Spaceflight-Relevant Challenges of Radiation and/or Reduced Weight Bearing Cause Arthritic Responses in Knee Articular Cartilage.

There is little known about the effect of both reduced weight bearing and exposure to radiation during spaceflight on the mechanically-sensitive cartilage lining the knee joint. In this study, we characterized cartilage damage in rat knees after periods of reduced weight bearing with/without exposure to solar-flare-relevant radiation, then cartilage recovery after return to weight bearing. Male Sprague Dawley rats (n = 120) were either hindlimb unloaded (HLU) via tail suspension or remained weight bearing in cages (GROUND). On day 5, half of the HLU and GROUND rats were 1 Gy total-body X-ray irradiated during HLU, and half were sham irradiated (SHAM), yielding 4 groups: GROUND-SHAM; GROUND-IR; HLU-SHAM; and HLU-IR. Hindlimbs were collected from half of each group of rats on day 13. The remaining rats were then removed from HLU or remained weight bearing, and hindlimbs from these rats were collected on day 62. On day 13, glycosaminoglycan (GAG) content in cartilage lining the tibial plateau and femoral condyles of HLU rats was lower than that of the GROUND animals. Likewise, on day 13, immunoreactivity of the collagen type II-degrading matrix metalloproteinase-13 (MMP-13) and of a resultant metalloproteinase-generated neoepitope VDIPEN was increased in all groups versus GROUND-SHAM. Clustering of chondrocytes indicating cartilage damage was present in all HLU and IR groups versus GROUND-SHAM on day 13. On day 62, after 49 days of reloading, the loss of GAG content was attenuated in the HLU-SHAM and HLU-IR groups, and the increased VDIPEN staining in all treatment groups was attenuated. However, the increased chondrocyte clustering remained in all treatment groups on day 62. MMP-13 activity also remained elevated in the GROUND-IR and HLU-IR groups. Increased T2 relaxation times, measured on day 62 using 7T MRI, were greater in GROUND-IR and HLU-IR knees, indicating persistent cartilage damage in the irradiated groups. Both HLU and total-body irradiation resulted in acute degenerative and pre-arthritic changes in the knee articular cartilage of rats. A return to normal weight bearing resulted in some recovery from cartilage degradation. However, radiation delivered as both a single challenge and when combined with HLU resulted in chronic cartilage damage. These findings suggest that radiation exposure during spaceflight leads to and/or impairs recovery of cartilage upon return to reloading, generating long-term joint problems for astronauts.

A reproducible radiation delivery method for unanesthetized rodents during periods of hind limb unloading.

Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm×30.5 cm×40.6 cm30.5 cm×30.5 cm×40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five centimeters of water-equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight-relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINACs at academic medical centers and the reliability of their dosimetry properties, this method may find great utility in the implementation of future ground-based studies that examine the combined spaceflight challenges of reduced loading and radiation while using the HLU rodent model.

A technique for murine irradiation in a controlled gas environment.

NASA’s extra-vehicular activities (EVAs) involve exposure to high energy photons while breathing 100% oxygen. Using previously verified mouse models, our laboratory is studying whether low dose irradiation under these hyperoxic conditions could lead to an increase in carcinogenic potential. To simulate the environment astronauts encounter during an EVA, enclosed chambers were constructed that allowed for mouse movement, controlled gas conditions, and uniform radiation dose delivery. Custom-built gas chambers with input/output gas valves and dividers that allowed for uniform gas flow were used to keep 6 unanesthetized mice separated while they were irradiated. The chambers were supplied with 100% oxygen or air using ball valves linked together with T-splitters. A calibrated ion chamber was used to verify the radiation dose distribution across an entire chamber. Mice were placed in the gas environments for 0.5 h, irradiated with a 10 or 18 MV photon beam from a medical linear accelerator, and left in their gas environment for 2 h post-irradiation. We irradiated 200 mice (5 different doses between 0-1000 mGy) under normoxic or 100% oxygen conditions. For the next step of this research, these mice will be euthanized 9 months post-irradiation, and lung tumors will be counted and sized to determine if hyperoxia increases the carcinogenic effect for this model.

