J.R. Olsen

Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer

PURPOSE To compare the efficacy of three lung stereotactic body radiotherapy (SBRT) regimens in a large institutional cohort. METHODS Between 2004 and 2009, 130 patients underwent definitive lung cancer SBRT to a single lesion at the Mallinckrodt Institute of Radiology. We delivered 18 Gy × 3 fractions for peripheral tumors (n = 111) and either 9 Gy × 5 fractions (n = 8) or 10 Gy × 5 fractions (n = 11) for tumors that were central or near critical structures. Univariate and multivariate analysis of prognostic factors was performed using the Cox proportional hazard model. RESULTS Median follow-up was 11, 16, and 13 months for the 9 Gy × 5, 10 Gy × 5, and 18 Gy × 3 groups, respectively. Local control statistics for Years 1 and 2 were, respectively, 75% and 50% for 9 Gy × 5, 100% and 100% for 10 Gy × 5, and 99% and 91% for 18 Gy × 3. Median overall survival was 14 months, not reached, and 34 months for the 9 Gy × 5, 10 Gy × 5, and 18 Gy × 3 treatments, respectively. No difference in local control or overall survival was found between the 10 Gy × 5 and 18 Gy × 3 groups on log-rank test, but both groups had improved local control and overall survival compared with 9 Gy × 5. Treatment with 9 Gy × 5 was the only independent prognostic factor for reduced local control on multivariate analysis, and increasing age, increasing tumor volume, and poor performance status predicted independently for reduced overall survival. CONCLUSION Treatment regimens of 10 Gy × 5 and 18 Gy × 3 seem to be efficacious for lung cancer SBRT and provide superior local control and overall survival compared with 9 Gy × 5.

Dose Escalation of Carmustine in Surgically Implanted Polymers in Patients With Recurrent Malignant Glioma: A New Approaches to Brain Tumor Therapy CNS Consortium Trial

PURPOSE This New Approaches to Brain Tumor Therapy CNS Consortium study sought to determine the maximum-tolerated dose (MTD) of carmustine (BCNU) that can be implanted in biodegradable polymers following resection of recurrent high-grade gliomas and the systemic BCNU exposure with increasing doses of interstitial BCNU. PATIENTS AND METHODS Forty-four adults underwent tumor debulking and polymer placement. Six patients per dose level were studied using polymers with 6.5%, 10%, 14.5%, 20%, and 28% BCNU by weight. Toxicities were assessed 1 month after implantation by a safety monitoring committee to determine whether subsequent escalations should occur. Nine additional patients were studied at the MTD to confirm safety. BCNU blood levels were obtained before and after polymer implantation. RESULTS No dose-limiting toxicities were identified at the 6.5%, 10%, or 14.5% dose levels, although difficulties with wound healing, seizures, and brain edema were noted. At the 20% dose, these effects seemed more prominent, and six additional patients were treated at this dose and tolerated treatment well. Three of four patients receiving the 28% polymers developed severe brain edema and seizures, and accrual to this cohort was stopped. Nine additional patients received 20% polymer, confirming this as the MTD. Maximum BCNU plasma concentrations with the 20% loaded polymers were 27 ng/mL. Overall median survival was 251 days. CONCLUSION The MTD of BCNU delivered in polymer to the surgical cavity is 20%. This polymer provides five times more BCNU than standard commercially available BCNU polymers and results in minimal systemic BCNU exposure. Additional studies are needed to establish the efficacy of high-dose BCNU polymers.

Patterns of failure after stereotactic body radiation therapy or lobar resection for clinical stage I non-small-cell lung cancer.

Introduction: The purpose of this study was to compare patterns of failure between lobar resection (lobectomy or pneumonectomy) and stereotactic body radiation therapy (SBRT) for patients with clinical stage I non–small-cell lung cancer (NSCLC). Methods: From January 2004 to January 2008, 338 patients underwent definitive treatment for pathologically confirmed clinical stage I NSCLC with lobar resection (n = 260) or SBRT (n = 78). Most surgical patients underwent lobectomy (n = 237). SBRT patients received a biologically effective dose of at least 100 Gy10. Lobar resection patients were younger, healthier, and had superior pulmonary function, whereas most of the patients in the SBRT group had T1 tumors. Final pathology upstaged 32.7% of surgery patients, and 20.0% received adjuvant chemotherapy. No SBRT patients received adjuvant chemotherapy. Results: In an unmatched comparison, 4-year lobar local control (98.7% versus 93.6%, p = 0.015) was greater for lobar resection versus SBRT, respectively, though primary tumor (98.7% versus 95.3%, p = 0.088), regional (82.9% versus 78.1%, p = 0.912), and distant control (76.1% versus 54.0%, p = 0.152) were similar. Overall survival (OS, 63.5% versus 29.6%, p < 0.0001) was greater for lobar resection, though cause-specific survival (CSS, 81.3% versus 75.3%, p = 0.923) was similar. In a T-stage matched comparison of 152 patients, there was no significant difference in patterns of failure or CSS, whereas OS favored surgery. Conclusion: Lobectomy/pneumonectomy or SBRT results in comparable patterns of failure for clinical stage I NSCLC. In this retrospective comparison, OS was superior for surgery, though CSS was similar. Randomized trials are necessary to control for fundamental differences in comorbidity, which impact interpretation of both tumor control and survival.

