Faculty Publications

PURPOSE: The aims of this study were to evaluate the factors contributing to errors in the treatment of cancer patients undergoing radiation therapy and to develop a grading system that allows for the comparison of errors. METHODS: Deviations in the prescribed treatment of patients undergoing radiation therapy were collected during 2003 in the Department of Radiation Oncology at Fox Chase Cancer Center. The deviations were classified according to responsibility as follows: therapist, physician, dosimetrist, physicist, machine, or all. The deviations in treatment were graded on an increasing scale ranging from 1 to 4, according to severity. Error analysis was made corresponding to treatment machine, therapist, dosimetrist, type of treatment, palliative or definitive treatment, type of cancer, time of occurrence, and machine census at the time of occurrence. RESULTS: A total of 33,757 patient treatments were delivered on 4 linear accelerators with 3,646 dose calculations performed by the physics staff during 2003. All treatments, both intensity-modulated radiation therapy and conventional therapy, were considered in this analysis. A total of 25 quality control (QC) events occurred during the study period. The crude error rate for therapists was 0.041%, and the crude error rate for dosimetrists and physicists was 0.22%. There were 17 level I errors (2 machine, 1 block mismounting, 4 dosimetrist, 1 all, and 9 therapist), 5 level II errors (3 dosimetrist, 1 therapist and dosimetrist, and 1 therapist), and 3 level III errors (3 therapist). Fifteen of the 25 QC events and 8 of 13 therapist events occurred after 12 pm. A correlation did not exist between the time of occurrence and machine census at the time of the QC events. However, more level I events occurred after 12 pm than before 12 pm. CONCLUSIONS: A review of QC events occurring during the course of radiation treatments allowed a change in the process of care to prevent the occurrence of some QC events. The QC event rate experienced by the department compares favorably with published results from similar academic centers. The periodic review of QC events allows for the opportunity to identify processes that can be adapted to reduce the occurrence of QC events in the future.

Purpose MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. Patients and Methods Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). Conclusion Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.

Purpose: We previously reported that protein kinase A type I (PKA(R1 alpha)) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy (RT) +/- short-term androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKA(R1 alpha) overexpression. Experimental Design: There were 313 cases in the RTOG 92-02 study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKA(R1 alpha) staining intensity was quantified manually and by image analysis. Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models. Results: The expression levels of PKA(R1 alpha), determined by manual and image analysis, were strongly correlated (P < 0.0001). In the multivariate analyses, manual-quantified and image analysis-quantified PKA(R1 alpha) staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P <= 0.01). Furthermore, the benefit of long-term AD over STAD was much less when PKA(R1 alpha) expression was high. Conclusions: PKA(R1 alpha) overexpression has been shown in two RTOG trials to be associated with an increased risk of failure after AD + RT. In this series of contemporary high-risk patients, PKA(R1 alpha) overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKA(R1 alpha) knockdown strategy. (Clin Cancer Res 2009;15(17):5478-84)

This study examined moderating effects of age on longitudinal associations among quality of life (QOL) and its demographic (e.g., age), clinical [e.g., prostate-specific antigen (PSA) level], and affective and cognitive predictors (i.e., distress, worries about recurrence, decisional regret, subjective life expectancy) in prostate cancer patients treated with external beam radiation (N = 391). Demographic and clinical characteristics were assessed at diagnosis, affective and cognitive variables at 6 months after diagnosis, and QOL at 12 months after diagnosis. Multiple-group analyses showed that among younger patients (< or =68 years old, n = 199), lower levels of decisional regret were associated with better functional QOL, and lower Gleason scores and PSA levels were associated with lower levels of distress and longer expected survival time, respectively. Being employed was related to higher levels of functional QOL and frequent worries about recurrence. Among older patients (>68 years old, n = 192), lower levels of distress were associated with higher levels of functional QOL, and longer expected survival time was associated with better functional and physical QOL.