Feasibility of optimizing the dose distribution in lung tumors using fluorine-18-fluorodeoxyglucose positron emission tomography and single photon emission computed tomography guided dose prescriptions.

The information provided by functional images may be used to guide radiotherapy planning by identifying regions that require higher radiation dose. In this work we investigate the dosimetric feasibility of delivering dose to lung tumors in proportion to the fluorine-18-fluorodeoxyglucose activity distribution from positron emission tomography (FDG-PET). The rationale for delivering dose in proportion to the tumor FDG-PET activity distribution is based on studies showing that FDG uptake is correlated to tumor cell proliferation rate, which is shown to imply that this dose delivery strategy is theoretically capable of providing the same duration of local control at all voxels in tumor. Target dose delivery was constrained by single photon emission computed tomography (SPECT) maps of normal lung perfusion, which restricted irradiation of highly perfused lung and imposed dose-function constraints. Dose-volume constraints were imposed on all other critical structures. All dose-volume/function constraints were considered to be soft, i.e., critical structure doses corresponding to volume/function constraint levels were minimized while satisfying the target prescription, thus permitting critical structure doses to minimally exceed dose constraint levels. An intensity modulation optimization methodology was developed to deliver this radiation, and applied to two lung cancer patients. Dosimetric feasibility was assessed by comparing spatially normalized dose-volume histograms from the nonuniform dose prescription (FDG-PET proportional) to those from a uniform dose prescription with equivalent tumor integral dose. In both patients, the optimization was capable of delivering the nonuniform target prescription with the same ease as the uniform target prescription, despite SPECT restrictions that effectively diverted dose from high to low perfused normal lung. In one patient, both prescriptions incurred similar critical structure dosages, below dose-volume/function limits. However, in the other patient, critical structure dosage from the nonuniform dose prescription exceeded dose-volume/function limits, and greatly exceeded that from the uniform dose prescription. Strict compliance to dose-volume/ function limits would entail reducing dose proportionality to the FDG-PET activity distribution, thereby theoretically reducing the duration of local control. Thus, even though it appears feasible to tailor lung tumor dose to the FDG-PET activity distribution, despite SPECT restrictions, strict adherence to dose-volume/function limits could compromise the effectiveness of functional image guided radiotherapy.

Radiation-induced pulmonary toxicity: a dose-volume histogram analysis in 201 patients with lung cancer.

PURPOSE: To relate lung dose-volume histogram-based factors to symptomatic radiation pneumonitis (RP) in patients with lung cancer undergoing 3-dimensional (3D) radiotherapy planning. METHODS AND MATERIALS: Between 1991 and 1999, 318 patients with lung cancer received external beam radiotherapy (RT) with 3D planning tools at Duke University Medical Center. One hundred seventeen patients were not evaluated for RP because of <6 months of follow-up, development of progressive intrathoracic disease making scoring of pulmonary symptoms difficult, or unretrievable 3D dosimetry data. Thus, 201 patients were analyzed for RP. Univariate and multivariate analyses were performed to test the association between RP and dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability derived from the Lyman and Kutcher models) and clinical factors, including tobacco use, age, sex, chemotherapy exposure, tumor site, pre-RT forced expiratory volume in 1 s, weight loss, and performance status. RESULTS: Thirty-nine patients (19%) developed RP. In the univariate analysis, all dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability) were associated with RP (p range 0.006-0.003). Of the clinical factors, ongoing tobacco use at the time of referral for RT was associated with fewer cases of RP (p = 0.05). These factors were also independently associated with RP according to the multivariate analysis (p = 0.001). Models predictive for RP based on dosimetric factors only, or on a combination with the influence of tobacco use, had a concordance of 64% and 68%, respectively. CONCLUSIONS: Dosimetric factors were the best predictors of symptomatic RP after external beam RT for lung cancer. Multivariate models that also include clinical variables were slightly more predictive.

Using plasma transforming growth factor beta-1 during radiotherapy to select patients for dose escalation.

