Biomedical subjects

R K Ten Haken

Publications and source records attributed to R K Ten Haken.

At least 19 recordsLinked to original sources

PubMed2003

Do dose-volume metrics predict pulmonary function changes in lung irradiation?

PURPOSE: To examine the ability of standard dose-volume metrics to predict pulmonary function changes as measured by pulmonary function tests (PFTs) in a group of patients with non-small-cell lung cancer treated with nonconventional beam arrangements on a Phase I dose-escalation study. In addition, we wanted to examine the correlation between these metrics. MATERIALS AND METHODS: Forty-three patients received a median treatment dose of 76.9 Gy (range 63-102.9). Eight patients also received induction chemotherapy with cisplatin and vinorelbine. They all had pre- and posttreatment PFTs >/=3 months (median 6.2) after treatment. The volume of normal lung treated to >20 Gy, effective volume, and mean lung dose were calculated for both lungs for all patients. Linear regression analysis was performed to determine whether correlations existed between the metrics and changes in the PFTs. Additionally, the three metrics were compared with each other to assess the degree of intermetric correlation. RESULTS: No correlation was found between the volume of normal lung treated to >20 Gy, effective volume, and mean lung dose and changes in the PFTs. Subgroup analyses of patients without atelectasis before irradiation, Stage I and II disease, or treatment without induction chemotherapy were also performed. Again, no correlation was found between the dose-volume metrics and the PFT changes. The intermetric correlation was good among all three dose-volume metrics. CONCLUSIONS: In this relatively small series of patients, dose-volume metrics that correlate with the risk of pneumonitis did not provide a good model to predict early changes in pulmonary function as measured with PFTs.

Aged↗

PubMed2003

Inclusion of organ deformation in dose calculations.

A previously described system for modeling organ deformation using finite element analysis has been extended to permit dose calculation. Using this tool, the calculated dose to the liver during radiotherapy can be compared using a traditional static model (STATIC), a model including rigid body motion (RB), and finally a model that incorporates rigid body motion and deformation (RBD). A model of the liver, consisting of approximately 6000 tetrahedral finite elements distributed throughout the contoured volume, is created from the CT data obtained at exhale. A deformation map is then created to relate the liver in the exhale CT data to the liver in the inhale CT data. Six intermediate phase positions of each element are then calculated from their trajectories. The coordinates of the centroid of each element at each phase are used to determine the dose received. These intermediate dose values are then time weighted according to a population-modeled breathing pattern to determine the total dose to each element during treatment. This method has been tested on four patient datasets. The change in prescribed dose for each patient's actual tumor as well as a simulated tumor of the same size, located in the superior, intermediate, and inferior regions of the liver, was determined using a normal tissue complication model, maintaining a predicted probability of complications of 15%. The average change in prescribed dose from RBD to STATIC for simulated tumors in the superior, intermediate, and inferior regions are 4.0 (range 2.1 to 5.3), -3.6 (range -5.0 to -2.2), and -14.5 (range -27.0 to -10.0) Gy, respectively. The average change in prescribed dose for the patient's actual tumor was -0.4 Gy (range -4.1 to 1.7 Gy). The average change in prescribed dose from RBD to RB for simulated tumors in the superior, intermediate, and inferior regions are -0.04 (range -2.4 to 2.2), 0.2 (range -1.5 to 1.9), and 3.9 (range 0.8 to 7.3) Gy, respectively. The average change in the prescribed dose for the patient's actual tumor was 0.7 Gy (range 0.2 to 1.1 Gy). This patient sampling indicates the potential importance of including deformation in dose calculations.

Computer Simulation↗

PubMed2001

The reproducibility of organ position using active breathing control (ABC) during liver radiotherapy.

