preoperative (89%) or postoperative (11%) chemoradiation and mesorectal excision. Median radiation dose was 45 Gy; 97% received concurrent infusional 5-fluorouracil, and 65% received adjuvant chemotherapy. Median follow-up interval was 5.7 years., Results: The 5-year rates of freedom from LR, freedom from DM, and OS were 90%, 79%, and 80%, respectively. On univariate analysis, significant predictors of LR were female sex, clinical T stage, pathologic T and N stages, and positive radial margin. Significant univariate predictors of DM were circumferential extent of tumor, tumor immobility, lymphovascular invasion, perineural involvement, and pathologic T and N stages. Significant univariate predictors of lower OS were age, circumferential extent of tumor, shorter distance from anal verge, tumor size, tumor immobility, anal canal involvement, lymphovascular invasion, perineural involvement, positive radial margin, and pathologic T and N stages. On Cox multivariate analysis, female sex and pathologic T and N stages independently predicted for LR; pathologic T and N stages independently predicted for DM; and age, circumferential extent of tumor, positive radial margin, and pathologic T and N stages independently predicted for lower OS., Conclusions: Pathologic T and N stages significantly predicted for all 3 end points (LR, DM and OS) on multivariate analysis. Investigations of more aggressive adjuvant chemotherapy appear warranted for pathologic stage T3/T4 or N1/2 rectal cancer.

Background: Data on direct non-health care and time costs are rarely collected, though the incorporation of such data is essential for performing cost-effectiveness analyses according to established guidelines., Objectives: To explore the challenges involved in collecting and analyzing these data from patients enrolled in a clinical trial., Methods: Through the use of a pilot study, the authors designed a questionnaire to collect these costs. They used this questionnaire in a clinical trial conducted at a comprehensive cancer center and a public community hospital. Patients in the trial were undergoing screening or diagnostic procedures through a clinical protocol designed to measure the effectiveness of fluorescence and reflectance spectroscopy for detecting cervical precancers. Direct non-health care costs were adjusted to 2003 constant dollars., Results: The authors successfully collected direct non-health care and time cost data, thus demonstrating the feasibility of acquiring such data. Compared to patients receiving diagnostic services for cervical cancer, those receiving screening services for the same condition in both settings incurred lower direct non-health care costs and time costs, as defined in the questionnaire. Compared to patients receiving either service at the comprehensive cancer center, those seeking either service at the public community hospital incurred lower direct non-health care costs and time costs. When outliers were removed, total direct non-health care costs and time costs substantially decreased for diagnostic patients in the comprehensive cancer center; total direct non-health care costs and time costs for other subgroups remained essentially unchanged., Conclusions: Direct non-health care and time cost data can be collected within a large-scale clinical trial. The setting (community v. specialty hospital) and population (patients receiving screening v. diagnostic examination) makes a difference regarding the cost totals. The order of magnitude of the final result depends on the context in which the non-health care and time cost data will be used.

Purpose: To determine the significance of prostate-specific antigen (PSA) nadir (nPSA) and the time to nPSA (T(nPSA)) in predicting biochemical or clinical disease-free survival (PSA-DFS) and distant metastasis-free survival (DMFS) in patients treated with definitive external beam radiotherapy (RT) for clinical Stage T1b-T2 prostate cancer., Methods and Materials: Nine participating institutions submitted data on 4839 patients treated between 1986 and 1995 for Stage T1b-T2cN0-NxM0 prostate cancer. All patients were treated definitively with RT alone to doses > or =60 Gy, without neoadjuvant or planned adjuvant androgen suppression. A total of 4833 patients with a median follow-up of 6.3 years met the criteria for analysis. Two endpoints were considered: (1) PSA-DFS, defined as freedom from PSA failure (American Society for Therapeutic Radiology and Oncology definition), initiation of androgen suppression after completion of RT, or documented local or distant failure; and (2) DMFS, defined as freedom from clinically apparent distant failure. In patients with failure, nPSA was defined as the lowest PSA measurement before any failure. In patients without failure, nPSA was the lowest PSA measurement during the entire follow-up period. T(nPSA) was calculated from the completion of RT to the nPSA date., Results: A greater nPSA level and shorter T(nPSA) were associated with decreased PSA-DFS and DMFS in all patients and in all risk categories (low [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level < or =10 ng/mL], intermediate [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level >10 but < or =20 ng/mL, or Stage T2b or T2c, Gleason score < or =6, and PSA level < or =20 ng/mL, or Gleason score 7 and PSA level < or =20 ng/mL], and high [Gleason score 8-10 or PSA level >20 ng/mL]), regardless of RT dose. The 8-year PSA-DFS and DMFS rate for patients with nPSA <0.5 ng/mL was 75% and 97%; nPSA > or =0.5 but <1.0 ng/mL, 52% and 96%; nPSA > or =1.0 but <2.0 ng/mL, 40% and 91%; and nPSA > or =2.0 ng/mL, 17% and 73%, respectively. The 8-year PSA-DFS and DMFS rate for patients with T(nPSA) <6 months was 27% and 66%; T(nPSA) > or =6 but <12 months, 31% and 85%; T(nPSA) > or =12 but <24 months, 42% and 94%; and T(nPSA) > or =24 months, 75% and 99%, respectively. A shorter T(nPSA) was associated with decreased PSA-DFS and DMFS, regardless of the nPSA. Both nPSA and T(nPSA) were significant predictors of PSA-DFS and DMFS in multivariate models incorporating clinical stage, Gleason score, initial PSA level, and RT dose. The significance of nPSA and T(nPSA) was supported by landmark analysis, as well as by analysis of nPSA and T(nPSA) as time-dependent covariates. A dose > or =70 Gy was associated with a lower nPSA level and longer T(nPSA) in all risk categories, and a greater dose was significantly associated with greater PSA-DFS and DMFS in multivariate analysis. Regression analysis confirmed that higher clinical stage, Gleason score, and initial PSA were associated with a greater nPSA level., Conclusion: The results of this large, multi-institutional analysis of 4833 patients have provided important evidence that nPSA and T(nPSA) after definitive external beam RT are not only predictive of a predominantly PSA endpoint (PSA-DFS), but are also predictive of distant metastasis in all clinical risk categories. Greater RT doses were associated with lower nPSA, longer T(nPSA), and improved PSA-DFS and DMFS.