PURPOSE: The ability to prescribe treatment based on relative risks for normal tissue injury has important implications for oncologists. In non-small-cell lung cancer, increasing the dose of radiation may improve local control and survival. Changes in plasma transforming growth factor beta (TGFbeta) levels during radiotherapy (RT) may identify patients at low risk for complications in whom higher doses of radiation could be safely delivered. PATIENT AND METHODS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved nodes to a dose of 73.6 Gy (1.6 Gy twice daily). If the plasma TGFbeta level was normal after 73.6 Gy, additional twice daily RT was delivered to successively higher total doses. The maximum-tolerated dose was defined as the highest radiation dose at which < or = one grade 4 (life-threatening) late toxicity and < or = two grade 3 to 4 (severe life-threatening) late toxicities occurred. RESULTS: Thirty-eight patients were enrolled. Median follow-up was 16 months. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGFbeta levels. Fourteen patients whose TGFbeta levels were normal after 73.6 Gy were escalated to 80 Gy (n = 8) and 86.4 Gy (n = 6). In the 86.4-Gy group, dose-limiting toxicity was reached because there were two (33%) grade 3 late toxicities. CONCLUSION: It is feasible to use plasma TGFbeta levels to select patients for RT dose escalation for non-small-cell lung cancer. The maximum-tolerated dose using this approach is 86.4 Gy.

Relating radiation-induced regional lung injury to changes in pulmonary function tests.

PURPOSE: To determine whether the sum of radiotherapy (RT)-induced reductions in regional lung perfusion is quantitatively related to changes in global lung function as assessed by reductions in pulmonary function tests (PFTs). METHODS AND MATERIALS: Two hundred seven patients (70% with lung cancer) who received incidental partial lung irradiation underwent PFTs (forced expiratory volume in 1 s and diffusion capacity for carbon monoxide) before and repeatedly after RT as part of a prospective clinical study. Regional lung function was serially assessed before and after RT by single photon emission computed tomography perfusion scans. Of these, 53 patients had 105 post-RT evaluations of changes in both regional perfusion and PFTs, were without evidence of intrathoracic disease recurrence that might influence regional perfusion and PFT findings, and were not taking steroids. The summation of the regional functional perfusion changes were compared with changes in PFTs using linear regression analysis. RESULTS: Follow-up ranged from 3 to 86 months (median 19). Overall, a significant correlation was found between the sum of changes in regional perfusion and the changes in the PFTs (p = 0.002-0.24, depending on the particular PFT index). However, the correlation coefficients were small (r = 0.16-0.41). CONCLUSIONS: A statistically significant correlation was found between RT-induced changes in regional function (i.e., perfusion) and global function (i.e., PFTs). However, the correlation coefficients are low, making it difficult to relate changes in perfusion to changes in the PFT results. Thus, with our current techniques, the prediction of changes in perfusion alone does not appear to be sufficient to predict the changes in PFTs accurately. Additional studies to clarify the relationship between regional and global lung injury are needed.

Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: preliminary results.

PURPOSE: To determine the incidence and dose dependence of regional cardiac perfusion abnormalities in patients with left-sided breast cancer treated with radiation therapy (RT) with and without doxorubicin (Dox). METHODS: Twenty patients with left-sided breast cancer underwent cardiac perfusion imaging using single photon emission computed tomography (SPECT) prechemotherapy, pre-RT, and 6 months post-RT. SPECT perfusion images were registered onto 3-dimensional (3D) RT dose distributions. The volume of heart in the RT field was quantified, and the regional RT dose was calculated. A decrease in regional cardiac perfusion was assessed subjectively by visual inspection and objectively using image fusion software. Ten patients received Dox-based chemotherapy (total dose 120-300 mg/m(2)), and 10 patients had no chemotherapy. RT was delivered by tangent beams in all patients to a total dose of 46-50 Gy. RESULTS: Overall, 60% of the patients had new visible perfusion defects 6 months post-RT. A dose-dependent perfusion defect was seen at 6 months with minimal defect appreciated at 0-10 Gy, and a 20% decrease in regional perfusion at 41-50 Gy. One of 20 patients had a decrease in left ventricle ejection fraction (LVEF) of greater than 10% at 6 months; 2/20 patients had developed transient pericarditis. No instances of myocardial infarction or congestive heart failure (CHF) have occurred. CONCLUSIONS: RT causes cardiac perfusion defects 6 months post-RT in most patients. Long-term follow-up is needed to assess whether these perfusion changes are transient or permanent and to determine if these findings are associated with changes in overall cardiac function and clinical outcome.

Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction?

PURPOSE: To determine whether changes in whole-lung pulmonary function test (PFT) values are related to the sum of predicted radiation therapy (RT)-induced changes in regional lung perfusion. PATIENTS AND METHODS: Between 1991 and 1998, 96 patients (61% with lung cancer) who were receiving incidental partial lung irradiation were studied prospectively. The patients were assessed with pre- and post-RT PFTs (forced expiratory volume in one second [FEV1] and diffusion capacity for carbon monoxide [DLCO]) for at least a 6-month follow-up period, and patients were excluded if it was determined that intrathoracic recurrence had an impact on lung function. The maximal declines in PFT values were noted. A dose-response model based on RT-induced reduction in regional perfusion (function) was used to predict regional dysfunction. The predicted decline in pulmonary function was calculated as the weighted sum of the predicted regional injuries: equation [see text] where Vd is the volume of lung irradiated to dose d, and Rd is the reduction in regional perfusion anticipated at dose d. RESULTS: The relationship between the predicted and measured reduction in PFT values was significant for uncorrected DLCO (P = .005) and borderline significant for DLCO (P = .06) and FEV1 (P = .08). However, the correlation coefficients were small (range,.18 to.30). In patients with lung cancer, the correlation coefficients improved as the number of follow-up evaluations increased (range,.43 to.60), especially when patients with hypoperfusion in the lung adjacent to a central mediastinal/hilar thoracic mass were excluded (range,.59 to.91). CONCLUSION: The sum of predicted RT-induced changes in regional perfusion is related to RT-induced changes in pulmonary function. In many patients, however, the percentage of variation explained is small, which renders accurate predictions difficult.

Functional imaging of normal tissues with nuclear medicine: applications in radiotherapy.

Functional imaging techniques are gaining significant interest from radiation oncologists. Many now claim the need for physical and physiological information during both treatment planning and in the study of normal tissue injury. Toward this goal, the nuclear medicine functional imaging modalities, single-photon emission computed tomography and positron-emission computed tomography, have been used. This article reviews the studies performed in radiotherapy that used these modalities, and attempts to stimulate further interest in this topic.

The role of lung perfusion imaging in predicting the direction of radiation-induced changes in pulmonary function tests.

BACKGROUND: The aim of this study was to determine whether preradiation (pre-RT) single photon emission computed tomography (SPECT) lung perfusion scans can be used to predict RT-induced changes in pulmonary function tests (PFTs). METHODS: Ninety-four patients irradiated for thoracic tumors had pre-RT SPECT lung perfusion scans. The presence of SPECT hypoperfusion distal to a central mediastinal tumor was qualitatively assessed visually without knowledge of PFT changes. Patients were grouped based on whether the diffusion capacity (DLCO) ever increased post-RT. Comparisons of patient groups were performed using 1-tailed Fisher exact tests. Patient follow-up was 6-56 months (mean, 30 months). To assess SPECT hypoperfusion objectively, the average dose to the computed tomography (CT)-defined lung was compared with the weighted-average dose (based on relative perfusion) to the SPECT-defined lung. The ratio between the CT- and SPECT-defined mean lung dose provided a quantitative assessment of hypoperfusion. The mean ratio for patients with central tumor and adjacent hypoperfusion was compared with that of the others (Wilcoxon rank-sum one-sided test). RESULTS: In patients with central tumors, 41% (9 of 22) with adjacent hypoperfusion had improvements in DLCO following radiation, versus 18% (3 of 17) of those without hypoperfusion (P = 0.11). In patients with lung carcinoma, the corresponding ratios were 40% (8 of 20) and 10% (1 of 10), respectively (P = 0.10). The mean ratio of CT dose to SPECT dose was 1.35 for patients with central tumors and adjacent hypoperfusion versus 1.16 for others (P = 0.017). CONCLUSIONS: The presence of SPECT hypoperfusion adjacent to a central mediastinal mass may identify patients likely to have improved PFTs following RT. Thus, SPECT imaging may be useful in models for predicting radiation-induced changes in PFTs.