PURPOSE: To evaluate the intrafraction and interfraction reproducibility of liver immobilization using active breathing control (ABC). METHODS AND MATERIALS: Patients with unresectable intrahepatic tumors who could comfortably hold their breath for at least 20 s were treated with focal liver radiation using ABC for liver immobilization. Fluoroscopy was used to measure any potential motion during ABC breath holds. Preceding each radiotherapy fraction, with the patient setup in the nominal treatment position using ABC, orthogonal radiographs were taken using room-mounted diagnostic X-ray tubes and a digital imager. The radiographs were compared to reference images using a 2D alignment tool. The treatment table was moved to produce acceptable setup, and repeat orthogonal verification images were obtained. The positions of the diaphragm and the liver (assessed by localization of implanted radiopaque intra-arterial microcoils) relative to the skeleton were subsequently analyzed. The intrafraction reproducibility (from repeat radiographs obtained within the time period of one fraction before treatment) and interfraction reproducibility (from comparisons of the first radiograph for each treatment with a reference radiograph) of the diaphragm and the hepatic microcoil positions relative to the skeleton with repeat breath holds using ABC were then measured. Caudal-cranial (CC), anterior-posterior (AP), and medial-lateral (ML) reproducibility of the hepatic microcoils relative to the skeleton were also determined from three-dimensional alignment of repeat CT scans obtained in the treatment position. RESULTS: A total of 262 fractions of radiation were delivered using ABC breath holds in 8 patients. No motion of the diaphragm or hepatic microcoils was observed on fluoroscopy during ABC breath holds. From analyses of 158 sets of positioning radiographs, the average intrafraction CC reproducibility (sigma) of the diaphragm and hepatic microcoil position relative to the skeleton using ABC repeat breath holds was 2.5 mm (range 1.8-3.7 mm) and 2.3 mm (range 1.2-3.7 mm) respectively. However, based on 262 sets of positioning radiographs, the average interfraction CC reproducibility (sigma) of the diaphragm and hepatic microcoils was 4.4 mm (range 3.0-6.1 mm) and 4.3 mm (range 3.1-5.7 mm), indicating a change of diaphragm and microcoil position relative to the skeleton over the course of treatment with repeat breath holds at the same phase of the respiratory cycle. The average population absolute intrafraction CC offset in diaphragm and microcoil position relative to skeleton was 2.4 mm and 2.1 mm respectively; the average absolute interfraction CC offset was 5.2 mm. Analyses of repeat CT scans demonstrated that the average intrafraction excursion of the hepatic microcoils relative to the skeleton in the CC, AP, and ML directions was 1.9 mm, 0.6 mm, and 0.6 mm respectively and the average interfraction CC, AP, and ML excursion of the hepatic microcoils was 6.6 mm, 3.2 mm, and 3.3 mm respectively. CONCLUSION: Radiotherapy using ABC for patients with intrahepatic cancer is feasible, with good intrafraction reproducibility of liver position using ABC. However, the interfraction reproducibility of organ position with ABC suggests the need for daily on-line imaging and repositioning if treatment margins smaller than those required for free breathing are a goal.

Humans↗

PubMed2001

Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.

PURPOSE: High-dose radiation may improve outcomes in non-small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated. MATERIALS AND METHODS: A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes >or= 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine. RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions. CONCLUSION: Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.

Adult↗

PubMed2001

Partial irradiation of the parotid gland.

Recent efforts to reduce xerostomia associated with irradiation (RT) of head and neck cancer include the use of conformal and intensity-modulated RT (IMRT) to partly spare the major salivary glands, notably the parotid glands, from a high radiation dose while treating adequately all the targets at risk of disease. Knowledge of the dose-volume-response relationships in the salivary glands would determine treatment planning goals and facilitate optimization of the RT plans. Recent prospective studies of salivary flows following inhomogeneous irradiation of the parotid glands have utilized dose-volume histograms (DVHs) and various models to assess these relationships. These studies found that the mean dose to the gland is correlated with the reduction of the salivary output. This is consistent with a pure parallel architecture of the functional subunits (FSUs) of the salivary glands. The range of the mean doses, which have been found in these studies to cause significant salivary flow reduction is 26 to 39 Gy.