Purpose: To determine whether prostate-specific antigen (PSA) doubling time predicts clinical outcomes in patients with prostate cancer that has been treated with combined radiation and hormone therapy., Methods and Materials: We reviewed the medical records of 621 men with nonmetastatic prostate cancer treated with radiation therapy and hormone therapy between 1989 and 2003. "Any" clinical failure was defined as any distant, nodal, or local failure, or the use of salvage therapy. "True" clinical failure was defined as any distant, nodal, or local failure. PSA doubling time was calculated by using the log PSA values from patients with a PSA failure as defined by the American Society of Therapeutic Radiology Oncology consensus statement. One hundred thirty-seven men were at intermediate risk for PSA failure (as determined by T2b, Gleason score of 7, or PSA 10.1-0 ng/mL) and 484 men were at high risk for failure (T2c-4; Gleason 8-10; or PSA >20 ng/mL). Pretreatment PSA value, Gleason score, tumor stage, timing and duration of hormone therapy, radiation therapy dose, and PSA doubling time were analyzed for any associations with time to clinical failure by using Cox regression analysis. Estimates of survival were calculated by using the Kaplan-Meier method. Pairwise comparisons were made by using the log-rank test., Results: Sixty-two men experienced any clinical failure, and 22 men experienced true clinical failure. Multivariate analysis revealed that pretreatment PSA (p = 0.013), Gleason score (p = 0.0019), and a PSA doubling time (PSADT) < or =8 months (p < 0.001) were independently associated with time to any clinical failure. Tumor stage, hormone therapy timing, hormone therapy duration, and radiation therapy dose were not statistically significant on multivariate or univariate analysis. Only hormone therapy duration (p = 0.008) and PSADT < or =8 months (<0.001) were significantly associated with time to true clinical failure. The estimated 5-year rate of any clinical failure was 9.4% for men with a PSADT >8 months and 60.4% for men with a PSA doubling time < or =8 months (p < 0.001). The estimated 5-year rate of true clinical failure was 6.5% for men with a PSADT >8 months and 68.5% for men with a PSADT < or =8 months (p < 0.001). Lower radiation dose was the only significant predictor of PSADT < or =8 months on multivariate regression analysis. The estimated 6-year overall survival rate after PSA failure was 79.1% for men with a PSADT >8 months and 29.7% for men with a PSADT < or =8 months. The median overall survival time for patients with a PSADT >8 months was not reached in this study. The median overall survival time for patients with a PSADT < or =8 months was 61.8 months (p = 0.015)., Conclusion: In men with prostate cancer that has been treated with combined hormone and radiation therapy, a posttreatment PSADT of < or =8 months is associated with worse clinical outcomes and may be an early surrogate marker for decreased survival. These patients should be considered for more aggressive salvage therapy protocols.

Purpose: Pooled data on 4,839 patients with T1-2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions have previously provided long-term biochemical failure (BF) and clinical outcomes using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. In this report we determined the sensitivity and specificity of several BF definitions using distant failure (DF) alone or clinical failure (CF), defined as local failure (LF) and/or DF., Materials and Methods: The pooled cohort was treated between 1986 and 1995 with external beam RT (60 Gy or greater) without pre-RT androgen suppression or planned post-RT adjuvant androgen suppression. Median followup was 6.3 years. The sensitivity and specificity of 102 definitions of BF relative to DF and LF were assessed., Results: The BF definitions with higher sensitivity and specificity than the ASTRO definition for DF only and CF are reported. The sensitivity and specificity of the ASTRO definition to predict DF alone was 55% and 68%, respectively. Three definitions had higher sensitivity and specificity, namely prostate specific antigen (PSA) greater than current nadir (lowest PSA prior to current measurement) plus 3 ng/ml (sensitivity 76% and specificity 72%), dated at the call (failure date as the date when the criterion was met), PSA greater than absolute nadir plus 2 ng/ml (sensitivity 72% and specificity 70%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 69% and specificity 73%). The sensitivity and specificity of the ASTRO definition to predict CF was 60% and 72%, respectively. Three definitions had higher sensitivity and specificity, namely PSA greater than current nadir plus 3 ng/ml (sensitivity 66% and specificity 77%), dated at the call, PSA greater than absolute nadir plus 2 ng/ml (sensitivity 64% and specificity 74%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 67% and specificity 78%)., Conclusions: Using what is to our knowledge the largest data set of patients with prostate cancer treated with RT alone we correlated multiple definitions of BF with the strict clinical end points of DF alone and CF (DF or local failure). Defining BF as PSA greater than absolute nadir plus 2 ng/ml, dated at the call, PSA greater than current nadir plus 3 ng/ml, dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated, had higher sensitivity and specificity for DF alone or CF compared with the ASTRO definition. This information should contribute to the discussion regarding suggested modifications to the ASTRO definition of biochemical failure.

Background: We retrospectively analyzed the clinical characteristics and outcomes of various racial and ethnic groups who underwent radiotherapy alone for localized or locally advanced prostate cancer., Methods: From April 1987 to January 1998, 964 patients underwent full-dose, external-beam radiotherapy alone for localized or locally advanced prostate cancer and were included in the study. The patients' medical records were reviewed for pertinent information., Results: Of the 964 patients, 810 were non-Hispanic white, 86 were African-American, 54 were Hispanic, and 14 were Asian. The most significant difference between groups was in the proportion of patients who presented with initial PSA levels > 20 ng/ml. More than 20% of men in all minority groups presented with a serum PSA > 20 ng/ml, compared to only 11% of whites (p = 0.0012). Similarly, 14% of minorities presented with Gleason scores > or = 8 compared to only 11% of whites (p = 0.0265). Hispanic and Asian patients exhibited a higher incidence of Gleason score > or = 8 prostate cancer. When comparing the time intervals of 1995-1998 vs. 1987-1994, the number of men presenting for EBRT with PSA levels < 10 ng/ml increased to 74% from 57% for Caucasians (p < 0,001), 71% from 40% for African Americans (p = 0.012), 67% from 49% for Hispanics (p = 0.1 18), and no change (50%) for Asians., Conclusions: The number of African-American patients presenting with favorable characteristics (PSA < 10 ng/ml) is increasing. These findings suggest that the message of screening and early detection may be reaching the African-American community. Continued diligence in screening and early detection may improve prostate cancer outcome for other minority populations.

Objectives: To determine whether a rise in the serum prostate-specific antigen (PSA) concentration 24 months or later after completion of external beam radiotherapy (EBRT) for prostate cancer could predict for biochemical failure., Methods: We evaluated the records of 1006 patients who had undergone full-dose EBRT alone as primary treatment for T1-T4NxM0 prostate cancer at our institution between April 1987 and January 1998. Patients who had biochemical failure--as determined by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition--prior to 24 months after EBRT were excluded. PSA increases of four different magnitudes (0.5, 0.8, 1.0, and 1.5 ng/mL above the 24-month nadir) were evaluated for their ability to predict ASTRO-defined biochemical failure., Results: A total of 745 patients met the analysis criteria. The rate of ASTRO-defined biochemical failure in patients with a PSA increase of 0.5, 0.8, 1.0, and 1.5 ng/mL above the 24-month nadir was 56%, 64%, 66%, and 71%, respectively. An increase of 1.5 ng/mL or more had a sensitivity of 80% and a specificity of 88% in the prediction of biochemical failure, with an accuracy of 86%., Conclusions: A PSA increase of 1.5 ng/mL or more above the 24-month nadir can be used to predict for ASTRO-defined failure after EBRT and may be used to identify patients at risk early-on.

