Robert E. Drzymala

Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients.

PURPOSE To determine the relation between the incidence of radiation pneumonitis and the three-dimensional dose distribution in the lung. METHODS AND MATERIALS In five institutions, the incidence of radiation pneumonitis was evaluated in 540 patients. The patients were divided into two groups: a Lung group, consisting of 399 patients with lung cancer and 1 esophagus cancer patient and a Lymph./Breast group with 78 patients treated for malignant lymphoma, 59 for breast cancer, and 3 for other tumor types. The dose per fraction varied between 1.0 and 2.7 Gy and the prescribed total dose between 20 and 92 Gy. Three-dimensional dose calculations were performed with tissue density inhomogeneity correction. The physical dose distribution was converted into the biologically equivalent dose distribution given in fractions of 2 Gy, the normalized total dose (NTD) distribution, by using the linear quadratic model with an alpha/beta ratio of 2.5 and 3.0 Gy. Dose-volume histograms (DVHs) were calculated considering both lungs as one organ and from these DVHs the mean (biological) lung dose, NTDmean, was obtained. Radiation pneumonitis was scored as a complication when the pneumonitis grade was grade 2 (steroids needed for medical treatment) or higher. For statistical analysis the conventional normal tissue complication probability (NTCP) model of Lyman (with n=1) was applied along with an institutional-dependent offset parameter to account for systematic differences in scoring patients at different institutions. RESULTS The mean lung dose, NTDmean, ranged from 0 to 34 Gy and 73 of the 540 patients experienced pneumonitis, grade 2 or higher. In all centers, an increasing pneumonitis rate was observed with increasing NTDmean. The data were fitted to the Lyman model with NTD50=31.8 Gy and m=0.43, assuming that for all patients the same parameter values could be used. However, in the low dose range at an NTDmean between 4 and 16 Gy, the observed pneumonitis incidence in the Lung group (10%) was significantly (p=0.02) higher than in the Lymph./Breast group (1.4%). Moreover, between the Lung groups of different institutions, also significant (p=0.04) differences were present: for centers 2, 3, and 4, the pneumonitis incidence was about 13%, whereas for center 5 only 3%. Explicitly accounting for these differences by adding center-dependent offset values for the Lung group, improved the data fit significantly (p < 10(-5)) with NTD50=30.5+/-1.4 Gy and m=0.30+/-0.02 (+/-1 SE) for all patients, and an offset of 0-11% for the Lung group, depending on the center. CONCLUSIONS The mean lung dose, NTDmean, is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose-effect relation between the NTDmean and the incidence of radiation pneumonitis, based on a large clinical data set, might be of value in dose-escalating studies for lung cancer. The validity of the obtained dose-effect relation will have to be tested in future studies, regarding the influence of confounding factors and dose distributions different from the ones in this study.

Dose-volume histograms

A plot of a cumulative dose-volume frequency distribution, commonly known as a dose-volume histogram (DVH), graphically summarizes the simulated radiation distribution within a volume of interest of a patient which would result from a proposed radiation treatment plan. DVHs show promise as tools for comparing rival treatment plans for a specific patient by clearly presenting the uniformity of dose in the target volume and any hot spots in adjacent normal organs or tissues. However, because of the loss of positional information in the volume(s) under consideration, it should not be the sole criterion for plan evaluation. DVHs can also be used as input data to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). The sensitivity of TCP and NTCP calculations to small changes in the DVH shape points to the need for an accurate method for computing DVHs. We present a discussion of the methodology for generating and plotting the DVHs, some caveats, limitations on their use and the general experience of four hospitals using DVHs.

Stereotactic Body Radiation Therapy for Early-Stage Non–Small-Cell Lung Cancer: The Pattern of Failure Is Distant

BACKGROUND Stereotactic body radiation therapy (SBRT) represents a substantial paradigm shift in the treatment of patients with medically inoperable Stage I/II non-small-cell lung cancer. We reviewed our experience using either three- or five-fraction SBRT for peripheral or central tumors, respectively. METHODS AND MATERIALS A total of 91 patients signed an institutional review board-approved consent form, were treated with SBRT, and have had > or =6 months of follow-up. Patients were referred for SBRT because of underlying comorbidities (poor performance status in 31 or poor lung function in 52) or refusal of surgery (8 patients). Of the cancers, 83 were peripheral and eight were central. Peripheral cancers received a mean dose of 18 Gy x three fractions. Cancers within 2 cm of the bronchus, esophagus, or brachial plexus were treated with 9 Gy x five fractions. RESULTS The median follow-up duration for these patients was 18 months (range, 6-42 months). TNM staging was as follows: 58 patients with T1N0M0, 22 with T2N0M0, 2 with T3N0M0 (chest wall), and 6 with T1N0M1 cancers. The median tumor diameter was 2 cm (range, 1-5 cm). The median forced expiratory volume in 1 s was 46% (range, 17-133%) and the median carbon monoxide diffusing capacity (DLCO) was 49% (range, 15-144%). Two-year local tumor control was achieved in 86% of patients. The predominant pattern of failure was the development of distant metastasis or second lung cancer. The development of distant metastasis was the only significant prognostic factor for overall survival on multivariate analysis. CONCLUSIONS Local tumor control was shown to be high using SBRT for non-small-cell lung cancer. Overall survival is highly coerrelated with the development of distant metastasis.