Dose-Response Relationship, Radiation↗

PubMed2001

Partial irradiation of the liver.

The use of three-dimensional radiotherapy (RT) and the prospective follow-up of patients for radiation-induced liver disease (RILD) have led to a more quantitative understanding of the partial organ tolerance of the liver compared with previous estimates based on clinical judgment alone. Parameters of both the Lyman normal tissue complication probability (NTCP) model and a local damage-organ injury (D-I) NTCP model have been fit to clinical data from patients who have received hepatic radiation. Based on analyses of over 180 patients, the liver exhibits a large volume effect and a low threshold volume for RILD. Mean liver dose is associated with RILD, and no cases of RILD have been reported in patients with a mean liver dose of less than 31 Gy. Most recent estimates of the partial liver tolerance to RT suggest that if less than 25% of the normal liver is treated with RT, then there may be no upper limit on dose associated with RILD. Estimates of the liver doses associated with a 5% risk of RILD for uniform irradiation of one third, two thirds, and the whole liver are 90 Gy, 47 Gy, and 31 Gy, respectively.

Chemical and Drug Induced Liver Injury↗

PubMed2001

A feasibility study of mutual information based setup error estimation for radiotherapy.

We have investigated a fully automatic setup error estimation method that aligns DRRs (digitally reconstructed radiographs) from a three-dimensional planning computed tomography image onto two-dimensional radiographs that are acquired in a treatment room. We have chosen a MI (mutual information)-based image registration method, hoping for robustness to intensity differences between the DRRs and the radiographs. The MI-based estimator is fully automatic since it is based on the image intensity values without segmentation. Using 10 repeated scans of an anthropomorphic chest phantom in one position and two single scans in two different positions, we evaluated the performance of the proposed method and a correlation-based method against the setup error determined by fiducial marker-based method. The mean differences between the proposed method and the fiducial marker-based method were smaller than 1 mm for translational parameters and 0.8 degree for rotational parameters. The standard deviations of estimates from the proposed method due to detector noise were smaller than 0.3 mm and 0.07 degree for the translational parameters and rotational parameters, respectively.

Algorithms↗

PubMed2000

Prostate position late in the course of external beam therapy: patterns and predictors.

PURPOSE: To examine prostate and seminal vesicles position late in the course of radiation therapy and to determine the effect and predictive value of the bladder and rectum on prostate and seminal vesicles positioning. METHODS AND MATERIALS: Twenty-four patients with localized prostate cancer underwent a computerized tomography scan (CT1) before the start of radiation therapy. After 4-5 weeks of radiation therapy, a second CT scan (CT2) was obtained. All patients were scanned in the supine treatment position with instructions to maintain a full bladder. The prostate, seminal vesicles, bladder, and rectum were contoured. CT2 was aligned via fixed bony anatomy to CT1. The geometrical center and volume of each structure were obtained and directly compared. RESULTS: The prostate shifted along a diagonal axis extending from an anterior-superior position to a posterior-inferior position. The dominant shift was to a more posterior-inferior position. On average, bladder and rectal volumes decreased to 51% (+/-29%) and 82% (+/-45%) of their pretreatment values, respectively. Multiple regression analysis (MRA) revealed that bladder movement and volume change and upper rectum movement were independently associated with prostate motion (p = 0.016, p = 0. 003, and p = 0.052 respectively). CONCLUSION: Patients are often instructed to maintain a full bladder during a course of external beam radiation therapy, in the hopes of decreasing bladder and small bowel toxicity. However, our study shows that large bladder volumes late in therapy are strongly associated with posterior prostate displacement. This prostate displacement may result in marginal miss.

Humans↗

PubMed2000

Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies.