The introduction of prostate-specific antigen (PSA) as a reliable tumor marker for prostate cancer brought significant changes in the end points used for outcome reporting after therapy. With regard to a definition of failure after radiation, a consensus was reached in 1996 that took into account the particular issues of an intact prostate after therapy. Over the next several years, the consensus definition issued by the American Society for Therapeutic Radiology and Oncology (ASTRO) was used and studied. Concerns and criticisms were raised. The sensitivity and specificity of this definition vs other proposals has been investigated, and differences in outcome analyzed and compared. Although the ASTRO definition came from analysis of datasets on external-beam radiation and most of the work on this topic has been with this modality, failure definitions for brachytherapy must be explored as well. The concept of a universal definition of failure that might be applied to multiple modalities, including surgery, should also be investigated, at least for comparative study and research purposes.

Bcl-2 is associated with resistance to radiotherapy in prostate cancer. It was recently demonstrated that transduction of LNCaP prostate cells with the PTEN gene resulted in Bcl-2 downregulation. We hypothesized that forced expression of PTEN in prostate cancer cells would sensitize cells to radiation, downregulate Bcl-2 expression, and potentiate the G2M block induced by radiation. Four cell lines - PC-3-Bcl-2 (Bcl-2 overexpression, deleted PTEN), PC-3-Neo (wild-type Bcl-2, deleted PTEN), LNCaP (Bcl-2 overexpression, deleted PTEN), and DU-145 (wild-type Bcl-2 and PTEN) - were transduced with a recombinant adenovirus-5 vector expressing the human wild-type PTEN cDNA under the control of a human cytomegalovirus promoter (Ad-MMAC). After correction for the effect of Ad-MMAC on plating efficiency, Ad-MMAC treatment reduced the surviving fractions after 2 Gy as follows: PC-3-Bcl-2, from 60.5 to 3.6%; PC-3-Neo, no reduction; LNCaP, from 29.6 to 16.3%; and DU-145, from 32.7 to 25.7%. PTEN expression was associated with the downregulation of Bcl-2 expression in PC-3-Bcl-2 and LNCaP cell lines. Ad-MMAC plus radiotherapy potentiated the G2M block seen with radiotherapy alone only in PC-3-Bcl-2 cells. These findings suggest that overexpression of Bcl-2 result in radioresistance and inability of radiation to cause its typical G2M cell-cycle arrest.

The purpose of this preliminary study was to determine the incidence of second malignancies after combined-modality therapy for adults with Hodgkin disease and relate it to the details of initial treatment. We retrospectively studied 286 patients ranging in age from 16 to 88 years with stage I or II Hodgkin disease who were treated between 1980 and 1995 with chemotherapy followed 3 to 4 weeks later by radiotherapy. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone was used in 161 cases, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) in 67 cases, Adriamycin, bleomycin, vinblastine, and dacarbazine in 19 cases, lomustine, vinblastine, procarbazine, and prednisone/doxorubicin, bleomycin, dacarbazine, and lomustine in 18 cases, and other chemotherapeutic regimens in the remaining 21 cases. The median radiotherapy dose was 40 Gy given in 20 daily 2-Gy fractions. Median follow-up of surviving patients was 7.4 years. There were 2,230 person-years of observation. Significantly increased relative risks (RR) were observed for acute myeloid leukemia (RR, 69.3; 95% CI, 14.3-202.6) and melanoma (RR, 7.3; 95% CI, 1.5-21.3). The 5-, 10-, and 15-year actuarial risks of acute myeloid leukemia were 0.8%, 1.3%, and 1.3%, respectively. Patients treated with MOPP had the highest 15-year actuarial risk of leukemia (1.6%). The 5-, 10-, and 15-year actuarial risks of solid tumors were 1.9%, 9.3%, and 16.8%, respectively. Consolidative radiotherapy to both sides of the diaphragm resulted in a trend toward an increased risk of solid tumors relative to radiotherapy to only one side of the diaphragm (p = 0.08). In an effort to reduce the risk of second malignancies, we have stopped using the alkylating agents nitrogen mustard and procarbazine and elective paraaortic and splenic radiotherapy after chemotherapy.

Purpose: To report the long-term outcome for patients with Stage T1-T2 adenocarcinoma of the prostate definitively irradiated in the prostate-specific antigen (PSA) era., Methods and Materials: Nine institutions combined data on 4839 patients with Stage T1b, T1c, and T2 adenocarcinoma of the prostate who had a pretreatment PSA level and had received >or=60 Gy as definitive external beam radiotherapy. No patient had hormonal therapy before treatment failure. The median follow-up was 6.3 years. The end point for outcome analysis was PSA disease-free survival at 5 and 8 years after therapy using the American Society for Therapeutic Radiology and Oncology (ASTRO) failure definition., Results: The PSA disease-free survival rate for the entire group of patients was 59% at 5 years and 53% at 8 years after treatment. For patients who had received >or=70 Gy, these percentages were 61% and 55%. Of the 4839 patients, 1582 had failure by the PSA criteria, 416 had local failure, and 329 had distant failure. The greatest risk of failure was at 1.5-3.5 years after treatment. The failure rate was 3.5-4.5% annually after 5 years, except in patients with Gleason score 8-10 tumors for whom it was 6%. In multivariate analysis for biochemical failure, pretreatment PSA, Gleason score, radiation dose, tumor stage, and treatment year were all significant prognostic factors. The length of follow-up and the effect of backdating as required by the ASTRO failure definition also significantly affected the outcome results. Dose effects were most significant in the intermediate-risk group and to a lesser degree in the high-risk group. No dose effect was seen at 70 or 72 Gy in the low-risk group., Conclusion: As follow-up lengthens and outcome data accumulate in the PSA era, we continue to evaluate the efficacy and durability of radiotherapy as definitive therapy for early-stage prostate cancer. Similar studies with higher doses and more contemporary techniques will be necessary to explore more fully the potential of this therapeutic modality.

