Racial disparities in prostate cancer outcome among prostate-specific antigen screening eligible populations in the United States.

Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69 years) are at a disproportionally high risk of poor outcomes. Patients and methods: The SEER database was used to study 390 259 men diagnosed with prostate cancer in the United States between 2004 and 2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 years versus not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P < 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P < 0.001) compared to non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 versus 1.55; 1.47-1.65; Pinteraction < 0.001) and PCSM (AHR 1.53; 1.37-1.70 versus 1.25; 1.14-1.37; Pinteraction = 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should be included in the updated USPSTF PSA screening guidelines.

Utilization of biopsy-based genomic classifier to predict distant metastasis after definitive radiation and short-course ADT for intermediate and high-risk prostate cancer.

BACKGROUND: We examined the ability of a biopsy-based 22-marker genomic classifier (GC) to predict for distant metastases after radiation and a median of 6 months of androgen deprivation therapy (ADT). METHODS: We studied 100 patients with intermediate-risk (55%) and high-risk (45%) prostate cancer who received definitive radiation plus a median of 6 months of ADT (range 3-39 months) from 2001-2013 at a single center and had available biopsy tissue. Six to ten 4 micron sections of the needle biopsy core with the highest Gleason score and percentage of tumor involvement were macrodissected for RNA extraction. GC scores (range, 0.04-0.92) were determined. The primary end point of the study was time to distant metastasis. Median follow-up was 5.1 years. There were 18 metastases during the study period. RESULTS: On univariable analysis (UVA), each 0.1 unit increase in GC score was significantly associated with time to distant metastasis (hazard ratio: 1.40 (1.10-1.84), P=0.006) and remained significant after adjusting for clinical variables on multivariable analysis (MVA) (adjusted hazard ratio: 1.36 (1.04-1.83), P=0.024). The c-index for 5-year distant metastasis was 0.45 (95% confidence interval: 0.27-0.64) for Cancer of the Prostate Risk Assessment score, 0.63 (0.40-0.78) for National Comprehensive Cancer Network (NCCN) risk groups, and 0.76 (0.57-0.89) for the GC score. Using pre-specified GC risk categories, the cumulative incidence of metastasis for GC>0.6 reached 20% at 5 years after radiation (P=0.02). CONCLUSIONS: We believe this is the first demonstration of the ability of the biopsy-based GC score to predict for distant metastases after definitive radiation and ADT for intermediate- and high-risk prostate cancer. Patients with the highest GC risk (GC>0.6) had high rates of metastasis despite multi-modal therapy suggesting that they could potentially be candidates for treatment intensification and/or enrollment in clinical trials of novel therapy.

Incidence and determinants of 1-month mortality after cancer-directed surgery.

BACKGROUND: Death within 1 month of surgery is considered treatment related and serves as an important health care quality metric. We sought to identify the incidence of and factors associated with 1-month mortality after cancer-directed surgery. PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results Program to study a cohort of 1 110 236 patients diagnosed from 2004 to 2011 with cancers that are among the 10 most common or most fatal who received cancer-directed surgery. Multivariable logistic regression analyses were used to identify factors associated with 1-month mortality after cancer-directed surgery. RESULTS: A total of 53 498 patients (4.8%) died within 1 month of cancer-directed surgery. Patients who were married, insured, or who had a top 50th percentile income or educational status had lower odds of 1-month mortality from cancer-directed surgery {[adjusted odds ratio (AOR) 0.80; 95% confidence interval (CI) 0.79-0.82; P < 0.001], (AOR 0.88; 95% CI 0.82-0.94; P < 0.001), (AOR 0.95; 95% CI 0.93-0.97; P < 0.001), and (AOR 0.98; 95% CI 0.96-0.99; P = 0.043), respectively}. Patients who were non-white minority, male, or older (per year increase), or who had advanced tumor stage 4 disease all had a higher risk of 1-month mortality after cancer-directed surgery, with AORs of 1.13 (95% CI 1.11-1.15), P < 0.001; 1.11 (95% CI 1.08-1.13), P < 0.001; 1.02 (95% 1.02-1.03), P < 0.001; and 1.89 (95% CI 1.82-1.95), P < 0.001 respectively. CONCLUSIONS: Unmarried, uninsured, non-white, male, older, less educated, and poorer patients were all at a significantly higher risk for death within 1 month of cancer-directed surgery. Efforts to reduce 1-month surgical mortality and eliminate sociodemographic disparities in this adverse outcome could significantly improve survival among patients with cancer.