PURPOSE: To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver RT. PATIENTS AND METHODS: From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 x 10 x 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT. RESULTS: The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P =.0003). CONCLUSION: The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.

Adult↗

PubMed1999

Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.

PURPOSE: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to < or =25% pre-RT flow at 12 months. RESULTS: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of < or =26 Gy should be a planning goal if substantial sparing of the gland function is desired.

Adult↗

PubMed1999

The effect of patient position and treatment technique in conformal treatment of prostate cancer.

PURPOSE: The relative value of prone versus supine positioning and axial versus nonaxial beam arrangements in the treatment of prostate cancer remains controversial. Two critical issues in comparing techniques are: 1) dose to critical normal tissues, and 2) prostate stabilization. METHODS AND MATERIALS: Ten patients underwent pretreatment CT scans in one supine and two prone positions (flat and angled). To evaluate normal tissue exposure, prostate/seminal vesicle volumes or prostate volumes were expanded 8 mm and covered by the 95% isodose surface by both 6-field axial and 4-field nonaxial techniques. A total of 280 dose-volume histograms (DVHs) were analyzed to evaluate dose to rectal wall and bladder relative to patient position and beam arrangement. A CT scan was repeated in each patient after 5 weeks of treatment. Prostate motion was assessed by comparing early to late scans by three methods: 1) center of mass shift, 2) superior pubic symphysis to anterior prostate distance, and 3) deviation of the posterior surface of the prostate. RESULTS: For prostate (P) or prostate/seminal vesicle (P/SV) treatments, prone flat was advantageous or equivalent to other positions with regard to rectal sparing. The mechanism of rectal sparing in the prone position may be related to a paradoxical retraction of the rectum against the sacrum, away from the P/SV. Although there was no clear overall preference for beam arrangement, substantial improvements in rectal sparing could be realized for individual patients. In this limited number of patients, there was no convincing evidence prostate position was stabilized by prone relative to supine position. CONCLUSIONS: Prone flat positioning was advantageous over other positions and beam arrangements in rectal sparing. This study suggests that patient position is a more critical a factor in conformal therapy than beam arrangement, and may improve the safety of dose escalation.

Humans↗

PubMed1999

Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients.

Tumor control probability (TCP) model calculations may be used in a relative manner to evaluate and optimize three-dimensional (3-D) treatment plans. Using a mathematical model which makes a number of simplistic assumptions, TCPs can be estimated from a 3-D dose distribution of the tumor given the dose required for a 50% probability of tumor control (D50) and the normalized slope (gamma) of the sigmoid-shaped dose-response curve at D50. The purpose of this work was to derive D50 and gamma from our clinical experience using 3-D treatment planning to treat non-small cell lung cancer (NSCLC) patients. Our results suggest that for NSCLC patients, the dose to achieve significant probability of tumor control may be large (on the order of 84 Gy) for longer (> 30 months) local progression-free survival.

Carcinoma, Non-Small-Cell Lung↗

PubMed1999

Use of segmental boost fields in the irradiation of inguinal lymphatic nodes.

En face electron fields to boost inguinal lymphatics have been used by oncologists for many years. With the introduction of multileaf collimators (MLC) and independent jaws, the practice of creating segmental fields to boost areas of interest has expanded. Typical anterior-posterior opposing field treatment of the pelvis may now be enhanced to include additional anterior segments to boost lymphatic tissue at a predetermined depth. This report illustrates the clinical implementation of one such segmental boost technique. Computer generated isodose plans utilize manual contour and CT-generated data for analysis of inguinal lymphatic depths. Potential areas of field overlap are discussed as well as the use of combined 6 and 15 MV photon energies to reduce areas of inhomogeneous dose. Technical details associated with MLC field size limits and other clinical factors are also discussed in relationship to smooth treatment delivery.

Groin↗

PubMed1999

A method for incorporating organ motion due to breathing into 3D dose calculations.