Purpose: This study compared the clinical toxicity and hematological effects of i.p. and s.c. administration of fms-like tyrosine kinase-3-ligand (Flt3-L; Amgen, Thousand Oaks, CA), a truncated glycoprotein that increases dendritic cells (DCs) and monocytes., Experimental Design: Patients with peritoneal carcinomatosis or mesothelioma were randomly assigned to treatment with Flt3-L (25 micro g/kg, maximum 1500 micro g), i.p. or s.c., days 1-5 and 8-12, then changed to the alternative route at 4 weeks. Treatment was continued s.c. or i.p. at 8 weeks., Results: Fifteen patients (14 evaluable) were randomized to receive i.p. (n = 8) or s.c. (n = 7) injections. Their median age was 55 years (range, 40-68 years). Primary tumors were as follows: ovarian/peritoneal cancer (n = 9); gastrointestinal cancer (n = 2); and mesothelioma (n = 4). Treatment was well tolerated without serious toxicity (24 i.p. cycles; 32 s.c. cycles). Treatment (i.p. or s.c.) resulted in significant increases in WBCs (WBC, monocytes, and Lin(-)DR(+) DCs), and platelets (during washout). Both interleukin (IL)-12(p70) and IL-10 were secreted by monocyte-derived DCs after in vitro exposure to maturation factors. Increased IL-12 versus IL-10 secretion responses and higher proportions of the CD11c(+) DC subset in post-Flt3-L specimens suggested a maturational shift toward the monocyte-derived DC phenotype had occurred. Three patients (2 with mesothelioma and 1 with gastrointestinal cancer) had stable disease for 8, 8, and 12+ months, respectively., Conclusions: Flt3-L, administered either i.p. or s.c., is well tolerated and produced similar increases in monocytes, DCs, and platelets. DCs from peripheral blood and peritoneal fluids showed cell surface phenotypic and cytokine maturational responses to activation stimuli. These findings suggested that Flt3-L, in combination with suitable activating agents, could be developed further in patients with epithelial ovarian cancer.

Purpose: We retrospectively analyzed the clinical characteristics and outcomes of Hispanic men compared with other groups who underwent radiotherapy alone for localized or locally advanced prostate cancer., Materials and Methods: Between April 1987 and January 1998, 964 men who underwent full dose external beam radiotherapy alone for localized or locally advanced prostate cancer were included in the study. Patient medical records were reviewed for pertinent information., Results: Of the 964 men 810 were non-Hispanic white, 54 were Hispanic and 86 were black Americans. The most significant difference among the groups was in the proportion of patients who presented with initial prostate specific antigen (PSA) greater than 20 ng/ml (22% of Hispanic vs 11% of white men, p = 0.0012). In addition, 17% of Hispanic men had a Gleason score of 8 or greater compared with 11% of white men (p = 0.0265). A greater proportion of Hispanic patients also had a less favorable posttreatment PSA nadir of greater than 1 ng/ml compared with white patients, (44% vs 26%, p = 0.0214), which may have translated into a trend toward a lower 5-year disease-free survival rate in Hispanics vs white men (52% vs 65%, p = 0.07)., Conclusions: Hispanic men presented with higher PSA and higher grade prostate cancer than white men. Furthermore, a higher percent of Hispanic men had a PSA nadir of 1 ng/ml or greater after radiotherapy, which may have been responsible for their trend toward a decreased 5-year disease-free survival rate compared with white men. Improved screening and early detection may improve disease-free survival in Hispanic men with localized prostate cancer.

Objectives: To assess patient-reported prostate cancer-specific quality of life 2 and 3 years after radiotherapy to the prostate in a randomized dose-escalation trial of 70 versus 78 Gy conducted from 1993 to 1998., Methods: Two years after completing radiotherapy, a questionnaire that assessed bladder, rectal, and sexual function was sent to 301 patients in the study. Three years after treatment, a second questionnaire was sent to the 175 patients with adequate follow-up., Results: Three years after radiotherapy, urinary incontinence was reported by 35% of patients, but only 6% required the use of a pad or other protective device. Patients reported increased leakage with a full bladder (urge incontinence) between the 2 and 3-year questionnaires (42% versus 50%; P = 0.03). At 3 years, 33% of patients reported rectal bleeding compared with 47% at 2 years (P = 0.006). Patients in the 78-Gy arm reported more frequent bowel movements at 3 years and less change in bowel function at 2 years than patients in the 70-Gy arm. Before radiotherapy, 84% of patients reported erections adequate for intercourse at least a few times during the previous year. After 2 and 3 years, this had decreased to 49% and 41%, respectively (P <0.02)., Conclusions: By patient-reported questionnaire, 78 Gy produced an increase in bowel movement frequency and no increase in bladder or sexual side effects at 3 years compared with 70 Gy. Comparing the results 2 and 3 years after radiotherapy, the symptoms of rectal bleeding had improved, erectile function had decreased, and urinary urge incontinence had increased.

The introduction of prostate-specific antigen (PSA) as a reliable tumor marker for prostate cancer brought significant changes in endpoints after therapy and in outcome reporting. Over the last 15 years we have collected follow-up information in this new era and struggled with failure definitions using this new tool. Parameters for failure after radiation were especially controversial due to the fact that, unlike surgery, a variable amount of normal prostate function and PSA production remained. In 1996, the ASTRO Consensus Conference established a PSA failure definition based on the available information at the time. It was commonly used for outcome reporting subsequently although criticisms have been voiced and alternate definitions proposed. A recently assembled multi-institutional database was used both for long-term outcome reporting with external beam radiation and to test various other failure definitions. A summary of these results and the associated issues are presented here.

Purpose: Traditionally, portal images have been used for verification of patient setup. More recently, direct prostate localization using ultrasound imaging has become available. The aim of this study was to use both modalities to measure daily setup error and prostate organ motion and their respective contributions to the overall uncertainty of prostate target localization., Methods and Materials: Thirty-five patients treated for prostate cancer with intensity-modulated radiotherapy (IMRT) between February 6 and July 2, 2001 underwent daily B-mode acquisition and targeting (BAT) ultrasound localization and weekly orthogonal portal imaging., Results: A total of 243 pairs of orthogonal portal films and the corresponding daily BAT images were reviewed. The mean shift +/- standard deviation in the right-left (RL), AP, and superinferior (SI) directions was 0.035 +/- 2.8 mm, -0.23 +/- 3.0 mm, and -0.013 +/- 2.0 mm, respectively, for portal films and -0.82 +/- 3.2 mm, -1.4 +/- 6.4 mm and -1.7 +/- 6.4 mm, respectively, for BAT images taken on the same day as the portal films. The mean prostate organ motion measurements were -0.89 +/- 3.3 mm (RL), -1.3 +/- 5.7 mm (AP), and -1.6 +/- 6.4 mm (SI). Without BAT localization, organ motion would have caused the clinical target volume to move outside the planning target volume margin in 23.3-41.8% of the treatments. Margins necessary to achieve complete coverage of the clinical target volume > 95% of the time without BAT would have been 5.3, 10.4 and 10.4 mm in the RL, AP, and SI dimensions, respectively., Conclusions: Prostate organ motion appears to predominate over setup error as the major component of variation in target localization. Without the use of BAT ultrasound prostate imaging, misses of the prostate can occur in a high percentage of treatments, despite patient setup verification with portal images. Relatively large planning target volume margins in the AP and SI dimensions may be necessary to overcome this.

