J.M. Michalski

Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer

CONTEXT Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management. OBJECTIVE To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer. DESIGN, SETTING, AND PATIENTS Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 1(1/2) and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009. MAIN OUTCOME MEASURES The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival. RESULTS A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported. CONCLUSION Patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.

The role of overall treatment time in the outcome of radiotherapy of prostate cancer: An analysis of biochemical failure in 4839 men treated between 1987 and 1995

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

Biochemical and clinical significance of the posttreatment prostate-specific antigen bounce for prostate cancer patients treated with external beam radiation therapy alone: a multiinstitutional pooled analysis.

The posttreatment prostate‐specific antigen (PSA) bounce phenomenon has been recognized in at least 20% of all patients treated with radiation. The purpose of the current report was to determine if there was a difference in biochemical and clinical control between the bounce and nonbounce (NB) patients using pooled data on 4839 patients with T1‐2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions between 1986 and 1995.

Biochemical and clinical significance of the posttreatment prostate-specific antigen bounce for prostate cancer patients treated with external beam radiation therapy alone Presented at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Atlanta, GA, October 3–7, 2004.

The posttreatment prostate‐specific antigen (PSA) bounce phenomenon has been recognized in at least 20% of all patients treated with radiation. The purpose of the current report was to determine if there was a difference in biochemical and clinical control between the bounce and nonbounce (NB) patients using pooled data on 4839 patients with T1‐2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions between 1986 and 1995.

A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: Final results of radiation therapy oncology group phase 3 randomized trial NRG oncology RTOG 9902

PURPOSE Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

Early toxicity predicts long-term survival in high-grade glioma.

Background:Patients with high-grade gliomas are treated with surgery followed by chemoradiation. The risk factors and implications of neurological side effects are not known.Methods:Acute and late ⩾ grade 3 neurological toxicities (NTs) were analysed among 2761 patients from 14 RTOG trials accrued from 1983 to 2003. The association between acute and late toxicity was analysed using a stepwise logistic regression model. The association between the occurrence of acute NT and survival was analysed as an independent variable.Results:There were 2610 analysable patients (86% glioblastoma, 10% anaplastic astrocytoma). All received a systemic agent during radiation (83% chemotherapy, 17% biological agents). Median radiation dose was 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis, older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, poor mental status and twice-daily radiation were associated with increased acute NT. In a stepwise logistic regression model the occurrence of acute NT was significantly associated with late NT (OR=2.40; 95% CI=1.2–4.8; P=0.014). The occurrence of acute NT predicted poorer overall survival, independent of recursive partitioning analysis class (median 7.8 vs 11.8 months).Interpretation:Acute NT is significantly associated with both late NT and overall survival.

Clinical implementation of dose-volume histogram predictions for organs-at-risk in IMRT planning

True quality control (QC) of the planning process requires quantitative assessments of treatment plan quality itself, and QC in IMRT has been stymied by intra-patient anatomical variability and inherently complex three-dimensional dose distributions. In this work we describe the development of an automated system to reduce clinical IMRT planning variability and improve plan quality using mathematical models that predict achievable OAR DVHs based on individual patient anatomy. These models rely on the correlation of expected dose to the minimum distance from a voxel to the PTV surface, whereby a three-parameter probability distribution function (PDF) was used to model iso-distance OAR subvolume dose distributions. DVH models were obtained by fitting the evolution of the PDF with distance. Initial validation on clinical cohorts of 40 prostate and 24 head-and-neck plans demonstrated highly accurate model-based predictions for achievable DVHs in rectum, bladder, and parotid glands. By quantifying the integrated difference between candidate DVHs and predicted DVHs, the models correctly identified plans with under-spared OARs, validated by replanning all cases and correlating any realized improvements against the predicted gains. Clinical implementation of these predictive models was demonstrated in the PINNACLE treatment planning system by use of existing margin expansion utilities and the scripting functionality inherent to the system. To maintain independence from specific planning software, a system was developed in MATLAB to directly process DICOM-RT data. Both model training and patient-specific analyses were demonstrated with significant computational accelerations from parallelization.

Quality of life following 3D conformal radiation therapy or permanent interstitial brachytherapy for localized prostate cancer

