Normalized Total Dose Research Articles

Beam intensity modulation for penumbra enhancement in the treatment of lung cancer

Purpose: A treatment planning study was performed for patients with lung cancer in order to investigate the extent to which doses to critical structures could be reduced by penumbra enhancement at the superior and inferior field edges, using beam intensity modulation (BIM) with a multileaf collimator. By applying two independent published models for the prediction of the incidence of normal tissue complications, the potential for dose escalation without increasing the incidence of pneumonitis was estimated. Methods and Materials: For 12 patients, the standard treatment technique was compared with the BIM technique using the Cadplan 3D planning system (Varian-Dosetek). Dose distributions in the healthy lung tissue were evaluated by considering both lungs minus the tumor as one functional unit. The following parameters were compared: (i) the average normalized total dose (NTD), (ii) the lung volume receiving an NTD of more than 20 Gy, and (iii) the calculated normal tissue complication probability (NTCP). Results: Due to the applied BIM technique, the field lengths could be reduced by 1.4 cm for all patients, while achieving a minimum dose at the superior and inferior parts of the target of 95% of the isocenter dose. Compared to the standard technique, BIM reduced the patient mean of the average NTD for the healthy lung tissue from 16.5 to 15.3 Gy. The volume of healthy lung tissue receiving an NTD of 20 Gy or more was reduced by 9.7% (range 2.2 to 23.1%). The calculated NTCP reduced from 10.7% to 7.6% on average. The length of the esophagus that received a dose of 60 Gy or more could be reduced for 5 of the 6 stage III patients in this study. Based on equal lung NTCPs for the standard technique and the BIM technique, a mean dose escalation of 5.7 Gy (range 1.1 to 16.0 Gy) was possible for the 12 patients in this study. Based on equal average NTDs for the two techniques, the patient mean of the allowed dose escalation was 6.5 Gy (range 1.1 to 18.2 Gy). All dose escalations would be possible without exceeding the spinal cord tolerance dose. Conclusions: The BIM technique reduced the dose delivery to critical tissues. Two published methods for estimating the incidence of pneumonitis both pointed to a potential for dose escalation of 6 to 7 Gy on average with the BIM technique, without increasing the incidence of pneumonitis. For 2 of the 12 patients in this study the estimated allowed dose escalation even exceeded 15 Gy.

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 α/β 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, NTD mean, 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, NTD mean, 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 NTD mean. The data were fitted to the Lyman model with NTD 50 = 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 NTD mean 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 NTD 50 = 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, NTD mean, is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose–effect relation between the NTD mean 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.

Late Complications After Postoperative Radiotherapy in Endometrial Cancer: Analysis of 317 Consecutive Cases With Application of Linear-Quadratic Model

Purpose: To evaluate the incidence and risk factors for late complications after postoperative radiotherapy in endometrial cancer patients. Methods and Material: We performed a detailed retrospective analysis of 317 endometrial cancer patients given postoperative radiotherapy. A total of 247 patients (78%) received both intracavitary (BRT) and external beam irradiation (XRT); 49 patients (15%) received only BRT, and 21 (7%) only XRT. BRT included radium (Ra) and cesium (Cs). The mean dose rate for both isotopes at 0.5 cm from the applicator surface was 0.47 ± 0.06 and 1.42 ± 0.41 Gy/h, and the mean total dose was 50.5 ± 10.3 and 48.4 ± 15.0 Gy, respectively. Mean BRT dose at 0.5 cm was 50.1 ± 11.7 Gy (range 14.5–71.0). Mean XRT dose in the International Commission on Radiation Units and Measurements (ICRU) reference point was 49.0 ± 3.7 Gy (range 22.0–66.0) given in fractions of 1.54–2.49 Gy (mean 2.0 ± 0.17) with a two- or four-field technique. Follow-up ranged from 4 to 21 years (median 7.3). Normalized total dose (NTD) including XRT and BRT doses was calculated based on a linear quadratic equation. Results: Five-year overall survival rate was 75%, and 5-year disease-free survival (censored for noncancer deaths) was 81%. Late radiotherapy complications of any grade occurred in 158 patients (51%), including bowel complications in 41% and urinary bladder complications in 21%. A total of 37 grade 3 or 4 complications were observed in 33 patients (11%), of whom 32 were treated with both XRT and BRT. Severe bowel and/or urinary bladder complications occurred in 24 patients: in 14 of 72 patients (19.4%) who received XRT and Cs BRT, and in 10 of 172 patients (6.0%) applied XRT and Ra BRT. The higher proportion of severe bowel and/or bladder complications in the former group was due to the particularly frequent rate of these events (30.0%) in a subset of 47 patients who received XRT combined with Cs BRT at the dose rate of 1.7 Gy/h and the total BRT dose of 60 Gy. Higher NTD, XRT fraction dose, BRT dose rate, Cs BRT, two-field XRT technique, short overall radiotherapy time, and older age were correlated with increased late-event risk in univariate analysis. Multivariate Cox analysis demonstrated that the independent risk factors for late bowel complications were NTD ( p = 0.000) and BRT dose rate ( p = 0.036), whereas for bladder complications they were BRT dose rate ( p = 0.005) and XRT fraction dose ( p = 0.041). Neither clinical factor (age, parity, prior abdominal surgery, FIGO stage, diabetes mellitus, or hypertension) nor the surgery-to-radiotherapy interval, nor overall radiotherapy time was independently associated with the risk of late bladder or bowel complications. Conclusions: The risk of late complications after postoperative radiotherapy in endometrial cancer depends mainly on treatment-related factors: NTD, BRT dose rate, and XRT fraction dose. The use of combined XRT and BRT increases the risk of late effects. NTD calculations including BRT dose rate and XRT fraction dose enable estimation of radiobiologically equivalent dose and can decrease the risk of mistakes when the radiotherapy regimen is changed.