To assess the prognostic value of neurologic function (NF) in patients with astrocytic spinal cord glioma, we conducted a retrospective study of 25 patients who were treated at our institution between January 1970 and December 1999. The median age was 40 years, and the median follow-up was 54 months. Nineteen patients had a biopsy, 5 had a subtotal resection, and 1 had a gross total resection. Twenty-two patients received postoperative radiotherapy to a median dose of 45 Gy. NF ratings of 1 and 2 were considered favorable, and 3 and 4 were considered unfavorable, based on a scale of 1 to 4. Dual neuropathologic review confirmed the tumor to be low, intermediate, or high grade, based on the WHO grades I-II, III, or IV, respectively. Actuarial rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed. Our study results revealed that an improved 5-year OS rate was associated with favorable NF at diagnosis (73% vs. 22% for patients with unfavorable NF; P = 0.04) and favorable NF before radiation therapy (89% vs. 28% for patients with unfavorable NF; P = 0.049). There was a significant difference in OS based on tumor grade ( P < 0.001) and age (risk ratio, 1.04; P = 0.027). PFS and LC were significantly better for young patients and those with lower tumor grade ( P < 0.05). A multivariate analysis of age, NF at diagnosis, and postoperative NF for all patients showed postoperative NF and age to be independent prognostic factors for OS. We conclude that favorable NF may be associated with improved outcome in patients with astrocytic spinal cord glioma.

Purpose: To determine the clinical variables associated with inadequate salvage cryotherapy and to correlate the disease-free survival rates associated with biopsy results in prostate cancer (CaP)., Methods and Materials: Between July 1992 and January 1995, 150 patients underwent salvage cryotherapy for locally recurrent CaP. Biopsy specimens were examined for the presence of cancer cells and normal or atypical glands, all of which were considered evidence of inadequate cryotherapy. Clinical variables, as predictors of biopsy results, were evaluated with univariate and multivariate analyses. The impact of the biopsy results on disease-free survival was also determined., Results: The number of cryoprobes and freeze-thaw cycles correlated with inadequate cryotherapy (p = 0.037 and p = 0.0022, respectively). The number of freeze-thaw cycles was an independent predictor of inadequate cryotherapy (p = 0.003). The finding of cancer cells in the biopsy specimens was the only histopathologic variable that affected disease-free survival (p = 0.016)., Conclusion: Complete ablation of the prostate gland and tumor is difficult to achieve with salvage cryotherapy. To optimize for complete ablation, salvage cryotherapy should include at least two freeze-thaw cycles and a minimum of five cryoprobes. The finding of atypical or normal epithelial tissue in biopsy specimens after salvage cryotherapy is not predictive of biochemical failure.

Objectives: To determine the clinical presentation and outcome of patients with high-grade bladder leiomyosarcoma., Methods: Between July 1986 and April 1998, 36 adult patients (mean follow-up 56 months) with a diagnosis of urinary bladder leiomyosarcoma were evaluated at the University of Texas M. D. Anderson Cancer Center. We retrospectively reviewed the records of these patients for information on clinical features, treatment, and outcome., Results: The mean age of the patients was 63 years. Twenty-six patients were white men in their seventh decade. The most common symptom at presentation was gross hematuria (81% of patients), followed by increased urinary frequency (28%), and dysuria (19%). Thirty-five patients were treated surgically for bladder leiomyosarcoma; of these, 12 (34%) developed recurrent disease (5 with local recurrence and 7 with distant metastasis), with a median time to diagnosis of recurrent disease of 8.3 months. The most common site of distant failure was the retroperitoneum. The disease-specific survival rate at 1, 3, and 5 years was 88.6%, 62.0%, and 62.0%, respectively. Multivariate analyses demonstrated that only the Memorial Sloan-Kettering Cancer Center disease stage system was a significant predictor of survival of patients with bladder leiomyosarcoma (P = 0.018)., Conclusions: In patients with high-grade leiomyosarcoma of the bladder, radical cystectomy in the face of localized disease, whether at the initial presentation or after neoadjuvant chemotherapy, can result in a 5-year, disease-specific survival rate of 62.0%.

Purpose: We established hazard rates for disease progression at different intervals after external beam radiotherapy alone in patients with clinically localized prostate cancer. We determined the likelihood of biochemical failure in those free of disease 5 years after radiotherapy and identified those at risk for early versus late biochemical failure., Materials and Methods: We reviewed the records of 964 patients treated with full dose external beam radiotherapy alone for T1 to T4, NxM0 prostate cancer. Followup prostate specific antigen (PSA) was measured 3 months after the completion of radiotherapy and every 3 to 6 months thereafter. Yearly hazard rates for biochemical failure were calculated each followup year., Results: Median followup of the whole study group was 48 months. Overall 5 and 10-year biochemical disease-free survival rates were 63.7% and 53.6%, respectively. Patients had a peak overall hazard rate 2 years after treatment. The hazard rate then decreased until year 6, when it increased slightly and remained elevated even at year 10. This late increase in the overall hazard rate was associated with late increases in the hazard rate in men with favorable prognostic factors, namely pretreatment PSA less than 10 ng./ml., Gleason score less than 5, clinical T stage T1 or T2, posttreatment PSA nadir less than 0.99 ng./ml. or radiation dose less than 68 Gy. In 13 of the 307 patients (3.9%) with biochemical failure the failure occurred more than 5 years after initial treatment., Conclusions: The peak risk of biochemical failure is 2 years after radiotherapy. Patients are at slight but persistent risk for biochemical failure more than 5 years after treatment. Hazard rate calculations beyond the median followup of 4 years can underestimate the true hazard.