Purpose: To compare the toxicity and biochemical outcomes of intensity-modulated radiation therapy (IMRT) and I-125 tran perineal permanent prostate seed implant (1251) for patients with low-risk prostate cancer. Methods and Materials: Between 1998 and 2004, a total of 374 low-risk patients (prostate-specific antigen < 10 ng/ ml, T1c-T2b, Gleason score of 6 or less, and no neoadjuvant hormones) were treated at Fox Chase Cancer Center (216 IMRT and 158 I-125 patients). Median follow-up was 43 months for IMRT and 48 months for I-125. The IMRT prescription dose ranged from 74-78 Gy, and I-125 prescription was 145 Gy. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicity was recorded by using a modified Radiation Therapy Oncology Group scale. Freedom from biochemical failure was defined by using the Phoenix definition (prostate-specific antigen nadir + 2.0 ng/ml). Results: Patients treated by using IMRT were more likely to be older and have a higher baseline American Urological Association symptom index score, history of previous transurethral resection of the prostate, and larger prostate volumes. On multivariate analysis, IMRT was an independent predictor of lower acute and late Grade 2 or higher GU toxicity and late Grade 2 or higher GI toxicity. Three-year actuarial estimates of late Grade 2 or higher toxicity were 2.4% for GI and 3.5% for GU by using IMRT compared with 7.7% for GI and 19.2% for GU for I-125, respectively. Four-year actuarial estimates of freedom from biochemical failure were 99.5% for IMRT and 93.5% for I-125 (p = 0.09). Conclusions: The IMRT and I-125 produce similar outcomes, although IMRT appears to have less acute and late toxicity. @ 2008 Elsevier Inc.

BACKGROUND. The American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure (BF) incorporates backdating, resulting in an artificial flattening of Kaplan-Meier curves and overly favorable estimates when follow-up is short. The nadir + 2 ng/mL (Nadir + 2; Phoenix) definition reduces these artifacts. The objective of the current study was to compare ASTRO and Phoenix BF estimates as determinants of distant metastasis (L)M), cause-specific mortality (CSM), and overall mortality (OM). METHODS. A total of 1831 patients with T1-4N0M0 prostate cancer were treated with external beam radiotherapy (RT) using conventional or three-dimensional conformal methods to at least 60 grays (Gy). The median follow-up was 71. months and the median RT dose was 72 Gy (range, 60-79 Gy). Cox regression models incorporating BF as a time-dependent covariate were used for both univariate and multivariate analyses. Other covariates included in the analyses were T classification, Gleason score, neoadjuvant/adjuvant androgen deprivation, age, RT dose, and pretreatment prostate-specific antigen. RESULTS. BF was observed in 389 men (21%) using the Phoenix definition and 460 men (25%) using the ASTRO definition. DM was observed in 84 patients (5%), 48 patients (3%) patients died of prostate cancer, and 404 patients (22%) died of any cause. The Phoenix definition of BF was found to be a significant predictor of DM, CSM, and OM, after controlling for other significant covariates. The ASTRO definition was found to be associated with CSM and DM, but not OM. CONCLUSIONS. The Phoenix definition of BF is a more robust determinant of patient outcome compared with the ASTRO definition. The correlation with mortality, including OM, and the independence of this correlation from the use of neoadjuvant/adjuvant androgen deprivation, supports the use of Nadir + 2 in prostate cancer clinical trials of RT with or without androgen deprivation.

PURPOSE: Few biochemical parameters have been related to mortality. The present study examined the clinical utility of the interval to biochemical failure (IBF) as a prognostic factor for distant metastasis (DM) and prostate cancer-specific mortality (PCSM) after radiotherapy. METHODS AND MATERIALS: The study group consisted of 211 T1c-T3Nx-N0M0 patients who had experienced BF among 1,174 men treated with three-dimensional conformal radiotherapy alone. Biochemical failure was defined as a post-treatment prostate-specific antigen (PSA) level of at, or greater than, the PSA nadir plus 2 ng/mL. Cox proportional hazards modeling was used to identify independent predictors of DM and PCSM on multivariate analysis. RESULTS: An IBF of <18 months was independently predictive for DM (p = 0.008), as was a Gleason score of 7-10 (p = 0.0005), PSA nadir >or=2 ng/mL (p = 0.04), and decreasing radiation dose (p = 0.02) on multivariate analysis, including increasing pretreatment PSA level, PSA nadir >or=2.5 ng/mL, PSA doubling time of <3 months, and Stage T3 disease. An IBF of <18 months was the only predictor of PCSM (p = 0.0003) in the same model. The actuarial 5-year DM rate for an IBF of <18 vs. >or=18 months was 52% vs. 20% (p < 0.0001), and the actuarial PCSM rate was 36% vs. 6%, respectively (p = 0.0001). CONCLUSIONS: The IBF is an important descriptor of the PSA kinetics after radiotherapy to identify men at high risk of clinical failure and death. A IBF of <18 months could aid in selecting men for early, aggressive salvage therapy or participation in a clinical trial.