Thomas J. Pugh

Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases

PURPOSE To evaluate the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with one to three lung metastases. PATIENTS AND METHODS Patients with one to three lung metastases with cumulative maximum tumor diameter smaller than 7 cm were enrolled and treated on a multi-institutional phase I/II clinical trial in which they received SBRT delivered in 3 fractions. In phase I, the total dose was safely escalated from 48 to 60 Gy. The phase II dose was 60 Gy. The primary end point was local control. Lesions with at least 6 months of radiographic follow-up were considered assessable for local control. Secondary end points included toxicity and survival. RESULTS Thirty-eight patients with 63 lesions were enrolled and treated at three participating institutions. Seventy-one percent had received at least one prior systemic regimen for metastatic disease and 34% had received at least two prior regimens (range, zero to five). Two patients had local recurrence after prior surgical resection. There was no grade 4 toxicity. The incidence of any grade 3 toxicity was 8% (three of 38). Symptomatic pneumonitis occurred in one patient (2.6%). Fifty lesions were assessable for local control. Median follow-up for assessable lesions was 15.4 months (range, 6 to 48 months). The median gross tumor volume was 4.2 mL (range, 0.2 to 52.3 mL). Actuarial local control at one and two years after SBRT was 100% and 96%, respectively. Local progression occurred in one patient, 13 months after SBRT. Median survival was 19 months. CONCLUSION This multi-institutional phase I/II trial demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.

Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

OBJECTIVE To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. METHODS AND MATERIALS Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. RESULTS 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). CONCLUSIONS Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen.

Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer

PURPOSE There is growing interest in the role of local therapies, including external beam radiotherapy (RT), for men with metastatic prostate cancer (mPCa). We used the National Cancer Database (NCDB) to evaluate the overall survival (OS) of men with mPCa treated with androgen deprivation (ADT) with and without prostate RT. METHODS The NCDB was queried for men with newly diagnosed mPCa, all treated with ADT, with complete datasets for RT, surgery, prostate-specific antigen (PSA) level, Gleason score, and Charlson-Deyo comorbidity score. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS From 2004 to 2012, 6,382 men with mPCa were identified, including 538 (8.4%) receiving prostate RT. At a median follow-up of 5.1 years, the addition of prostate RT to ADT was associated with improved OS on univariate (P < .001) and multivariate analysis (hazard ratio, 0.624; 95% CI, 0.551 to 0.706; P < .001) adjusted for age, year, race, comorbidity score, PSA level, Gleason score, T stage, N stage, chemotherapy administration, treating facility, and insurance status. Propensity score analysis with matched baseline characteristics demonstrated superior median (55 v 37 months) and 5-year OS (49% v 33%) with prostate RT plus ADT compared with ADT alone (P < .001). Landmark analyses limited to long-term survivors of ≥1, ≥3, and ≥5 years demonstrated improved OS with prostate RT in all subsets (all P < .05). Secondary analyses comparing the survival outcomes for patients treated with therapeutic dose RT plus ADT versus prostatectomy plus ADT during the same time interval demonstrated no significant differences in OS, whereas both therapies were superior to ADT alone. CONCLUSION In this large contemporary analysis, men with mPCa receiving prostate RT and ADT lived substantially longer than men treated with ADT alone. Prospective trials evaluating local therapies for mPCa are warranted.

Is androgen deprivation therapy necessary in all intermediate-risk prostate cancer patients treated in the dose escalation era?

PURPOSE The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). METHODS Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. RESULTS Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). CONCLUSIONS Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF.

Declining use of brachytherapy for the treatment of prostate cancer

PURPOSE To analyze the recent trends in the utilization of external beam radiation therapy (EBRT) and brachytherapy (BT) for the treatment of prostate cancer. METHODS AND MATERIALS Using the Surveillance, Epidemiology, and End Results (SEER) database, information was obtained for all patients diagnosed with localized prostate adenocarcinoma between 2004 and 2009 who were treated with radiation as local therapy. We evaluated the utilization of BT, EBRT, and combination BT+EBRT by the year of diagnosis and performed a multivariable analysis to determine the predictors of BT as treatment choice. RESULTS Between 2004 and 2009, EBRT monotherapy use increased from 55.8% to 62.0%, whereas all BT use correspondingly decreased from 44.2% to 38.0% (BT-only use decreased from 30.4% to 25.6%, whereas BT+EBRT use decreased from 13.8% to 12.3%). The decline of BT utilization differed by patient race, SEER registry, median county income, and National Comprehensive Cancer Network risk categorization (all p<0.001), but not by patient age (p=0.763) or marital status (p=0.193). Multivariable analysis found that age, race, marital status, SEER registry, median county income, and National Comprehensive Cancer Network risk category were independent predictors of BT as treatment choice (all p<0.001). Moreover, after controlling for all available patient and tumor characteristics, there was decreasing utilization of BT with increasing year of diagnosis (odds ratio for BT=0.920, 95% confidence interval: 0.911-0.929, p<0.001). CONCLUSIONS Our analysis reveals decreasing utilization of BT for prostate cancer. This finding has significant implications in terms of national health care expenditure.