Purpose: We set out to determine whether patients who underwent prostatectomy for recurrence after external-beam radiotherapy for prostate cancer had a higher incidence of alterations in the apoptotic pathway than did patients who underwent surgery as initial treatment., Materials and Methods: Twenty patients who underwent unsuccessful full-dose external-beam radiotherapy for prostate cancer and subsequently underwent salvage radical surgery (radio-recurrent group), and 20 patients matched for various clinical parameters who underwent only radical prostatectomy for localized or locally advanced prostate cancer (radio-naive group), were studied. Tissue samples were examined for immunoreactivity for p53, p21, Bcl-2, and Ki-67 proteins. Statistically, the two groups were compared using exact logistic regression., Results: Fifty-five percent of the tumors from patients initially treated with radiotherapy were noted to overexpress Bcl-2; whereas, in the radio-naive group, no patient had Bcl-2 overexpression (p = 0.0004). More patients who underwent salvage radical surgery were found to have a higher mean proliferative index (Ki-67 staining) (39.6%), compared with patients undergoing prostatectomy alone (22.1%), p = 0.0800. No significant difference was noted in immunohistochemical expression of p53 and p21 between the two groups., Conclusions: Patients undergoing radical prostatectomy after radiotherapy had a significantly higher rate of Bcl-2 overexpression than did patients who underwent surgery as the initial treatment. Alterations in the apoptotic pathway may be important in the development of local recurrence after radiation therapy.

Purpose: The purpose is to determine dose-limiting toxicity, pharmacokinetics,pharmacodynamics, and immunobiology after i.p. injections of recombinant human IL-12 (rhIL-12)., Experimental Design: rhIL-12 was administered to 29 previously treated patients with peritoneal carcinomatosis from Müllerian carcinomas, gastrointestinal tract carcinomas and peritoneal mesothelioma in a Phase I trial. rhIL-12 doses were increased from 3 to 600 ng/kg. Three or more patients at each level received weekly i.p. injections of rhIL-12., Results: Dose-limiting toxicity (elevated transaminase) occurred in 2 of 4 patients at the 600 ng/kg dose. More frequent toxicities included fever, fatigue, abdominal pain, nausea, and catheter-related infections. Ten patients received 300 ng/kg with acceptable frequency and severity of side effects. Two patients (one with ovarian cancer and one with mesothelioma) had no remaining disease at laparoscopy. Eight patients had stable disease and 19 progressive disease. At 300 ng/kg i.p., IL-12 was cleared from peritoneal fluid in a biphasic manner with a terminal-phase half-life of 18.7 h; peritoneal fluid levels of IL-12 5 min after i.p. injection were 100-200 pg/ml, and serum levels reached approximately 10 pg/ml between 24 and 36 h. IL-1-alpha, IL-2, IL-10, tumor necrosis factor alpha, and IFN-gamma were determined in serum and peritoneal fluid. IFN-gamma, IL-10, and tumor necrosis factor alpha were detected most frequently. Immunobiological effects included peritoneal tumor cell apoptosis, decreased tumor cell expression of basic fibroblast growth factor and vascular endothelial growth factor, elevated IFN-gamma and IFN-inducible protein 10 transcripts in peritoneal exudate cells, and increased proportions of peritoneal CD3(+) relative to CD14(+) cells., Conclusions: rhIL-12 at 300 ng/kg by weekly i.p. injection is biologically active and adequately tolerated for Phase II studies.

Purpose: We characterize the prostate-specific antigen (PSA) bounce in patients who underwent external beam radiation therapy for prostate cancer and correlate the PSA bounce with the development of biochemical disease progression., Materials and Methods: In this study 964 patients received full dose radiation therapy alone. Followup PSA values were obtained 3 months after completion of radiotherapy and every 3 to 6 months thereafter. Median followup of the entire study group was 48 months. All time intervals were calculated from the completion date of radiation therapy. PSA bounce was defined as an initial increase in serum PSA of at least 0.5 ng./ml., followed by a decrease to pre-bounce baseline serum PSA values no more than 60 months after external beam radiation therapy., Results: Of the 964 patients 119 (12%) had a PSA bounce. PSA bounce was unrelated to age, race, pretreatment PSA, Gleason score, clinical T stage or radiation dose. Mean time to PSA bounce was 9 months from the time of therapy. The respective 1 and 5-year biochemical disease-free survival rates were 100% and 82.1% for patients with PSA bounce and 93.9% and 57.7% for those without PSA bounce (p = 0.0001)., Conclusions: Of men with prostate cancer treated with external beam radiation therapy 12% experienced a transient increase in PSA (PSA bounce) followed by a return to pre-bounce levels after radiation. The PSA bounce phenomenon was not predictive of time to biochemical recurrence.

OBJECTIVE.: Our objective was to compare by response rate the therapeutic options of loop electrosurgical excision procedure (LEEP), laser therapy, and wide local excision in managing high-grade vulvar intraepithelial neoplasia in a pilot study for a randomized clinical trial. MATERIALS AND METHODS.: Between 1995 and 1999, 109 patients presenting with vulvar lesions were registered at a comprehensive cancer center and 2 associated colposcopy clinics. From these 109, we identified 74 patients with lesions histologically proven to be vulvar intraepithelial neoplasia who underwent treatment with CO2 laser, wide local excision, or LEEP. Clinical and pathological features were reviewed retrospectively. Wilcoxon rank sum test and life table analyses were used to compare groups. Response rates for this retrospective study will be used to calculate the sample size for a prospective clinical trial. RESULTS.: Our population was similar to others reported in the literature in age, range of diagnoses, and follow-up. Only 1 of 74 patients (1%) had invasive cancer. In a subset of 62 patients treated for the first time, LEEP and wide local excision were equal in their ability to achieve complete response. Laser ablation was the least successful of all methods (10/20 with laser, 3/20 with LEEP, and 2/22 with wide local excision experienced recurrences [p = .04]). No statistically significant differences among the 3 were noted in time to recurrence (p = .24). Age, age at first intercourse, and number of sexual partners were not correlated with recurrence and did not confound the results. Using a chi approximation, an alpha error of 0.05, and a power of 0.80, researchers should enroll 25 patients per arm if improvement over standard therapy is expected to be 40%, 45 if expected to be 30%, and 95 if expected to be 20%. CONCLUSIONS.: Because of differences in recurrence rate and length of hospital stay and indications of potential differences in cost found in this pilot, LEEP merits comparison in a prospective randomized clinical trial with wide local excision and laser therapy in which recurrence rate, patient treatment preference, and cost-effectiveness are evaluated. Patients entered in such a trial should be stratified according to their risk of invasion. If the risk of invasion is high, then the laser should be used to excise a sample rather than ablate.

Purpose: We determined the biochemical failure rate in patients 60 years and younger, and older than 60 years old who were treated with external beam radiation for localized prostate cancer or locally advanced prostate cancer. We also evaluated prognostic factors in the 2 age groups., Materials and Methods: We reviewed the medical records of 964 patients who received full dose radiotherapy as the only treatment for prostate cancer. Followup prostate specific antigen was measured 3 to 6 months after the completion of radiotherapy and every 3 to 6 months thereafter. Biochemical failure was defined using the criteria established by the American Society for Therapeutic Radiology and Oncology Consensus Panel. Median followup in the whole study group was 48 months., Results: Of the 98 men 60 years or younger 46 (47%) had biochemical failure, whereas 261 (30%) of the 866 older than 60 years old had biochemical failure. The 5 and 7-year biochemical disease-free survival rates were 55% and 47% in the younger men, and 65% and 59% in the older men, respectively. These rates were significantly lower in the younger men (p = 0.017 and 0.027, respectively). Multivariate regression showed that in men 60 years or younger initial prostate specific antigen, Gleason score and lower radiation doses were predictive of biochemical failure., Conclusions: Men with prostate cancer who are 60 years or younger and treated with radiotherapy may be at significant risk for long-term biochemical failure.