Prospective Clinical Trial of Positron Emission Tomography/Computed Tomography Image-Guided Intensity-Modulated Radiation Therapy for Cervical Carcinoma With Positive Para-Aortic Lymph Nodes

PURPOSE To describe a more aggressive treatment technique allowing dose escalation to positive para-aortic lymph nodes (PALN) in patients with cervical cancer, by means of positron emission tomography (PET)/computed tomography (CT)-guided intensity-modulated radiation therapy (IMRT). Here, we describe methods for simulation and planning of these treatments and provide objectives for target coverage as well as normal tissue sparing to guide treatment plan evaluation. METHODS AND MATERIALS Patients underwent simulation on a PET/CT scanner. Treatment plans were generated to deliver 60.0 Gy to the PET-positive PALN and 50.0 Gy to the PALN and pelvic lymph node beds. Treatment plans were optimized to deliver at least 95% of the prescribed doses to at least 95% of each target volume. Dose-volume histograms were calculated for normal structures. RESULTS The plans of 10 patients were reviewed. Target coverage goals were satisfied in all plans. Analysis of dose-volume histograms indicated that treatment plans involved irradiation of approximately 50% of the bowel volume to at least 25.0 Gy, with less than 10% receiving at least 50.0 Gy and less than 1% receiving at least 60.0. With regard to kidney sparing, approximately 50% of the kidney volume received at least 16.0 Gy, less than 5% received at least 50.0 Gy, and less than 1% received at least 60.0 Gy. CONCLUSIONS We have provided treatment simulation and planning methods as well as guidelines for the evaluation of target coverage and normal tissue sparing that should facilitate the more aggressive treatment of cervical cancer.

Online Magnetic Resonance Image Guided Adaptive Radiation Therapy: First Clinical Applications

PURPOSE To demonstrate the feasibility of online adaptive magnetic resonance (MR) image guided radiation therapy (MR-IGRT) through reporting of our initial clinical experience and workflow considerations. METHODS AND MATERIALS The first clinically deployed online adaptive MR-IGRT system consisted of a split 0.35T MR scanner straddling a ring gantry with 3 multileaf collimator-equipped (60)Co heads. The unit is supported by a Monte Carlo-based treatment planning system that allows real-time adaptive planning with the patient on the table. All patients undergo computed tomography and MR imaging (MRI) simulation for initial treatment planning. A volumetric MRI scan is acquired for each patient at the daily treatment setup. Deformable registration is performed using the planning computed tomography data set, which allows for the transfer of the initial contours and the electron density map to the daily MRI scan. The deformed electron density map is then used to recalculate the original plan on the daily MRI scan for physician evaluation. Recontouring and plan reoptimization are performed when required, and patient-specific quality assurance (QA) is performed using an independent in-house software system. RESULTS The first online adaptive MR-IGRT treatments consisted of 5 patients with abdominopelvic malignancies. The clinical setting included neoadjuvant colorectal (n=3), unresectable gastric (n=1), and unresectable pheochromocytoma (n=1). Recontouring and reoptimization were deemed necessary for 3 of 5 patients, and the initial plan was deemed sufficient for 2 of the 5 patients. The reasons for plan adaptation included tumor progression or regression and a change in small bowel anatomy. In a subsequently expanded cohort of 170 fractions (20 patients), 52 fractions (30.6%) were reoptimized online, and 92 fractions (54.1%) were treated with an online-adapted or previously adapted plan. The median time for recontouring, reoptimization, and QA was 26 minutes. CONCLUSION Online adaptive MR-IGRT has been successfully implemented with planning and QA workflow suitable for routine clinical application. Clinical trials are in development to formally evaluate adaptive treatments for a variety of disease sites.