The association between insurance status and prostate cancer outcomes: implications for the Affordable Care Act.

BACKGROUND: The Affordable Care Act (ACA) aims to expand health insurance coverage to over 30 million previously uninsured Americans. To help evaluate the potential impact of the ACA on prostate cancer care, we examined the associations between insurance coverage and prostate cancer outcomes among men <65 years old who are not yet eligible for Medicare. METHODS: The Surveillance, Epidemiology and End Results Program was used to identify 85 203 men aged <65 years diagnosed with prostate cancer from 2007 to 2010. Multivariable logistic regression modeled the association between insurance status and stage at presentation. Among men with high-risk disease, the associations between insurance status and receipt of definitive therapy, prostate cancer-specific mortality (PCSM) and all-cause mortality were determined using multivariable logistic, Fine and Gray competing-risks and Cox regression models, respectively. RESULTS: Uninsured patients were more likely to be non-white and come from regions of rural residence, lower median household income and lower education level (P<0.001 for all cases). Insured men were less likely to present with metastatic disease (adjusted odds ratio (AOR) 0.23; 95% confidence interval (CI) 0.20-0.27; P<0.001). Among men with high-risk disease, insured men were more likely to receive definitive treatment (AOR 2.29; 95% CI 1.81-2.89; P<0.001), and had decreased PCSM (adjusted hazard ratio 0.56; 95% CI 0.31-0.98; P=0.04) and all-cause mortality (adjusted hazard ratio 0.60; 0.39-0.91; P=0.01). CONCLUSIONS: Insured men with prostate cancer are less likely to present with metastatic disease, more likely to be treated if they develop high-risk disease and are more likely to survive their cancer, suggesting that expanding health coverage under the ACA may significantly improve outcomes for men with prostate cancer who are not yet eligible for Medicare.

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer.

PURPOSE: To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). METHODS AND MATERIALS: The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033). CONCLUSION: A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer.

PURPOSE: An investigation was performed of the clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following external-beam radiation therapy (RT) for men with PSA-detected or clinically palpable prostate cancer. METHODS AND MATERIALS: A Cox regression multivariable analysis was used to determine whether the percent of positive prostate biopsies provided clinically relevant information about PSA outcome following external beam RT in 473 men while accounting for the previously established risk groups based on the pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Commission on Cancer (AJCC) clinical T stage. RESULTS: Controlling for the known prognostic factors, the percent of positive prostate biopsies added clinically significant information (p = 0.02) regarding time to PSA failure following RT. Specifically, 76% of the patients in the intermediate risk group (1992 AJCC T(2b) or biopsy Gleason 7 or PSA > 10 ng/mL and < or = 20 ng/mL) could be classified into either an 30% or 85% 5-year PSA control cohort using the preoperative prostate biopsy data. CONCLUSION: The previously validated stratification of PSA outcome following radical prostatectomy (RP) using the percent of positive prostate biopsies in intermediate-risk patients is also clinically significant for men treated with external beam RT. The percent positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and 1992 AJCC clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome following RP or external beam RT.

A technique for optimization of digitally reconstructed radiographs of the chest in virtual simulation.