The purpose of this study was to review the clinical course of patients diagnosed with vulvar melanoma. Charts of patients diagnosed between 1970 and 1997 were reviewed for demographics, lesion characteristics, disease duration and extent, and treatments. Actuarial survival curves were computed by the Kaplan Meier method and compared by Cox proportional hazards regressions. Fifty-one patients (median age 54) with vulvar melanoma presented with a vulvar mass (39%), pain (30%), bleeding (24%), and itching (20%). Anatomical distribution was mucosa of the vulva (65%), vulvar epidermal site (21%), or unspecified vulva (14%), with 20% having multifocal disease at diagnosis. Histologic types were superficial spreading or nodular (50% each). Median lesion characteristics were diameter 2 cm, Breslow index 4.4 mm, and Clark level IV. Distribution of patients per American Joint Committee on Cancer (AJCC) stage was 29%, 50%, 16%, and 7% for stages I, II, III and IV, respectively. Inguinal node metastases were unilateral in 16% and bilateral in 7%. Despite complete surgical resection, 32 patients (63%) recurred. Median survival for all patients was 41 months (range, 5-324), with 91% 5-year survival for patients with stage I and 31% for stage >or= IIA (P = 0.0002). As with cutaneous melanoma, the AJCC classification, Breslow's thickness, and Clark's levels are the major predictors of overall survival (P = 0.0001 each) and disease-free survival (P

Chemotherapy given sequentially or concurrently with external beam radiation therapy has emerged as a standard for the treatment of locally advanced lung cancer. Gene therapy by adenovirus-mediated wild-type p53 gene transfer has been shown to inhibit lung cancer growth in vitro, in animal models, and in human clinical trials. However, no information is available on the combined effects of p53 gene transfer, chemotherapy, and radiation therapy on lung cancer growth in vitro and in vivo. Therefore, we developed two-dimensional and three-dimensional isobologram modeling and statistical methods to evaluate the synergistic, additive, or antagonistic efficacy among these therapeutic agents in human non-small cell lung cancer cell lines A549, H460, H322, and H1299, at the ID50 and ID80 levels. The combination of these three therapeutic agents exhibited synergistic inhibitory effects on tumor cell growth in all four cell lines at both the ID50 and the ID80 levels in vitro. In mouse models with H1299 and A549 xenografts, combined treatment synergistically inhibited tumor growth in the absence of any apparent increase in toxicity, when compared with other treatment and control groups. Together, our findings suggest that a combination of gene therapy, chemotherapy, and radiation therapy may be an effective strategy for human cancer treatment.

Transforming growth factor beta (TGF-beta) is an important family of cytokines that may promote tumor growth in vivo through several mechanisms including interference with antitumor T-cell immune responses, alteration of factors in the stroma and matrix, and the promotion of angiogenesis. TGF-beta isotypes have been detected in malignant and normal ovarian tissues. We have determined by quantitative immunohistochemistry the density of TGF-beta1, TGF-beta2, and human leukocyte antigen (HLA) Class I and Class II antigens on malignant cells in paired primary and metastatic specimens from 10 patients with ovarian carcinoma. Cryostat sections of specimens from the carcinomas and from normal ovaries of three women of similar age without ovarian cancer were stained respectively with specific antibodies to TGF-beta1, TGF-beta2, and HLA Class I and II antigens, and with isotype-matched control antibodies. Antigen density was quantitated blindly as mean absorbance on a SAMBA 4000 image analyzer. TGF-beta1 and TGF-beta2 were overexpressed in both primary and metastatic tumor specimens in comparison with normal ovarian tissue. No statistical correlation was found between the expression of TGF-beta1 or TGF-beta2 and HLA class I or HLA class II, which suggests that TGF-beta isotypes could have effects on the immune system other than down-modulation of these HLA molecules. Furthermore, the lack of association between levels of TGF-beta expression and the reduced expression of HLA molecules could suggest that tumor cells expressing both HLA and TGF-beta may be suitable targets for adaptive immunotherapy. Additional studies are necessary to determine whether TGF-beta expressed by ovarian cancer cells merits evaluation as a therapeutic target.

Background: We have previously argued against the calculation of cancer-specific death rates as philosophically undefined and biased. Deaths attributed to cancer during a particular year occur in patients diagnosed during an unknown distribution of past times, so cancer-specific death rates cannot be used to assess changes in the impact of cancer on survival of the population at specific periods of diagnosis., Purpose: Our goal was to develop and analyze three measures of the impact of cancer on population survival that do not use the attributed cause of death: 1) the age-adjusted proportion of the population diagnosed with cancer in a particular year and projected to be dead of any cause by a particular age; 2) the same measure corrected for population mortality; and 3) the expected years of life lost to a 20-year-old individual because of the possibility of a diagnosis of cancer., Methods: Data on all adults diagnosed with any cancer during the period from January 1973 through December 1990 were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. The measures were calculated separately for various combined sex and race groups. Three 2-year diagnosis periods spaced 5 years apart were considered: 1975-1976, 1980-1981, and 1985-1986. A statistical model was used to extrapolate survival beyond observation; the same model was used for patients diagnosed in the three time periods to minimize the effect of possible model misspecification on changes., Results: Cancer incidence increased for three of the four sex-race groups; age-adjusted changes from 1975 through 1976 to 1985 through 1986 were +11.5% for white men, +6.9% for white women, +15.1% for black men, and -9.2% for black women. Human immunodeficiency virus (HIV)-related cancers were responsible for an increased cancer incidence at early ages in white men in the latest time period studied. There was a decrease in the incidence of gynecologic cancers at early ages; the decrease was greater among black women (-55.1%) than among white women (-39.3%). Age- and incidence-adjusted 5-year survival increased by 17.9% for white men, 2.3% for white women, and 7.4% for black men and decreased by 14.1% for black women. When the data from 1985 through 1986 were compared with those from 1975 through 1976, the expected number of years lost to a 20-year-old individual because of cancer changed as follows for the various sex-race groups: +1.4% for white men (-4.0% if HIV-related cancers were not included in the calculation), +2.1% for white women, +12.2% for black men, and +8.8% for black women., Conclusions: For white men and women, there has been an increase in both the incidence of and survival following the diagnosis of cancer; the two effects nearly cancel in our measures. The experience of black men and women has worsened because of increasing incidence or decreased survival.