Radiation-induced pulmonary injury: symptomatic versus subclinical endpoints.

PURPOSE: To assess the relationship between radiation (RT)-induced pulmonary symptoms and subclinical changes in pulmonary functions tests (PFT) and radiographs. MATERIALS AND METHODS: A total of 184 patients irradiated between 1992 and 1998 were prospectively evaluated for RT-induced pulmonary symptoms, changes in computed tomography (CT) density, reductions in single photon emission CT (SPECT) perfusion, and changes in pulmonary functions tests (forced expiratory volume in 1 s [FEV1] and diffusion capacity to carbon monoxide [DLCO]). Comparisons between the evaluable patients with (N=34) and without (N=106) RT-induced pulmonary symptoms were made. RESULTS: Within 6 months of RT, 80% of the RT-induced symptoms were noted. There was no association between the presence or absence of RT-induced pulmonary symptoms and the frequency of RT-induced radiographic changes (p=0.53), or in the dose-response curve for RT-induced reductions in regional perfusion. Overall, RT-induced changes in SPECT images were more commonly seen than increased density changes on CT (p<0.001). Most patients with pulmonary symptoms had relatively low pre-RT PFTs and experienced further declines following RT. CONCLUSIONS: Regional radiographic changes in CT-defined tissue density or SPECT-defined tissue perfusion are similar in patients with and without RT-induced pulmonary symptoms because these endpoints do not consider the volume of lung affected. RT-induced pulmonary symptoms are better related to post-RT PFT because they are an assessment of whole lung function. Additional studies are necessary to better define models that can predict the degree of radiation-induced changes in whole lung function.

The effect of pressure from the table top and patient position on pelvic organ location in patients with prostate cancer.

PURPOSE: To assess the impact of pressure from the table top and patient position on the relationship of the prostate, rectum, and bladder to the bony pelvis. METHODS AND MATERIALS: In 9 patients with prostate cancer (3 status postprostatectomy), computed tomography (CT) scans were obtained in four positions: supine with and without false table top under the buttocks, prone with and without false table top under the lower abdomen. In four patients, a fifth scan was obtained in the first position (supine with table top in place) to assess the impact of changes in bladder/rectal fullness over time. Urination and defecation were not permitted between scans. For each patient, the four (or five) CT scans were registered to each other. RESULTS: The anal canal and the rectum caudal to the coccyx shifted posteriorly in 7/9 patients when the support under the buttocks was removed in the supine position. When pressure from the table top was removed in the prone position, the anterior bladder extension increased. The superior rectum was adjacent to the prostate in all scans and the prostate/superior rectum/bladder generally moved together. Rectal fullness changed with time and rectal gas position was gravity-dependent and shifted with patient position. Bladder volume increased with time. Organs had shifted and/or changed fullness between the first and fifth scan obtained in the same patient position approximately 90 min apart, mostly due to increase in bladder volume. All patients found the supine position most comfortable. CONCLUSIONS: The bladder and rectal fullness vary with time, confounding the ability to attribute changes in organ location to positional factors. Pressure from the table top affects the relative location of pelvic organs and, in part, is responsible for changes previously attributed to position/gravity.

A neural network to predict symptomatic lung injury.

A nonlinear neural network that simultaneously uses pre-radiotherapy (RT) biological and physical data was developed to predict symptomatic lung injury. The input data were pre-RT pulmonary function, three-dimensional treatment plan doses and demographics. The output was a single value between 0 (asymptomatic) and 1 (symptomatic) to predict the likelihood that a particular patient would become symptomatic. The network was trained on data from 97 patients for 400 iterations with the goal to minimize the mean-squared error. Statistical analysis was performed on the resulting network to determine the model's accuracy. Results from the neural network were compared with those given by traditional linear discriminate analysis and the dose-volume histogram reduction (DVHR) scheme of Kutcher. Receiver-operator characteristic (ROC) analysis was performed on the resulting network which had Az = 0.833 +/- 0.04. (Az is the area under the ROC curve.) Linear discriminate multivariate analysis yielded an Az = 0.813 +/- 0.06. The DVHR method had Az = 0.521 +/- 0.08. The network was also used to rank the significance of the input variables. Future studies will be conducted to improve network accuracy and to include functional imaging data.