Multimodality image registration quality assurance for conformal three-dimensional treatment planning.

PURPOSE We present a quality assurance methodology to determine the accuracy of multimodality image registration and fusion for the purpose of conformal three-dimensional and intensity-modulated radiation therapy treatment planning. Registration and fusion accuracy between any combination of computed tomography (CT), magnetic resonance (MR), and positron emission computed tomography (PET) imaging studies can be evaluated. METHODS AND MATERIALS A commercial anthropomorphic head phantom filled with water and containing CT, MR, and PET visible targets was modified to evaluate the accuracy of multimodality image registration and fusion software. For MR and PET imaging, the water inside the phantom was doped with CuNO(3) and 18F-fluorodeoxyglucose (18F-FDG), respectively. Targets consisting of plastic spheres and pins were distributed throughout the cranium section of the phantom. Each target sphere had a conical-shaped bore with its apex at the center of the sphere. The pins had a conical extension or indentation at the free end. The contours of the spheres, sphere centers, and pin tips were used as anatomic landmark models for image registration, which was performed using affine coordinate-transformation tools provided in a commercial multimodality image registration/fusion software package. Four sets of phantom image studies were obtained: primary CT, secondary CT with different phantom immobilization, MR, and PET study. A novel CT, MR, and PET external fiducial marking system was also tested. RESULTS The registration of CT/CT, CT/MR, and CT/PET images allowed correlation of anatomic landmarks to within 2 mm, verifying the accuracy of the registration software and spatial fidelity of the four multimodality image sets. CONCLUSIONS This straightforward phantom-based quality assurance of the image registration and fusion process can be used in a routine clinical setting or for providing a working image set for development of the image registration and fusion process and new software.

Three-dimensional photon treatment planning of the intact breast☆

Three-dimensional treatment planning for the intact breast was performed on two patients who had undergone CT scanning. A total of 38 treatment plans were evaluated. Multiple plans were evaluated for each patient including plans with and without inhomogeneity corrections, plans using varying photon energies of 60Co, 4 MV, 6 MV, 10 MV, and 15 MV, and three-dimensionally unconstrained plans. Increased hot spots were appreciated in the central axis plane when lung inhomogeneity corrections were used. Additional hot spots were appreciated in off-axis planes towards the cephalad and caudad aspects of the target volume because of lung inhomogeneity corrections and changes in the breast contour. The use of 60Co was associated with an increase in the magnitude and volume of hot spots, whereas the use of higher energy photons such as 10 MV and 15 MV was associated with an unacceptable target coverage at shallow depths. Therefore, for the two patients studied, the use of a medium energy photon beam (such as from a 6 MV linear accelerator) appeared to be the energy of choice for treatment of the intact breast. The three-dimensionally unconstrained plans were able to improve slightly upon the standard plans, particularly with relationship of dose to normal tissue structures. Areas for future research were identified, including the use of tissue compensators.

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.

Combined endovascular embolization and stereotactic radiosurgery in the treatment of large arteriovenous malformations: Clinical article

OBJECT Large cerebral arteriovenous malformations (AVMs) are often not amenable to direct resection or stereotactic radiosurgery (SRS) treatment. An alternative treatment strategy is staged endovascular embolization followed by SRS (Embo/SRS). The object of this study was to examine the experience at Washington University in St. Louis with Embo/SRS for large AVMs and review the results in earlier case series. METHODS Twenty-one cases involving patients with large AVMs treated with Embo/SRS between 1994 and 2006 were retrospectively evaluated. The AVM size (before and after embolization), procedural complications, radiological outcome, and neurological outcome were examined. Radiological success was defined as AVM obliteration as demonstrated by catheter angiography, CT angiography, or MR angiography. Radiological failure was defined as residual AVM as demonstrated by catheter angiography, CT angiography, or MR angiography performed at least 3 years after SRS. RESULTS The maximum diameter of all AVMs in this series was > 3 cm (mean 4.2 cm); 12 (57%) were Spetzler-Martin Grade IV or V. Clinical follow-up was available in 20 of 21 cases; radiological follow-up was available in 19 of 21 cases (mean duration of follow-up 3.6 years). Forty-three embolization procedures were performed; 8 embolization-related complications occurred, leading to transient neurological deficits in 5 patients (24%), minor permanent neurological deficits in 3 patients (14%), and major permanent neurological deficits in none (0%). Twenty-one SRS procedures were performed; 1 radiation-induced complication occurred (5%), leading to a permanent minor neurological deficit. Of the 20 patients with clinical follow-up, none experienced cerebral hemorrhage. In the 19 patients with radiological follow-up, AVM obliteration was confirmed by catheter angiography in 13, MR angiography in 2, and CT angiography in 1. Residual nidus was found in 3 patients. In patients with follow-up catheter angiography, the AVM obliteration rate was 81% (13 of 16 cases). CONCLUSIONS Staged endovascular embolization followed by SRS provides an effective means of treating large AVMs not amenable to standard surgical or SRS treatment. The outcomes and complication rates reported in this series compare favorably to the results of other reported therapeutic strategies for this very challenging patient population.