Purpose: This study was conducted to test for the relationship between tumor and normal tissue radiosensitivity, by comparing local tumor control to the severity of acute and late normal tissue reactions in head and neck cancer patients treated by definitive radiotherapy., Methods and Materials: Two hundred eighty-six patients with head and neck cancer who were treated at the University of Texas M. D. Anderson Cancer Center between 1983 and 1993 were selected for the study. Of these, 124 (43%) were treated by a concomitant boost regimen and 162 (57%) by hyperfractionation. All patients had at least 1 year of follow-up. The tumor stage distribution according to the 1992 American Joint Committee on Cancer (AJCC) staging system was as follows: T1, 3%; T2, 53%; T3, 40%; T4, 4%. The average doses delivered were 71.2 Gy and 76.2 Gy for the concomitant boost and hyperfractionation regimens, respectively, with no significant variation between patients. Acute and late reactions were recorded using the Radiation Therapy Oncology Group (RTOG)/European Organization for Research on Treatment of Cancer (EORTC) grading system (0 to 4). The median follow-up period was 38 months (range: 12-107 months). The time to local tumor recurrence was analyzed in relation to the severity of acute and late reactions expressed as the maximum recorded grades, and to the time intensity of acute mucositis, expressed as the area under the curve of mucositis grade vs. time. Univariate and multivariate analyses also included T stage, N stage, and site of origin as other prognostic variables, and were carried out using a proportional hazards model., Results: Fifty-four patients (19%) suffered local failure. T stage was found to significantly influence local control (p = 0.009). There was a nonsignificant trend for higher failure rates in patients with maximum Grade 1 or 2 vs. those with Grade 3 or 4 acute mucositis (28 and 18%, respectively; p = 0.17). No correlation was found between the severity of late reactions and local tumor control after radiotherapy. Analysis by time intensity of mucositis revealed a wide variation between individuals with a nonsignificant trend for higher local failure rates in patients with low mucositis time intensity scores., Conclusions: These clinical results suggest a possible relationship between normal tissue and tumor radiosensitivity. However, additional studies with a larger numbers of patients, and using refined normal tissue endpoints that incorporate a time function are needed to fully elucidate this question.

In rats with left ventricular (LV) hypertrophy, we investigated whether abnormalities of skeletal muscle could result in reduced exercise tolerance in the absence of reduced cardiac function. LV pressure overload was induced by partial constriction of the abdominal aorta (AC) with controls subjected to sham operation. Cardiac and skeletal muscle function and blood flow were assessed in vivo 3 and 6 weeks later. AC induced LV hypertrophy of 41% and 37% at 3 and 6 weeks post-operation. In AC rats, cardiac index was 31 +/- 8 and 35 +/- 4 ml/min/100 g at 3 and 6 weeks compared to 38 +/- 4 and 34 +/- 2 ml/min/100 g in controls (N.S.). Fatigue index of the soleus (type-I rich) muscle in AC rats was reduced by 14% (P < 0.05) at both time points, while that of the tibialis anterior (mixed fiber) muscle was unchanged at 3 weeks but reduced by 18% (P < 0.05) at 6 weeks. Function of the extensor digitorum longus (type-IIB rich) muscle was unaltered at both time points. Blood flow at rest was paradoxically increased in muscles which exhibited increased fatigue susceptibility. At 3 weeks, blood flow during fatigue stimulation was reduced by 33% in the soleus muscle; the only muscle to exhibit impaired fatigue resistance at this time point. Blood flow during stimulation remained unaltered in the EDL and TA muscles. Thus, impaired fatigue resistance was observed in skeletal muscle with high oxidative and oxidative glycolytic fiber content during the compensatory phase of LV hypertrophy, prior to overt cardiac dysfunction. A selective impairment of blood flow to these muscles during exercise may play a causal role in exercise intolerance.

Background: Metastatic colorectal cancer is generally incurable. The most active regimen available, 5-fluorouracil (5-FU) and folinic acid (Leucovorin), produces response rates of approximately 25% to 30%. Methyl-lomustine is a nitrosourea with modest activity against colorectal cancer. A randomized trial was undertaken to evaluate the impact the addition of methyl-lomustine would have on response, duration of survival, and survival rates in patients with advanced colorectal cancer., Methods: The methyl-lomustine/5-FU/Leucovorin (MFL) regimen consisted of methyl-lomustine (110 mg/m2), administered on Day 1 of each 8-week cycle with six weekly boluses of 5-FU (600 mg/m2), and Leucovorin (500 mg/m2). The FL treatment arm consisted of the administration of 5-FU and Leucovorin as described above. Patients were evaluated for response and toxicity after each 8-week cycle., Results: Of 319 patients included in this trial, 297 (93.1%) had disease evaluable for response and toxicity: 145 received MFL, and 152 received FL. In this trial, 526 courses of MFL and 529 courses of FL were administered. Methyl-lomustine/5-FU/Leucovorin treatment resulted in 4 complete and 30 partial responses (response rate, 21.9%), and FL treatment resulted in 9 complete and 33 partial responses (response rate, 26.4%). There was no significant difference in median survival duration between patients in the two arms (MFL = 48 weeks, FL = 51 weeks). However, MFL was significantly more toxic with greater myelosuppression than was FL (Grade 3-4 neutropenia: MFL = 56 patients, FL = 27 patients, P < 0.001; Grade 3-4 thrombocytopenia: MFL = 49 patients, FL = 2 patients, P < 0.001; Grade 3-4 anemia: MFL = 15 patients, FL = 6 patients, P < 0.001; and more prolonged median duration of granulocytopenia: MFL = 9 days, FL = 7 days, P < 0.001; and thrombocytopenia: MFL = 14 days, FL = 7.5 days, P < 0.001)., Conclusion: Because the addition of methyl-lomustine in the MFL schedule markedly increased the toxicity of the regimen and because the FL regimen was as effective as MFL, the authors recommend that Leucovorin and 5-FU remain the treatment choice for treating patients with metastatic colorectal cancer.

The bremsstrahlung spectrum from an 8-MeV linear accelerator has been measured using a NaI(T1) spectrometer system. The spectrum shows a low-energy cutoff at 0.4 MeV and the maximum photon energy to be approximately 6% greater than the nominal energy. The maximum emission of energy fluence was 1.6 and 1.8 MeV for measured and calculated values, respectively. The fast neutron dose in the photon beam was approximately 0.09% of the x-ray dose. The weighted mean energy was 2.3 MeV, measured value, and 2.4 MeV, calculated value.