Long‐term outcomes for men with high‐risk prostate cancer treated definitively with external beam radiotherapy with or without androgen deprivation

Men with high‐risk prostate cancer are often thought to have very poor outcomes in terms of disease control and survival even after definitive treatment. However, results after external beam radiotherapy have improved significantly through dose escalation and the use of androgen deprivation therapy (ADT). This report describes long‐term findings after low‐dose (< 75.6 Gy) or high‐dose (≥ 75.6 Gy) external beam radiation, with or without ADT.

Cardiac mortality in patients with stage I and II diffuse large B-cell lymphoma treated with and without radiation: a surveillance, epidemiology, and end-results analysis.

PURPOSE Standard therapy for stage I and II diffuse large B-cell lymphoma consists of combined modality therapy with anthracycline-based chemotherapy, anti-CD20 antibody, and radiation therapy (RT). Curative approaches without RT typically utilize more intensive and/or protracted chemotherapy schedules. Anthracycline-based chemotherapy regimens are associated with a dose-dependent risk of left ventricular systolic dysfunction. We hypothesize that patients treated without RT, i.e., those who are treated with greater total chemotherapy cycles and hence cumulative anthracycline exposure, are at increased risk of cardiac mortality. METHODS AND MATERIALS The rate of cardiac-specific mortality (CSM) was analyzed in patients with stage I and II diffuse large B-cell lymphoma diagnosed between 1988 and 2004 by querying the National Cancer Institute Surveillance, Epidemiology, and End-Results database. Analyzable data included gender, age, race, stage, presence of extranodal disease, and RT administration. RESULTS A total of 15,454 patients met selection criteria; 6,021 (39%) patients received RT. The median follow-up was 36 months (range, 6-180 months). The median age was 64 years. The actuarial incidence rates of CSM at 5, 10, and 15 years were 4.3%, 9.0%, and 13.8%, respectively, in patients treated with RT vs. 5.9%, 10.8% and 16.1%, respectively, in patients treated without RT (p < 0.0001; hazard ratio, 1.35; 95% confidence interval [CI]: 1.16-1.56). The increase in cardiac deaths for patients treated without RT persisted throughout the follow-up period. On multivariate analysis, treatment without RT remained independently associated with an increased risk of CSM (Cox hazard ratio, 1.32; 95% CI: 1.13-1.54; p = 0.0005). CONCLUSIONS Increased anthracycline exposure in patients treated only with chemotherapy regimens may result in an increase in cardiac deaths, detectable only through analysis of large sample sizes. Confirmatory evaluation through meta-analysis of randomized data and design of large prospective trials is warranted.

Endorectal magnetic resonance imaging for predicting pathologic T3 disease in Gleason score 7 prostate cancer: Implications for prostate brachytherapy

PURPOSE To determine the ability of endorectal magnetic resonance imaging (erMRI) and other pretreatment factors to predict the presence and extent of extraprostatic extension (EPE) in men with Gleason score (GS) 7 prostate cancer. METHODS AND MATERIALS We included patients with clinical stage T1c-T2c, GS=7 (3+4 or 4+3), and prostate-specific antigen (PSA) <10ng/mL who underwent pre-prostatectomy erMRI. We compared pathologic EPE findings with pretreatment factors. RESULTS One hundred seventy-one men were eligible for inclusion. Pretreatment characteristics were: median age=60 years (42-76); median PSA 4.9ng/mL (0.4-9.9); GS 3+4=61%; T1c=51%; T2a=25%; T2b=21%; T2c=3%; ≥50% positive cores=46%; EPE-positive (EPE+) erMRI=28%. Thirty-three percent had pathologic EPE. Increasing T-stage (p<0.0001) and EPE+ erMRI (p<0.0001) were significant predictors of pathologic EPE, whereas GS (4+3 vs. 3+4) (p=0.14), percentage of positive core biopsies (p=0.15), and pretreatment PSA (p=0.41) were not. Median EPE distance was 1.75mm (range, <1-15mm). The rates of EPE >5mm and EPE >3mm were 11% and 15%, respectively. The odds ratios for erMRI detection of any EPE and of EPE >5mm were 3.06 and 3.75, respectively. CONCLUSIONS T-stage and EPE+ erMRI predict pathologic EPE in men with GS 7 prostate cancer. The ability of erMRI to detect EPE increases with increasing EPE distance. These findings may be useful in patient selection for prostate brachytherapy monotherapy.

Phase I trial of bortezomib and concurrent external beam radiation in patients with advanced solid malignancies

PURPOSE To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. METHODS AND MATERIALS An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m(2), 1.3 mg/m(2), and 1.6 mg/m(2)/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, defined as any grade 4 hematologic toxicity, any grade ≥3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for ≥2 weeks. RESULTS A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m(2). One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). CONCLUSIONS The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m(2) is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m(2).

Outcomes after prostate brachytherapy are even better than predicted

During the first 3 years after prostate cancer treatment with radiation therapy, benign prostate‐specific antigen (PSA) bounces are difficult for clinicians to distinguish from a biochemical recurrence, which can result in unnecessary interventions and erroneous predictions of outcomes. The objective of this study was to evaluate a commonly used PSA failure definition in a multinational, multi‐institutional study after monotherapy with prostate brachytherapy.