Abstract Purpose: Both 3D Conformal Radiation Therapy (3DCRT) and Transperineal Interstitial Permanent Brachytherapy (TIPPB) are offered as suitable non-surgical alternatives to radical prostatectomy. Despite equivalent cancer control, very little data has been published that compares Quality of Life (QOL) in contemporary cohorts of patients choosing these treatments. Materials and Methods: Since 1998, patients selecting either 3DCRT alone or TIPPB (monotherapy or boost after external beam) for primary management of localized prostate cancer were asked to participate in a prospective assessment of QOL measures. In this preliminary report, 41 3DCRT and 40 TIPPB (34 monotherapy, 6 boost) patients completed validated QOL instruments at each followup visit. QOL instruments included the International Prostate Symptom Score (IPSS), FACT-P, and Sexual Adjustment Questionnaire (SAQ). Results: The average age of men in each group was 69 years. Choice of treatment was left to the patient unless there were significant medical or technical contraindications to either modality. 3DCRT total doses ranged from 61-78 Gy (mean 73.5Gy) and TIPPB doses were 145Gy (TG43) in 34 I-125 implants and 115 Gy in 1 Pd-103 (monotherapy) or 90 Gy in 5 Pd-103 (boost) implants. Patients undergoing TIPPB reported significantly worse urinary and sexual function than their counterparts receiving 3DCRT. The mean cumulative IPSS was 12.5 with TIPPB compared to 8.3 with 3DCRT (p=0.036). Differences were most pronounced in the first 12 months after treatment, particularly with respect to the strength of stream and the need to strain. TIPPB patients were more likely to report a need to urinate frequently (p=0.02), require a pad (p=0.001), be bothered (p=0.02), or have activity limited by urinary side effects (p=0.01). TIPPB patients were less likely to resume sexual activity within 6 months after treatment (p=0.0003) and engaged in sexual activity less often (p= 0.016) than 3DCRT patients. They were also more likely to express dissatisfaction with sex (p=0.009) and less willing to initiate sexual activity (p=0.02). TIPPB patients also reported a small, but significant increase frequency of trouble moving their bowels (p=0.018), and lack of energy (p=0.05). When differences occurred between the two groups, they were most dramatic in the first 6 to 9 months with some differences persisting for more than one year. Conclusion: Although both treatments are effective in the management of early stage prostate cancer, patients undergoing TIPPB have significantly more urinary, sexual, and bowel troubles than similar patients treated with 3DCRT.

SU‐E‐J‐167: Iterative Reconstruction Techniques for Radiation Therapy CT Simulations: A Phantom Study

Purpose: To compare the Philips iDose4 iterative reconstruction techniques with filtered back‐projection techniques (FBP) in Radiation Therapy and provide clinical practice insights. Methods: An anthropomorphic pelvis phantom with added‐bolus layers was used to mimic patients with 38–58 cm lateral diameters. For each phantom size, a set of CT scans were acquired on a Philips Brilliance 64‐slice CT simulator with the mAs spanning the minimum to maximum dose. Images were reconstructed using FBP and iDose4 with noise reduction levels 1–6 for each scan, and evaluated on noise levels, contrast‐to‐noise ratios (CNR), CT number variations, and manual prostate contouring accuracy. Simulated prostate IMRT treatment plans based on these reconstructions were compared. Results: In general, greater‐dose scans yielded greater CNR and lower noise, iDose4 reduced noise up to 66.1% and increased the CNR up to 53.2% compared to FBP. Only changing iDose4 noise reduction levels induced minor noise variations (0.21–4.83HU) and CT Number variations (<1 HU). Without changing reconstruction filters, the spatial resolution (represented by MTF), was similar on images reconstructed by FBP and iDose4 . Very‐low‐dose scans yielded severe photon starvation artifacts, which decreased target visualization and could not be eliminated by iDose4 , especially for the 58 cm phantom size. The gamma pass rates of the IMRT prostate treatment plans conducted using FBP or iDose4 based simulations were greater than 99.9% using 3%/3 mm criteria once they provide same segmentations as the ground truth. Conclusion: Compared against FBP, iDose4 reduced noise, increased CNR and CT number consistency, produced pleasant images without losing structure details, but the improvements of target delineation confidence varied based on patient sizes and radiation output. Especially, very‐low‐dose scans (causing severe photon starvation artifacts) should be avoided when using iDose4 for obese patients. The iDose4 usage should be driven by target contour conspicuity and CT# accuracy instead of noise/CNR considerations.

TH‐D‐AUD A‐09: An Error Reporting and Tracking Database Tool for Process Improvement in Radiation Oncology

Patient and employee safety is a critical concern in radiation therapy (RT). Current QA practices and operation processes in RT are typically developed based on rather prescriptive task group reports and regulatory agency requirements. Typically, these programs are not developed with the goal of process optimization and safety but are brute‐force efforts to prevent catastrophic errors. Other industries have been developing processes to improve quality and safety of their operations and products since the 1940s. These processes have become quite sophisticated and the result is that numerous industries have much better performance records than healthcare and RT. Recently the National Academy of Engineering and the Institute of Medicine recommended the systematic application of systems engineering approaches for reforming our health care delivery system. The AAPM subsequently formed a task group charged with developing a structured systematic QA program approach for RT based on industrial principles and practices. Optimization of RT processes and implementation of industrial techniques requires the acquisition of data regarding performance statistics and failure or error rates of individual departments. Most facilities do not have the infrastructure to effectively collect and analyze such data. We have developed an efficient and effective process for collecting, storing, and analyzing the failure rate data in individual RT facilities that will support process improvement in patient care and safety. The process is based on a web‐based tool for reporting events. The tool is designed so individual events can be reported in as little as two minutes. Events are categorized based on function area, type, and severity of failure. All events are systematically processed using web‐based tools and stored for future analysis and evaluation of failure methods and process improvement and prioritization of efforts in an individual RT facility. This work is supported in part by the National Patient Safety Foundation grant.