INTRODUCTION: Virtual simulation (VS) of radiotherapy uses CT data. Digitally reconstructed radiographs (DRRs) are a critical element of this process, and the quality of these images is frequently suboptimal. We present techniques to improve DRR quality for clinical purposes. The results of two approaches to DRR optimization are presented. METHODS AND MATERIALS: One approach to DRR optimization is to use traditional radiographs as a guide and to adjust the algorithm parameters based on image and objective contrast to produce images that more closely resemble traditional radiographs (Method 1). Another approach is to focus on the visibility of specific anatomic structures. Using this method, two DRR images are optimized manually by interactively adjusting reconstruction parameters, then they are combined into a single composite image (Method 2). DRRs for the chest region, generated using both methods, were evaluated by clinical staff based on usability for treatment verification and field definition. RESULTS: Using Method 1, the resulting DRRs more closely resembled traditional radiographs. This technique allows DRR quality to be improved with little user interaction. These DRRs are generally adequate for clinical use, but not optimal for sites such as the chest. Images generated using Method 2 were considered clinically superior in terms of visibility of specific anatomic structures. These images also compare well with traditional radiographs, although they show an increased contrast level between bone and lower density structures. CONCLUSION: Both Methods 1 and 2 can be used to improve DRR quality for clinical purposes. For the chest region, the additional effort required by Method 2 to achieve a more detailed image appears justified.

Clinical utility of percent-positive prostate biopsies in predicting biochemical outcome after radical prostatectomy or external-beam radiation therapy for patients with clinically localized prostate cancer.

BACKGROUND AND PURPOSE: The clinical utility of the percentage of positive prostate biopsies in predicting prostate specific antigen (PSA) outcome after radical prostatectomy (RP) or external-beam radiation therapy (EBRT) for men with PSA-detected or palpable prostate cancer is not established. METHODS: A Cox regression multivariable analysis was used to determine whether percent-positive prostate biopsies provided clinically relevant information about PSA outcome after RP in 960 men, while accounting for the previously established risk groups based on the pretreatment PSA concentration biopsy Gleason score, and the 1992 American Joint Commission on Cancer clinical T stage. RESULTS: In the intermediate-risk group, 80% of the patients (stage T(2b) or biopsy Gleason 7 or PSA 10-20 ng/mL) could be classified into either an 11% or an 86% 4-year PSA control cohort using the preoperative prostate biopsy data. These findings were validated using an independent surgical (N = 823) and radiation (N = 473) data set. Percent-positive prostate biopsies added clinically significant information regarding time to PSA failure after RP. CONCLUSIONS: The percentage of positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome after RP or EBRT.

Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer.

CONTEXT: Combined treatment using radiation therapy (RT) and androgen suppression therapy (AST) is used to treat men with clinically localized adenocarcinoma of the prostate, but outcome using this combined therapy compared with RT alone is not known. OBJECTIVE: To determine the relative efficacy of RT plus AST vs RT alone among men with clinically localized prostate cancer. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 1586 men with prostate cancer who were treated between January 1989 and August 1999 using 3-dimensional conformal RT with (n = 276) or without (n = 1310) 6 months of AST. MAIN OUTCOME MEASURE: Relative risk (RR) of prostate-specific antigen (PSA) failure (defined according to the American Society for Therapeutic Radiology and Oncology consensus statement), by treatment and high-, intermediate-, or low-risk group based on serum PSA level, biopsy Gleason score, and 1992 American Joint Commission on Cancer clinical tumor category. RESULTS: Estimates of 5-year PSA outcome after RT with or without AST were not statistically different among low-risk patients (P =.09), whereas intermediate- and high-risk patients treated with RT plus AST had significantly better outcomes than those treated with RT alone (P<.001 and =.009, respectively). The RR of PSA failure in low-risk patients treated with RT plus AST was 0.5 (95% confidence interval [CI], 0.3-1.1) compared with patients treated with RT alone. The RRs of PSA failure in intermediate-risk and high-risk patients treated with RT plus AST compared with RT alone were 0.2 (95% CI, 0. 1-0.3) and 0.4 (95% CI, 0.2-0.8), respectively. CONCLUSIONS: Our data suggest a significant benefit in 5-year PSA outcomes for men with clinically localized prostate cancer in intermediate- and high-risk groups treated with RT plus AST vs those treated with RT alone. Results from prospective randomized trials currently under way are needed to validate these findings. JAMA. 2000;284:1280-1283

Investigating the clinical utility of the percent of positive prostate biopsies in predicting PSA outcome following local therapy for patients with clinically localized prostate cancer.

The clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following radical prostatectomy (RP), or external beam radiation therapy (RT), for men with PSA detected, or clinically palpable prostate cancer was investigated. After accounting for the established prognostic significance of the PSA level, biopsy Gleason score and the clinical T-stage, the percent of positive prostate biopsies added clinically significant information regarding time to PSA failure following RP. These findings were validated in the intermediate risk patients using an independent surgical and radiation data set. Prostate Cancer and Prostatic Diseases (2000) 3, 259-264

Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer.

PURPOSE: To present nomograms providing estimates of prostate-specific antigen (PSA) failure-free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT. RESULTS: Pretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P < .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality. CONCLUSION: Men at high risk (> 50%) for early (< or = 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.

Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer.

CONTEXT: Interstitial radiation (implant) therapy is used to treat clinically localized adenocarcinoma of the prostate, but how it compares with other treatments is not known. OBJECTIVE: To estimate control of prostate-specific antigen (PSA) after radical prostatectomy (RP), external beam radiation (RT), or implant with or without neoadjuvant androgen deprivation therapy in patients with clinically localized prostate cancer. DESIGN: Retrospective cohort study of outcome data compared using Cox regression multivariable analyses. SETTING AND PATIENTS: A total of 1872 men treated between January 1989 and October 1997 with an RP (n = 888) or implant with or without neoadjuvant androgen deprivation therapy (n = 218) at the Hospital of the University of Pennsylvania, Philadelphia, or RT (n = 766) at the Joint Center for Radiation Therapy, Boston, Mass, were enrolled. MAIN OUTCOME MEASURE: Actuarial freedom from PSA failure (defined as PSA outcome). RESULTS: The relative risk (RR) of PSA failure in low-risk patients (stage T1c, T2a and PSA level < or =10 ng/mL and Gleason score < or =6) treated using RT, implant plus androgen deprivation therapy, or implant therapy was 1.1 (95% confidence interval [CI], 0.5-2.7), 0.5 (95% CI, 0.1-1.9), and 1.1 (95% CI, 0.3-3.6), respectively, compared with those patients treated with RP. The RRs of PSA failure in the intermediate-risk patients (stage T2b or Gleason score of 7 or PSA level >10 and < or =20 ng/mL) and high-risk patients (stage T2c or PSA level >20 ng/mL or Gleason score > or =8) treated with implant compared with RP were 3.1 (95% CI, 1.5-6.1) and 3.0 (95% CI, 1.8-5.0), respectively. The addition of androgen deprivation to implant therapy did not improve PSA outcome in high-risk patients but resulted in a PSA outcome that was not statistically different compared with the results obtained using RP or RT in intermediate-risk patients. These results were unchanged when patients were stratified using the traditional rankings of biopsy Gleason scores of 2 through 4 vs 5 through 6 vs 7 vs 8 through 10. CONCLUSIONS: Low-risk patients had estimates of 5-year PSA outcome after treatment with RP, RT, or implant with or without neoadjuvant androgen deprivation that were not statistically different, whereas intermediate- and high-risk patients treated with RP or RT did better then those treated by implant. Prospective randomized trials are needed to verify these findings.

Calculated prostate cancer volume greater than 4.0 cm3 identifies patients with localized prostate cancer who have a poor prognosis following radical prostatectomy or external-beam radiation therapy.