Dosimetric predictors of chest wall pain after lung stereotactic body radiotherapy

PURPOSE To identify risk factors for the development of chest wall (CW) pain after thoracic stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS A registry of patients with lung lesions treated with lung SBRT was explored to identify patients treated with 54 Gy in three fractions or 50 Gy in five fractions. One hundred and forty-six lesions in 140 patients were identified; complete electronic treatment plans were available on 86 CWs. The CW was contoured as a 3 cm outward expansion from the involved lung. Univariate and multivariate analyses were used to correlate patient, tumor, and dosimetric factors to the development of CW toxicity. RESULTS CW pain occurred in 22 patients (15.7%). The Kaplan-Meier estimated risk of CW pain at 2 years was 20.1% (95% C.I., 13.2-28.8%). On univariate analysis of patient factors, elevated BMI (p=0.026) and connective tissue disease (p=0.036) correlated with CW pain. The percent of CW receiving 30, 35, or 40 Gy was most predictive of CW pain on multivariate analysis using logistic regression, while V40 alone was predictive using Cox regression. A V30 threshold of 0.7% and V40 threshold of 0.19% was correlated with a 15% risk of CW pain. CONCLUSIONS We have described patient and dosimetric parameters that correlate with CW pain after lung SBRT. The risk of CW pain may be mitigated by attempting to reduce the relative proportion of CW receiving 30-40 Gy during treatment planning.

Five Fractions of Radiation Therapy Followed by 4 Cycles of FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer

BACKGROUND Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy. METHODS AND MATERIALS Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of FOLFOX [5-fluorouracil, oxaliplatin, leucovorin]. Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls. RESULTS 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%). CONCLUSION This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.

An automated method for adaptive radiation therapy for prostate cancer patients using continuous fiducial-based tracking.

Electromagnetic tracking technology is primarily used for continuous prostate localization during radiotherapy, but offers potential value for evaluation of dosimetric coverage and adequacy of treatment for dynamic targets. We developed a highly automated method for daily computation of cumulative dosimetric effects of intra- and inter-fraction target motion for prostate cancer patients using fiducial-based electromagnetic tracking. A computer program utilizing real-time tracking data was written to (1) prospectively determine appropriate rotational/translational motion limits for patients treated with continuous isocenter localization; (2) retrospectively analyze dosimetric target coverage after daily treatment, and (3) visualize three-dimensional rotations and translations of the prostate with respect to the planned target volume and dose matrix. We present phantom testing and a patient case to validate and demonstrate the utility of this application. Gamma analysis of planar dose computed by our application demonstrated accuracy within 1%/1 mm. Dose computation of a patient treatment revealed high variation in minimum dose to the prostate (D(min)) over 40 fractions and a drop in the D(min) of approximately 8% between a 5 mm and a 3 mm PTV margin plan. The infrastructure has been created for patient-specific treatment evaluation using continuous tracking data. This application can be used to increase confidence in treatment delivery to targets influenced by motion.

Tumor volume and subvolume concordance between FDG-PET/CT and diffusion-weighted MRI for squamous cell carcinoma of the cervix.

To compare [18F]fluorodeoxyglucose (FDG) / positron emission tomography (PET) / computed tomography (CT) and magnetic resonance imaging (MRI) for evaluating patients with cervical cancer. We compared tumor characteristics on FDG‐PET and apparent diffusion coefficient (ADC) maps on diffusion‐weighted MRI (DWI) to evaluate concordance of two functional imaging techniques.

Comparison of onboard low-field magnetic resonance imaging versus onboard computed tomography for anatomy visualization in radiotherapy.

ABSTRACT Background. Onboard magnetic resonance imaging (OB-MRI) for daily localization and adaptive radiotherapy has been under development by several groups. However, no clinical studies have evaluated whether OB-MRI improves visualization of the target and organs at risk (OARs) compared to standard onboard computed tomography (OB-CT). This study compared visualization of patient anatomy on images acquired on the MRI-60Co ViewRay system to those acquired with OB-CT. Material and methods. Fourteen patients enrolled on a protocol approved by the Institutional Review Board (IRB) and undergoing image-guided radiotherapy for cancer in the thorax (n = 2), pelvis (n = 6), abdomen (n = 3) or head and neck (n = 3) were imaged with OB-MRI and OB-CT. For each of the 14 patients, the OB-MRI and OB-CT datasets were displayed side-by-side and independently reviewed by three radiation oncologists. Each physician was asked to evaluate which dataset offered better visualization of the target and OARs. A quantitative contouring study was performed on two abdominal patients to assess if OB-MRI could offer improved inter-observer segmentation agreement for adaptive planning. Results. In total 221 OARs and 10 targets were compared for visualization on OB-MRI and OB-CT by each of the three physicians. The majority of physicians (two or more) evaluated visualization on MRI as better for 71% of structures, worse for 10% of structures, and equivalent for 14% of structures. 5% of structures were not visible on either. Physicians agreed unanimously for 74% and in majority for > 99% of structures. Targets were better visualized on MRI in 4/10 cases, and never on OB-CT. Conclusion. Low-field MR provides better anatomic visualization of many radiotherapy targets and most OARs as compared to OB-CT. Further studies with OB-MRI should be pursued.