Quantitative pulmonary single photon emission computed tomography for radiotherapy applications.

Pulmonary imaging using single photon emission computed tomography (SPECT) is the focus of current radiotherapy research, including dose-response analysis and three-dimensional (3D) radiation treatment planning. Improvement in the quantitative capability of SPECT may help establish its potential role in this application as well as others requiring accurate knowledge of pulmonary blood flow. The purposes of this study were to quantitatively evaluate SPECT filtered backprojection (FBP) and ordered subset-expectation maximization (OS-EM) reconstruction implementations for measuring absolute activity concentration in lung phantom experiments, and to incorporate quantitative SPECT techniques in 3D-RTP for lung cancer. Quantitative FBP (nonuniform iterative Chang attenuation compensation, scatter correction, and 3D postreconstruction Metz filtering) and OS-EM implementations were compared with a "clinical" implementation of FBP (uniform multiplicative Chang attenuation compensation and post-reconstruction von Hann filtering), for their ability to improve quantification of inactive and active spherical defects in the lungs of an anthropomorphic torso phantom. Activity concentration estimates were found to depend on many factors, such as region of interest size, scatter subtraction constant (k), postreconstruction deconvolution filtering and, in the case of OS-EM, total number of iterations. In general, reconstruction implementations incorporating compensation for nonuniform attenuation and scatter provided reduced bias relative to the clinical implementation. Potential applications to lung radiotherapy, including dose-functional histograms and treatment planning are also discussed. SPECT has the potential to provide accurate estimates of lung activity distributions that, together with improved image quality, may be useful for the study and prediction of therapeutic response.

The effect of patient-specific factors on radiation-induced regional lung injury.

PURPOSE: To assess the impact of patient-specific factors on radiation (RT)-induced reductions in regional lung perfusion. METHODS: Fifty patients (32 lung carcinoma, 7 Hodgkin's disease, 9 breast carcinoma and 2 other thoracic tumors) had pre-RT and > or = 24-week post-RT single photon emission computed tomography (SPECT) perfusion images to assess the dose dependence of RT-induced reductions in regional lung perfusion. The SPECT data were analyzed using a normalized and non-normalized approach. Furthermore, two different mathematical methods were used to assess the impact of patient-specific factors on the dose-response curve (DRC). First, DRCs for different patient subgroups were generated and compared. Second, in a more formal statistical approach, individual DRCs for regional lung injury for each patient were fit to a linear-quadratic model (reduction = coefficient 1 x dose + coefficient 2 x dose2). Multiple patient-specific factors including tobacco history, pre-RT diffusion capacity to carbon monoxide (DLCO), transforming growth factor-beta (TGF-beta), chemotherapy exposure, disease type, and mean lung dose were explored in a multivariate analysis to assess their impact on the coefficients. RESULTS: None of the variables tested had a consistent impact on the radiation sensitivity of regional lung (i.e., the slope of the DRC). In the formal statistical analysis, there was a suggestion of a slight increase in radiation sensitivity in the dose range >40 Gy for nonsmokers (vs. smokers) and in those receiving chemotherapy (vs. no chemotherapy). However, this finding was very dependent on the specific statistical and normalization method used. CONCLUSION: Patient-specific factors do not have a dramatic effect on RT-induced reduction in regional lung perfusion. Additional studies are underway to better clarify this issue. We continue to postulate that patient-specific factors will impact on how the summation of regional injury translates into whole organ injury. Refinements in our methods to generate and compare SPECT scans are needed.

Multimodality nuclear medicine imaging in three-dimensional radiation treatment planning for lung cancer: challenges and prospects.