PURPOSE: Patients with palpable extraprostatic disease (T3) have a poor prostate-specific antigen (PSA) failure-free (bNED) survival rate after radical prostatectomy (RP) or external-beam radiation therapy (RT). This study was performed to validate or refute the prognostic value of the previously defined calculated prostate cancer volume (cV(Ca)). PATIENTS AND METHODS: For patients with clinically localized disease (T1c,2), a Cox regression multivariable analysis was used to assess the ability of the cV(Ca) value to predict time to posttherapy PSA failure following RP or RT. RESULTS: The cV(Ca) value was a significant predictor (P < or = .0005) of time to posttherapy PSA failure in both an RP and RT data set independent of the one used to derive the cV(Ca)-based clinical staging system. In both RP- and RT-managed patients, estimates of 3-year bNED survival were not statistically different for patients with either T1c,2 disease and a cV(Ca) greater than 4.0 cm3 (RP, 27%; RT, 18%) or T3 disease (RP, 37%; RT, 34%). Despite pathologic T2 disease, the 3-year estimate of bNED survival was at most 51% in RP-managed patients with T1c,2 disease and cV(Ca) greater than 4.0 cm3. CONCLUSION: A cV(Ca) greater than 4.0 cm3 identified patients with T1c.2 disease whose bNED survival was poor after RT or RP despite pathologic T2 disease that suggests the presence of occult micrometastatic disease in many of these patients. Prospective randomized trials to evaluate the impact on survival of adjuvant systemic therapy in these high-risk patients are justified.

Radiation-associated morbidity in patients undergoing small-field external beam irradiation for prostate cancer.

PURPOSE: To quantify complication rates after small-field external beam irradiation for adenocarcinoma of the prostate in a uniformly treated patient population with long follow-up using a simple tool designed to identify subtle treatment-related side effects; and to identify clinical and technical variables associated with increased morbidity after irradiation. METHODS AND MATERIALS: A total of 441 patients with nonmetastatic adenocarcinoma of the prostate treated at the Joint Center for Radiation Therapy between 1985 and 1989 were eligible for analysis. Gastrointestinal, genitourinary, and sexual function were assessed retrospectively using a patient self-scoring, five-grade toxicity scale. Seven clinical and 15 technical variables were recorded for each patient. The association between the clinical and technical variables and rectal, bladder, and sexual side effects was examined. The 375 patients who received small-field (<12.5 x 12.5-cm) external beam irradiation via a four-field box on a 6-MV (n = 74, or 20% of patients), 8-MV (n = 140, or 37%), or 15-MV (n = 161, or 43%) linear accelerator form the basis for the study. Ninety-one percent of patients received treatment with 1.8-2.0 Gy fractions to a delivered dose of at least 66 Gy. Follow-up was complete through 62 months in living patients, with five (1%) of the entire group lost to follow-up. RESULTS: A total of 137 of 354 evaluable patients (39%) reported rectal complications after treatment; however, 20 patients(6%) had heme-positive stools as their only symptom and 66 (19%) had mild symptoms not requiring treatment. Only 14% of the entire group required intervention. Of 356 patients, 117 (33%) evaluable for bladder complications developed genitourinary changes: In 14 patients (4%) asymptomatic hematuria occurred, 71 (20%) had mild symptoms not requiring treatment, and 32 (9%) required treatment. Of the 171 patients who were potent prior to radiation, 106 (62%) reported impotence after treatment. No statistically significant association was identified between any clinical or technical variables (including machine energy) assessed and complications. CONCLUSIONS: In this retrospective review, treatment-related bowel and bladder side effects were not identified in the majority of patients despite the use of a grading system designed to identify subtle changes. Impotence, however, was common. Although pretreatment clinical characteristics varied among patients, they could not be used to predict the subsequent development of complications. The only treatment-related characteristic that varied in this study was machine energy, which did not correlate with complications.

Patient-reported symptoms after primary therapy for early prostate cancer: results of a prospective cohort study.