Radiotherapy Alone for Non-Small Cell Lung Carcinoma Five-year disease-free survival and patterns of failure

One hundred and fifty-three patients with inoperable non-small cell lung cancer (NSCLC) treated with radiotherapy alone have been retrospectively analysed. Normalized Total Dose (NTD) as defined by Macejewski, TN-stage (AJC-system) and histology have been examined with respect to 5-year disease-free survival (DFS) and the patterns of failure so as to identify subgroups of patients that routinely should be treated with radical intent. The 5-year DFS for T1, 2-N0, 1 and T3-N0, 1 staged patients was 30% (7/23) and 25% (4/16) respectively when the tumor NTD (a/b = 10 Gy) was 56-64 Gy vs. 12% (5/41) and 0% (0/10) when the NTD was 48-55 Gy. This difference was statistically significant for the squamous cell histology group. The higher doses significantly altered the patterns of death in N0, 1 staged squamous cell carcinoma and adenocarcinoma patients. Forty-five percent (22/55) and 41% (12/29) of squamous cell and adenocarcinoma patients respectively, died from local relapse without evidence of distant metastases when NTD less tha 55 Gy were given vs. 21% (9/42) and 13% (2/15) when the NTD delivered was 56-64 Gy (p < 0.05). Although for N2, 3 staged patients or patients with direct extension of the tumor into the mediastinum death from local relapse occurred in 38% (10/26) of the high NTD treated patients vs. 51% (19/37) of the low-dose treated ones, the difference was not statistically significant. It is concluded that NSCLC patients should not à priori be considered as non-radiocurable. At least 30% of the patients with early local stages can be long-term disease-free survivors with radiation NTD up to 60 Gy and better results are to be expected with higher doses. Advanced T-stage without mediastinal involvement should be treated with radical intent since a high NTD could give cure rates of over 25%. The disappointing results for patients with mediastinal disease could perhaps be attributed to the low NTD delivered. For patients with good performance status, hyperfractionated regimens delivering high tumor doses should be tested and chemotherapy should be adapted to these radiation treatment schedules.

Dose and volume effects on fibrosis after breast conservation therapy

Purpose : To analyze factors involved in the development of fibrosis in the boost area after breast conservation therapy (BCT) in patients treated with continuous low dose rate iridium implants following 50 Gy whole breast irradiation. Methods and Materials : Fibrosis was estimated by palpation in 404 patients by four physicians. The median follow-up (FUP) duration was 70 months (range 30–133 months). Original implant data were used for reconstruction and dose-volume calculations. The total dose of the external whole breast irradiation and iridium implants was expressed in Normalized Total Dose (NTD): the total dose given in fractions of 2 Gy, which is biologically equivalent to the actual dose given according to the linear-quadratic model, using an α/ β value of 2 Gy, and 1.5 h for the recovery half-life of sublethal damage repair. To identify predictors of fibrosis we used a proportional odds model in a polychotomous logistic regression analysis. Results : Seven independent factors were identified that were related to the severity of fibrosis: age, duration of FUP, clinical T-size, photon beam energy, NTD level, implant volume, and adjuvant chemotherapy. From the proportional odds model, a volume exponent could be estimated (0.16 ± 0.04) that enabled us to determine dose-effect relations for different volumes. A 10-fold higher risk of fibrosis was seen when the total dose was above 79 Gy as compared with doses lower than 70 Gy. A fourfold increase in risk of fibrosis was seen for each 100 cm 3 increase in irradiated boost volume. The use of adjuvant chemotherapy resulted in a twofold increase in the risk of fibrosis (dose modifying factor approximately 1.08). The application of Co-60 beams had a similar effect. The relative odds for the other factors were smaller (1.4 for each 10 years of older age, and 1.2 for clinical T-size over 20 mm). The FUP-period had a nonlinear effect: relative odds 2.2 at 6 years, 3.6 at 7–8 years, and 2.8 at 9–11 years. The dose rate (mean 0.57, range 0.26 – 0.89 Gy/h) had no influence on the development of fibrosis and there was no correlation between dose rate and irradiated volume. Conclusions : To optimize cosmetic results after BCT, both the total dose and the irradiated volume should be kept as low as possible. Minimum effective dose levels still have to be established. The boost volume can be minimized by more conformal brachytherapy techniques and optimal localization. It may be worthwhile to take adjuvant chemotherapy into account in decisions on boost dose levels.

