Clair J. Beard

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.

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 beams-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.

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.

Testicular Cancer Survivorship: Research Strategies and Recommendations

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer.

Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients.

PURPOSE A retrospective study was performed to define clinical characteristics and therapeutic outcome for patients with large-cell and immunoblastic lymphoma of the mediastinum. PATIENTS AND METHODS Fifty-seven patients who presented with primary, mediastinal large-cell and immunoblastic lymphoma were retrospectively studied to determine initial sites of disease, radiologic characteristics, treatment, outcome, and factors that have prognostic significance for progression-free and overall survival. RESULTS Fifty-six of the 57 patients had disease that was confined to sites above the diaphragm. Bulky disease and extensive intrathoracic infiltration were common in these patients. All patients were treated with intensive chemotherapy regimens, and 44% of patients received chest irradiation. The overall 5-year survival by Kaplan-Meier estimation was 50% with a freedom-from-relapse rate of 45%. Predictors of disease relapse after chemotherapy included the presence of a pleural effusion (P = .015), a number of involved extranodal sites (P < .01), and a lactic dehydrogenase (LDH) ratio > 3.0 (LDH value/upper limit of assay; P = .04) as well as an incomplete treatment response as evidenced by residual mass on chest radiograph (P = .02) or persistent gallium 67 avidity (P = .01) after chemotherapy. Predictors of decreased survival included the presence of pleural effusion (P = .001), the number of involved extranodal sites (P = .022), and a positive posttreatment 67Ga scan (P = .027). CONCLUSION Patients with primary mediastinal large-cell and immunoblastic lymphoma have an approximate 50% chance of surviving disease-free after initial therapy. The presence of pleural effusion at presentation was associated with an extremely poor outcome. Bulk disease per se was a negative predictive factor only in patients without pleural effusions when compared with patients who did not have bulk disease. In addition, all patients with involvement of two or more extranodal sites relapsed when treated with standard chemotherapy.

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 beams 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.

Equivalent biochemical failure-free survival after external beam radiation therapy or radical prostatectomy in patients with a pretreatment prostate specific antigen of 4–20 ng/ml

PURPOSE Biochemical failure-free survival stratified by the pretreatment prostate-specific antigen (PSA) and biopsy Gleason score (bGl) is determined for prostate cancer patients managed definitively with external beam radiation therapy or radical retropubic prostatectomy. METHODS AND MATERIALS A Cox regression multivariable analysis evaluating the variables of PSA, bGl, and clinical stage was used to evaluate the end point of time to PSA failure in 867 and 757 consecutive prostate cancer patients managed definitively with external beam radiation therapy or radical retropubic prostatectomy, respectively. PSA failure-free survival was determined using Kaplan-Meier analysis. Comparisons were made using the log rank test. RESULTS The pretreatment PSA, bGl, and clinical stage (T3,4 vs. T1,T2) were found to be independent predictors of time to post-treatment PSA failure for both surgically and radiation managed patients using Cox regression multivariable analysis. Patients with a pretreatment PSA of > 4 ng/ml and < or = 20 ng/ml could be classified into risk groups for time to post-therapy PSA failure: low = PSA > 4-10 ng/ml and bGl < or = 4; intermediate = PSA > 4-10 and bGl 5-7; or PSA > 10-20 ng/ml and bGl < or = 7; high = PSA > 4-20 ng/ml and bGl > or = 8. Two-year PSA failure-free survival for surgically managed and radiation-managed patients, respectively, were 98% vs. 92% (p = 0.45), 77% vs. 81% (p = 0.86), and 51% vs. 53% (p = 0.48) for patients at low, intermediate, and high risk for post-therapy PSA failure. CONCLUSIONS There was no statistical difference in the 2-year PSA failure-free survival for potentially curable patients managed definitively with surgery or radiation therapy when a retrospective comparison stratifying for the pretreatment PSA and bGl was performed.

Impact of the Percentage of Positive Prostate Cores on Prostate Cancer–Specific Mortality for Patients With Low or Favorable Intermediate-Risk Disease

PURPOSE We investigated whether pretreatment factors predicted time to prostate cancer-specific mortality (PCSM) after conventional-dose and conformal radiation therapy (CRT). PATIENTS AND METHODS Between 1988 and 2002, 421 patients with low (prostate-specific antigen [PSA] level < or = 10 ng/mL and biopsy Gleason score < or = 6) or favorable intermediate-risk (PSA > 10 to 15 ng/mL or biopsy Gleason score 3 + 4, but not both factors) disease underwent CRT (median dose, 70.4 Gy). Cox regression multivariable analysis was performed to determine whether the PSA level, Gleason score, T category, or the percentage of positive cores (% PC) predicted time to PCSM after CRT. After a median follow-up of 4.5 years, 117 (28%) patients have died. RESULTS The % PC was the only significant predictor (Cox P < or =.03). The relative risk of PCSM after CRT for patients with > or = 50% as compared with less than 50% PC was 10.4 (95% CI, 1.2 to 87; Cox P =.03), 6.1 (95% CI, 1.3 to 28.6; Cox P =.02), and 12.5 (95% CI, 1.5 to 107; Cox P =.02) in men with a PSA < or = 10 and Gleason score < or = 6, PSA < or = 10 and Gleason score < or = 7, and PSA < or = 15 and Gleason score < or = 6, respectively. By 5 years after CRT, 5% to 9% compared with less than 1% (log-rank P < or =.01) of these patients experienced PCSM if they had > or = 50% compared with less than 50% PC, respectively. CONCLUSION CRT dose-escalation techniques, the addition of hormonal therapy, or both should be considered in the management of patients with low or favorable intermediate-risk disease and > or = 50% PC.

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.

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.