PURPOSE: To assess complications of therapy for early (nonmetastatic) prostate cancer. PATIENTS AND METHODS: A prospective study of a cohort of 279 men who sought treatment advice and completed required pretreatment forms. The measures were self-reported patient symptoms and other measures of quality of life before therapy and at 3 and 12 months afterward. RESULTS: Bowel and bladder symptoms were uncommon pretreatment. Patients frequently reported irritative bowel and bladder symptoms at 3 months after radiotherapy, although these subsided somewhat at 12 months. Substantial ("a lot") urinary incontinence and wearing of absorptive pads were reported by 11% and 35% at 12 months after surgery and varied little by age. Incontinence occurred after radiotherapy infrequently, and only in men more than 65 years old. Inadequate erections, present in one third of men pretreatment, were nearly universal at 3 months after surgery, although some improvement, primarily in men under 65 years of age, was evident at 12 months. Sexual dysfunction after radiotherapy increased less but continually through 12 months, suggesting that observed treatment-related differences would decline with further follow-up. CONCLUSION: External-beam radiotherapy of early prostate cancer is followed by bowel and bladder irritability, by increasingly severe sexual dysfunction and, in men aged more than 65 years, occasional urinary incontinence. Greater sexual dysfunction and urinary incontinence occur in the year following radical prostatectomy. These postsurgical complication rates from patient questionnaires are greater than have been reported in other treatment series and confirm the results of two retrospective studies of patient-reported complications.

Treatment outcome after tangential radiation therapy without axillary dissection in patients with early-stage breast cancer and clinically negative axillary nodes.

PURPOSE: To determine the risk of nodal failure in patients with early-stage invasive breast cancer with clinically negative axillary lymph nodes treated with two-field tangential breast irradiation alone, without axillary lymph node dissection or use of a third nodal field. METHODS AND MATERIALS: Between 1988 and 1993, 986 evaluable women with clinical Stage I or II invasive breast cancer were treated with breast-conserving surgery and radiation therapy. Of these, 92 patients with clinically negative nodes received tangential breast irradiation (median dose, 45 Gy) followed by a boost, without axillary dissection. The median age was 69 years (range, 49-87). Eighty-three percent had T1 tumors. Fifty-three patients received tamoxifen, 1 received chemotherapy, and 2 patients received both. Median follow-up time for the 79 survivors was 50 months (range, 15-96). Three patients (3%) have been lost to follow-up after 20-32 months. RESULTS: No isolated regional nodal failures were identified. Two patients developed recurrence in the breast only (one of whom had a single positive axillary node found pathologically after mastectomy). One patient developed simultaneous local and distant failures, and six patients developed distant failures only. One patient developed a contralateral ductal carcinoma in situ, and two patients developed other cancers. CONCLUSION: Among a group of 92 patients with early-stage breast cancer (typically T1 and also typically elderly) treated with tangential breast irradiation alone without axillary dissection, with or without systemic therapy, there were no isolated axillary or supraclavicular regional failures. These results suggest that it is feasible to treat selected clinically node-negative patients with tangential fields alone. Prospective studies of this approach are warranted.

Locally advanced rectal carcinoma: pelvic control and morbidity following preoperative radiation therapy, resection, and intraoperative radiation therapy.