Three-dimensional treatment planning and conformal radiation therapy: preliminary evaluation *

Preliminary clinical results are presented for 209 patients with cancer who had treatment planned on our three-dimensional radiation treatment planning (3-D RTP) system and were treated with external beam conformal radiation therapy. Average times (min) for CT volumetric simulation were: 74 without or 84 with contrast material; 36 for contouring of tumor/target volume and 44 for normal anatomy; 78 for treatment planning; 53 for plan evaluation/optimization; and 58 for verification simulation. Average time of daily treatment sessions with 3-D conformal therapy or standard techniques was comparable for brain, head and neck, thoracic, and hepatobiliary tumors (11.8-14 min and 11.5-12.1, respectively). For prostate cancer patients treated with 3-D conformal technique and Cerrobend blocks, mean treatment time was 19 min; with multileaf collimation it was 14 min and with bilateral arc rotation, 9.8 min. Acute toxicity was comparable to or lower than with standard techniques. Sophisticated 3-D RTP and conformal irradiation can be performed in a significant number of patients at a reasonable cost. Further efforts, including dose-escalation studies, are necessary to develop more versatile and efficient 3-D RTP systems and to enhance the cost benefit of this technology in treatment of patients with cancer.

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.

Errors in radiation oncology: A study in pathways and dosimetric impact

As complexity for treating patients increases, so does the risk of error. Some publications have suggested that record and verify (R&V) systems may contribute in propagating errors. Direct data transfer has the potential to eliminate most, but not all, errors. And although the dosimetric consequences may be obvious in some cases, a detailed study does not exist. In this effort, we examined potential errors in terms of scenarios, pathways of occurrence, and dosimetry. Our goal was to prioritize error prevention according to likelihood of event and dosimetric impact. For conventional photon treatments, we investigated errors of incorrect source‐to‐surface distance (SSD), energy, omitted wedge (physical, dynamic, or universal) or compensating filter, incorrect wedge or compensating filter orientation, improper rotational rate for arc therapy, and geometrical misses due to incorrect gantry, collimator or table angle, reversed field settings, and setup errors. For electron beam therapy, errors investigated included incorrect energy, incorrect SSD, along with geometric misses. For special procedures we examined errors for total body irradiation (TBI, incorrect field size, dose rate, treatment distance) and LINAC radiosurgery (incorrect collimation setting, incorrect rotational parameters). Likelihood of error was determined and subsequently rated according to our history of detecting such errors. Dosimetric evaluation was conducted by using dosimetric data, treatment plans, or measurements. We found geometric misses to have the highest error probability. They most often occurred due to improper setup via coordinate shift errors or incorrect field shaping. The dosimetric impact is unique for each case and depends on the proportion of fields in error and volume mistreated. These errors were short‐lived due to rapid detection via port films. The most significant dosimetric error was related to a reversed wedge direction. This may occur due to incorrect collimator angle or wedge orientation. For parallel‐opposed 60° wedge fields, this error could be as high as 80% to a point off‐axis. Other examples of dosimetric impact included the following: SSD, ~2%/cm for photons or electrons; photon energy (6 MV vs. 18 MV), on average 16% depending on depth, electron energy, ~0.5cm of depth coverage per MeV (mega‐electron volt). Of these examples, incorrect distances were most likely but rapidly detected by in vivo dosimetry. Errors were categorized by occurrence rate, methods and timing of detection, longevity, and dosimetric impact. Solutions were devised according to these criteria. To date, no one has studied the dosimetric impact of global errors in radiation oncology. Although there is heightened awareness that with increased use of ancillary devices and automation, there must be a parallel increase in quality check systems and processes, errors do and will continue to occur. This study has helped us identify and prioritize potential errors in our clinic according to frequency and dosimetric impact. For example, to reduce the use of an incorrect wedge direction, our clinic employs off‐axis in vivo dosimetry. To avoid a treatment distance setup error, we use both vertical table settings and optical distance indicator (ODI) values to properly set up fields. As R&V systems become more automated, more accurate and efficient data transfer will occur. This will require further analysis. Finally, we have begun examining potential intensity‐modulated radiation therapy (IMRT) errors according to the same criteria. PACS numbers: 87.53.Xd, 87.53.St