The purpose of this study was to determine the utility of quantitative single photon emission computed tomography (SPECT) lung perfusion scans and F-18 fluorodeoxyglucose positron emission computed tomography (PET) during X-ray computed tomography (CT)-based treatment planning for patients with lung cancer. Pre-radiotherapy SPECT (n = 104) and PET (n = 35) images were available to the clinician to assist in radiation field design for patients with bronchogenic cancer. The SPECT and PET scans were registered with anatomic information derived from CT. The information from SPECT and PET provides the treatment planner with functional data not seen with CT. SPECT yields three-dimensional (3D) lung perfusion maps. PET provides 3D metabolic images that assist in tumor localization. The impact of the nuclear medicine images on the treatment planning process was assessed by determining the frequency, type, and extent of changes to plans. Pre-radiotherapy SPECT scans were used to modify 11 (11%) treatment plans; primarily altering beam angles to avoid highly functioning tissue. Fifty (48%) SPECT datasets were judged to be 'potentially useful' due to the detection of hypoperfused regions of the lungs, but were not used during treatment planning. PET data influenced 34% (12 of 35) of the treatment plans examined, and resulted in enlarging portions of the beam aperture (margins) up to 15 mm. Challenges associated with image quality and registration arise when utilizing nuclear medicine data in the treatment planning process. Initial implementation of advanced SPECT image reconstruction techniques that are not typically used in the clinic suggests that the reconstruction method may influence dose response data derived from the SPECT images and improve image registration with CT. The use of nuclear medicine transmission computed tomography (TCT) for both SPECT and PET is presented as a possible tool to reconstruct more accurate emission images and to aid in the registration of emission data with the planning CT. Nuclear medicine imaging techniques appear to be a potentially valuable tool during radiotherapy treatment planning for patients with lung cancer. The utilization of accurate nuclear medicine image reconstruction techniques and TCT may improve the treatment planning process.

Incorporation of functional status into dose-volume analysis.

The dose-volume histogram (DVH) has gained wide acceptance as a mechanism for reducing the voluminous data of a three-dimensional dose distribution into a two-dimensional graph. These graphs are often converted to a single figure of merit. This data reduction technique is used both for clinical treatment plan evaluation and as part of proposed systems for estimating control and complication probabilities. It has long been recognized that a major shortcoming of the DVH as an analysis tool is that all spatial information is discarded. A subtler problem, which is addressed in this work, is that the DVH also implies homogeneity of biological consequence of irradiation in what may be a functionally heterogeneous volume of tissue. An extension to the DVH, the functional dose-volume histogram, or dose-function histogram (DFH), is proposed, that explicitly includes quantitative three-dimensional functional information. The concept is illustrated by the use of SPECT imaging to assess the functional status of irradiated lung.

Regional dose response to pulmonary irradiation using a manual method.

PURPOSE: To better understand the dose dependence of radiation therapy (RT)-induced changes in regional lung perfusion and tissue density, using a manual method to reduce inaccuracies that might be present in previously described automated methods. MATERIALS AND METHODS: Patients who were to receive RT for tumors in and around the thorax, wherein portions of healthy lung would be incidentally irradiated, were prospectively studied. Changes in regional perfusion and tissue density were assessed by comparison of pre- and post-RT single photon emission computed tomography (SPECT), lung perfusion scans and computed tomography (CT) scans, respectively. The three-dimensional dose distribution was calculated on the pre-RT CT scan and correlated to the other scans via image registration. Study volumes were defined by hand and individually visualized on pre- and post-RT scans. The manually generated dose response data were compared to data generated using automated methods. The relationship between CT density and SPECT perfusion was also determined. RESULTS: Thirteen patients with lung cancer were evaluated for changes in tissue density and 11 patients were evaluated for changes in regional perfusion at 12 months post-RT. In general, density increases with increasing regional dose, with marked changes at >60 Gy. Regional perfusion decreases with increasing regional dose. In the low dose regions, relative perfusion increases by 35% on average. Manually measured dose responses correlated well with those determined automatically. The relationship between regional perfusion and CT density indicates a wide range of perfusion over a narrow range of CT density, with markedly reduced perfusion at CT densities of > -600 and < -900 H. CONCLUSIONS: The manually generated CT density dose response data broadly agree with data previously generated using automated methods. The manually generated perfusion dose response data are in fairly good agreement with automated data, lending credibility to the accuracy of the automated methods. Regional perfusion is markedly diminished where CT density is outside the range of normal lung tissue.

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.