PURPOSE: To determine the impact of intraoperative radiation therapy (IORT) combined with preoperative external beam irradiation and surgical resection in patients with locally advanced, unresectable rectal carcinoma. METHODS AND MATERIALS: Between 1982 and 1993, 40 patients with locally advanced colorectal cancer unresectable at initial presentation were treated with preoperative external beam radiation therapy (median dose 50.4 Gy). Thirty patients received concurrent 5-fluorouracil. Twenty-seven patients had primary tumors and 13 had recurrent disease; 1 patient had a solitary hepatic metastasis at the time of surgery. Four to 6 weeks after radiation, surgical resection was undertaken, and if microscopic or gross residual disease was encountered, IORT was delivered to the tumor bed. Patients with an unevaluable or high-risk margin were also considered for IORT. IORT was delivered through a dedicated 300-kVp orthovoltage unit. The median dose of IORT was 12.5 Gy (range 8-20). The dose was typically prescribed to a depth of 1-2 cm. The median follow-up was 33 months (range 5-100). RESULTS: Thirty-three patients were able to undergo a curative resection (83%). Five patients had gross residual disease despite aggressive surgery. Seven patients did not receive IORT: six because of clear margins, and one with gross disease that could not be treated for technical reasons. The remainder of the patients (26) received IORT to the site of pelvic adherence. The crude local control rates for patients following complete resection with negative margins were 92% for patients treated with IORT and 33% for patients without IORT. IORT was ineffective for gross residual disease. Pelvic control was none of four in this setting. The crude local control rate of patients with primary cancer was 73% (16 of 22), as opposed to 27% (3 of 11) for these with recurrent cancer. The 5-year actuarial overall survival and local control rates for patients undergoing gross complete resection and IORT were 64% and 75%, respectively. Seventeen of the 26 patients (65%) who received IORT experienced pelvic complications, as opposed to two patients (28%) who did not receive IORT. The incidence of complications was similar in the patients with primary versus recurrent disease. All cases were successfully treated with the placement of a posterior thigh myocutaneous flap. Of note, no pelvic osteoradionecrosis was seen in this series. CONCLUSION: Patients with locally advanced carcinoma of the rectum were aggressively treated with combined modality therapy consisting of preoperative external beam radiotherapy, surgery, and IORT. The pelvic control rate was 82% for patients with minimal residual disease. IORT failed to control gross residual disease. The incidence of pelvic wound healing problems was 65% in this series; however, a reconstructive procedure which replaced irradiated tissue with a vascularized myocutaneous flap was successful in treating this complication. We believe that IORT has therapeutic merit in the treatment of locally advanced rectal cancer, particularly in the setting of minimal residual disease.

Complications after treatment with external-beam irradiation in early-stage prostate cancer patients: a prospective multiinstitutional outcomes study.

PURPOSE: To use data from a prospective quality-of-life study to assess differences in disease-specific and general health-related quality-of-life changes after treatment with different external-beam irradiation techniques for prostate cancer. PATIENTS AND METHODS: Patients were divided into three groups based on their pretreatment field size and planning technique: whole pelvis, small field, or conformal. Measures of bowel, urinary, and sexual function and of global health-related quality-of-life parameters (from the Health Survey Short Form [SF-36] and the Profile of Mood States [POMS]) were obtained from self-report questionnaires completed before initiation of therapy and at 3 and 12 months after therapy. RESULTS: Irritative gastrointestinal and genitourinary side effects were frequent 3 months after treatment, but were substantially improved at 12 months. Sexual dysfunction increased steadily over the study period. The POMS and the SF-36 did not demonstrate significant changes over time. Despite small patient numbers, we found trends in favor of conformal therapy across several symptom measures, including sexual function. In the fatigue, energy, and vigor subscales, patients who received whole-pelvis treatment fared significantly worse than those in the other two groups. CONCLUSION: Prospective, detailed data from a feasibility study allowed us to assess the effect of technique on quality of life following external-beam irradiation. Although limited by the small planned sample size, these results suggest that smaller radiation fields limit treatment-related complications, including, unexpectedly, sexual dysfunction. However, confirmation in a larger study is necessary.

A numerical simulation of organ motion and daily setup uncertainties: implications for radiation therapy.