Quantitative effect of combined chemotherapy and fractionated radiotherapy on the incidence of radiation-induced lung damage: A prospective clinical study

Purpose : The objective of this work was to assess the incidence of radiological changes compatible with radiation-induced lung damage as determined by computed tomography (CT), and subsequently calculate the dose effect factors (DEF) for specified chemotherapeutic regimens. Methods and Materials : A prospective, clinical study was conducted to determine the response of normal lung tissue to combined chemotherapy and radiotherapy. Radiation treatments were administered once daily, 5 days-per-week. Six clinical protocols were evaluated: ABVD (adriamycin, bleomycin, vincristine, and DTIC) followed by 35 Gy in 20 fractions; MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) followed by 35 Gy in 20; MOPP/ABVD followed by 35 Gy in 20; CAV (cyclophosphamide, adriamycin, and vincristine) followed by 25 Gy in 10; and 5-FU (5-fluorouracil) concurrent with either 50–52 Gy in 20–21 or 30–36 Gy in 10–15 fractions. CT examinations were taken before and at predetermined intervals following radiotherapy. CT evidence for the development of radiation-induced damage was defined as an increase in lung density within the irradiated volume. The radiation dose to lung was calculated using a CT-based algorithm to account for tissue inhomogeneities. Different fractionation schedules were converted using two isoeffect models, the estimated single dose (ED) and the normalized total dose (NTD). Results : A total of 102 patients were entered and 70 completed the study. Forty-two patients developed CT changes compatible with lung damage. The actuarial incidence of radiological pneumonitis was 71% for the ABVD, 49% for MOPP, 52% for MOPP/ABVD, 67% for CAV, 73% for 5-FU radical, and 58% for 5-FU palliative protocols. Depending on the isoeffect model selected and the method of analysis, the DEF was 1.11–1.14 for the ABVD, 0.96–0.97 for the MOPP, 0.96–1.02 for the MOPP/ABVD, 1.03–1.10 for the CAV, 0.74–0.79 for the 5-FU radical, and 0.94 for the 5-FU palliative protocols. Conclusion : Quantitative dose effect factors (DEF) were measured by comparing the incidences of CT-observed lung damage in patients receiving chemotherapy and radiotherapy to those receiving radiotherapy alone. The addition of ABVD or CAV appeared to reduce the tolerance of lung to radiation.

The simultaneous boost technique: the concept of relative normalized total dose

The simultaneous boost technique in radiotherapy consists of delivering the boost treatment (additional doses to reduced volumes) simultaneously with the basic (large-field) treatment for all treatment sessions. Both the dose per fraction delivered by the basic-treatment fields and by the boost-treatment fields have to be reduced to end up with the same total dose in the boost volume as in the original schedule, where the basic treatment preceded the boost treatment. These dose reductions and corresponding weighting factors have been calculated using the linear-quadratic (LQ) model and the concept of Normalized Total Dose (NTD). Relative Normalized Total Dose (RNTD) distributions were computed to evaluate the dose distributions resulting for the simultaneous boost technique with respect to acute and late normal tissue damage and tumor control. For the example of the treatment of prostatic cancer the weighting factors were calculated on the basis of the NTD for late normal tissue damage. For the treatment of oropharyngeal cancer the NTD for acute normal tissue damage was used to determine the weighting factors. In this last example a theoretical sparing of late normal tissue damage can be demonstrated. A second advantage of the simultaneous boost technique is that the megavoltage images of the large basic-treatment fields facilitates the determination of the position of the patient with respect to the small boost-treatment fields.

Use of normalized total dose to represent the biological effect of fractionated radiotherapy

There are currently a number of radiobiological models to account for the effects of dose fractionation and time. Normalized total dose (NTD) is not another new model but is a previously reported, clinically useful form in which to represent the biological effect, determined by any specific radiobiological dose-fractionation model, of a course of radiation using a single set of standardized, easily understood terminology. The generalized form of NTD reviewed in this paper describes the effect of a course of radiotherapy administered with nonstandard fractionation as the total dose of radiation in Gy that could be administered with a given reference fractionation such as 2 Gy per fraction, 5 fractions per week that would produce an equivalent biological effect (probability of complications or tumor control) as predicted by a given dose-fractionation formula. The use of normalized total dose with several different exponential and linear-quadratic dose-fraction formulas is presented.