A method is proposed that incorporates the effects of intratreatment organ motion due to breathing on the dose calculations for the treatment of liver disease. Our method is based on the convolution of a static dose distribution with a probability distribution function (PDF) which describes the nature of the motion. The organ motion due to breathing is assumed here to be one-dimensional (in the superior-inferior direction), and is modeled using a periodic but asymmetric function (more time spent at exhale versus inhale). The dose distribution calculated using convolution-based methods is compared to the static dose distribution using dose difference displays and the effective volume (Veff) of the uninvolved liver, as per a liver dose escalation protocol in use at our institution. The convolution-based calculation is also compared to direct simulations that model individual fractions of a treatment. Analysis shows that incorporation of the organ motion could lead to changes in the dose prescribed for a treatment based on the Veff of the uninvolved liver. Comparison of convolution-based calculations and direct simulation of various worst-case scenarios indicates that a single convolution-based calculation is sufficient to predict the dose distribution for the example treatment plan given.

Algorithms↗

PubMed1999

Quantization of setup uncertainties in 3-D dose calculations.

Random setup errors can lead to erroneous prediction of the dose distribution calculated for a patient using a static computed tomography (CT) model. Multiple recomputations of the dose distribution covering the range of expected patient positions provides a way to estimate a course of treatment. However, due to the statistical nature of the setup uncertainties, many courses of treatment must be simulated to calculate a distribution of average dose values delivered to a patient. Thus, direct simulation methods can be time consuming and may be impractical for routine clinical treatment planning applications. Methods have been proposed to efficiently calculate the distribution of average dose values via a convolution of the dose distribution (calculated on a static CT model) with a probability distribution function (generally Gaussian) that describes the nature of the uncertainty. In this paper, we extend the convolution-based calculation to calculate the standard deviation of potential outcomes sigmaD(x,y,z) about the distribution of average dose values, and we characterize the statistical significance of this quantity using the central limit theorem. For an example treatment plan based on a treatment protocol in use at our institution, we found that there is a 68% probability that the actual dose delivered to any point (x,y,z) will be within 3% of the average dose value at that point. The standard deviation also yields confidence limits on the dose distribution, and these may be used to evaluate treatment plan stability.

Algorithms↗

PubMed1999

A mathematical model for correcting patient setup errors using a tilt and roll device.

An algorithm is presented for determining how to adjust the actuators of a tilt and roll table. The algorithm is based on a geometrical model of the table, which was designed with six degrees of freedom. This design and algorithm allows complete translational and rotational corrections to be applied to the target volume position on a daily basis.

Algorithms↗

PubMed1999

Conformal and intensity modulated irradiation of head and neck cancer: the potential for improved target irradiation, salivary gland function, and quality of life.

PURPOSE: To develop techniques which facilitate sparing of the major salivary glands while adequately treating the targets in patients requiring comprehensive bilateral neck irradiation (RT). PATIENTS AND METHODS: Conformal and static, multisegmental intensity modulated (IMRT) techniques have been developed. The salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms. Subjective xerostomia questionnaires have been developed and validated. The pattern of local-regional recurrences has been examined using CT scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans and regenerating the dose distributions at the recurrence sites. RESULTS: Target coverage and dose homogeneity in IMRT treatment plans were found to be significantly better than standard RT plans. Significant parotid gland sparing was achieved. The relationships among dose, irradiated volume and saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean dose of 26 Gy was found to be the threshold for stimulated saliva. Subjective xerostomia was significantly reduced in patients irradiated with parotid sparing techniques, compared to patients with similar tumors treated with standard RT. The large majority of recurrences occurred inside high-risk targets. CONCLUSIONS: Tangible gains in salivary gland sparing and target coverage are being achieved and an improvement in some measures of quality of life is suggested by our findings. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to targets judged to be at highest risk may improve tumor control.

Dose-Response Relationship, Radiation↗

PubMed1998

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-Response Relationship, Radiation↗