PURPOSE: In radiotherapy planning, the clinical target volume (CTV) is typically enlarged to create a planning target volume (PTV) that accounts for uncertainties due to internal organ and patient motion as well as setup error. Margin size clearly determines the volume of normal tissue irradiated, yet in practice it is often given a set value in accordance with a clinical precedent from which variations are rare. The (CTV/PTV) formalism does not account for critical structure dose. We present a numerical simulation to assess (CTV) coverage and critical organ dose as a function of treatment margins in the presence of organ motion and physical setup errors. An application of the model to the treatment of prostate cancer is presented, but the method is applicable to any site where normal tissue tolerance is a dose-limiting factor. METHODS AND MATERIALS: A Monte Carlo approach was used to simulate the cumulative effect of variation in overall tumor position, for individual treatment fractions, relative to a fixed distribution of dose. Distributions of potential dose-volume histograms (DVHs), for both tumor and normal tissues, are determined that fully quantify the stochastic nature of radiotherapy delivery. We introduce the concept of Probability of Prescription Dose (PoPD) isosurfaces as a tool for treatment plan optimization. Outcomes resulting from current treatment planning methods are compared with proposed techniques for treatment optimization. The standard planning technique of relatively large uniform margins applied to the CTV, in the beam's eye view (BEV), was compared with three other treatment strategies: (a) reduced uniform margins, (b) nonuniform margins adjusted to maximize normal tissue sparing, and (c) a reduced margin plan in which nonuniform fluence profiles were introduced to compensate for potential areas of reduced dose. RESULTS: Results based on 100 simulated full course treatments indicate that a 10 mm CTV to PTV margin, combined with an additional 5 mm dosimetric margin, provides adequate CTV coverage in the presence of known treatment uncertainties. Nonuniform margins can be employed to reduce dose delivered to normal tissues while preserving CTV coverage. Nonuniform fluence profiles can also be used to further reduce dose delivered to normal tissues, though this strategy does result in higher dose levels delivered to a small volume of the CTV and normal tissues. CONCLUSIONS: Monte Carlo-based treatment simulation is an effective means of assessing the impact of organ motion and daily setup error on dose delivery via external beam radiation therapy. Probability of Prescription Dose (PoPD) isosurfaces are a useful tool for the determination of nonuniform beam margins that reduce dose delivered to critical organs while preserving CTV dose coverage. Nonuniform fluence profiles can further alter critical organ dose with potential therapeutic benefits. Clinical consequences of this latter approach can only be assessed via clinical trials.

Analysis of prostate and seminal vesicle motion: implications for treatment planning.

PURPOSE: To quantify prostate and seminal vesicle positional changes (target motion) between treatment planning and delivery, and to identify the factors contributing to target motion. METHODS AND MATERIALS: Thirty patients with adenocarcinoma of the prostate were prospectively evaluated by analyzing two sequential planning computerized tomography (CT) scans (S1, obtained prior to treatment, and S2, obtained during the fourth week of treatment) for each patient. All anatomical volumes of interest (soft tissue and bony) were reconstructed from transverse CT images and projected onto anterior and lateral beam's-eye view projections. Positional changes between S1 and S2 were eliminated by applying a rigid body translation and rotation. Target motion was then measured by recording the positional change between S1 and S2 at the edges (right, left, superior, inferior). Potential correlation of target motion with bladder volume, rectal volume, and rectal diameter changes were evaluated by linear regression analysis. RESULTS: Neither the prostate nor seminal vesicles remained fixed with respect to bony anatomy between S1 and S2. The distribution of positional changes were generally small (< 0.5 cm), but maximum displacements of 1.5-2.2 cm did occur, particularly in the lateral view. In this study, bladder volume changes between the scans were small and did not correlate with target motion (P = 0.67). Both rectal volume and rectal diameter changes correlated with target motion for both the prostate (p = 0.004 and 0.005, respectively) and seminal vesicles (p < 0.001 and < 0.001, respectively). However, neither the initial rectal volume nor the initial rectal diameter could be used to predict subsequent target motion when evaluated either singly or as part of a multiple regression model. CONCLUSIONS: Target motion occurs during the course of treatment planning and delivery and should be considered when designing conformal radiation fields. Although the target position at the time of planning CT may differ substantially from the mean treatment position, target motion cannot be predicted by evaluating simply measured parameters from a single scan, or double scan sequence.