Principles of fractionated total body irradiation before bone marrow transplantation

The hyperfractioned total body irradiation has advantages in tumor control rate, patient tolerance and survival. The technical application is simple and easy to integrate in the daily routine of a radiotherapy department. The reduced time in the life island and the low incidence of acute reactions increases the patients quality of life. It turned out, that single dose TBI is not very suitable. This was already stated by Lester Peters in 1980.     

Basic and clinical studies of total body irradiation for bone marrow transplantation

Basic and clinical studies of total body irradiation (TBI) with respect to the dose distribution are described. TBI was performed with 10 MV X-rays at the Department of Radiology of Hyogo College of Medicine Hospital. Two opposed bilateral fields were used, the source-axis distance was 400 cm, and the dose rate was 10 cGy/min. At 55 cm from the rear concrete wall, the back-scattered radiation from the wall was 0.91% of the radiation dose. The beam flatness was +/- 2.9% within 130 cm of the diagonal by using a beam flattening filter improved. The surface dose was 93.5% of the peak dose by the acrylic bolus (1.5 cm thickness) placed on the source side 45 cm from the center of the body axis. We devised compensating filters using lead plates to improve dose distribution of the head, neck and thorax. The effectiveness of the compensating filters in producing a homogeneous dose distribution was checked by the thermoluminescent dosimeters (TLDs) in a Rando phantom. The average dose distribution to each site when the compensators used was 94% for the head, 104% for the neck, and 99% for the thorax when the scheduled dose was taken as 100%. TBI was performed 4 to 1 days before bone marrow transplantation, and 10 Gy was given in equal daily fractions of 2.5 Gy over 4 days. During TBI, the patients were placed in the supine position with the knees bent. The body surface dose was measured with pairs of TLDs at the head, neck, thorax, and pelvis in 32 patients. At the pelvis, the dose was measured simultaneously with an ionization chamber. The average doses were 91% for the head, 95% for the neck, 93% for the thorax, and 106% for the pelvis.     

Interstitial pneumonitis after allogeneic bone marrow transplantation following total body irradiation.

The records of 40 patients who received allogeneic bone marrow transplantation (BMT) at Hyogo College of Medicine under the same conditioning regimen using cyclophosphamide and total body irradiation (TBI) from January 1984 to August 1989 were analyzed. The dose rate of TBI was 10 cGy per minute, and the total dose was 10 Gy (2.5 Gy daily for 4 days). Interstitial pneumonitis (IP) occurred in 13 of 40 patients, and was fatal in five patients. The probability of developing IP during the first year was 31%. We performed univariate analysis on the following factors but did not find any significant risk factors for IP: age and sex of patient, sex mismatch, ABO mismatch, grade of acute graft-versus-host disease, post immunosuppression regimen, and number of marrow cells transfused.     

Total lymphoid irradiation and total body irradiation for allogeneic bone marrow transplantation in aplastic anemia

Between April 1980 and June 1989, 15 patients with severe aplastic anemia (SAA) were treated at Hyogo College of Medicine with bone marrow transplantation (BMT) after preparation consisting of cyclophosphamide (CY) and total lymphoid irradiation (TLI) or total body irradiation (TBI) for the purpose of reducing the incidence of graft rejection. All patients had initial evidence of engraftment after the first transplantation except for one patient who died of heart failure due to CY on the third day after transplantation and could not be evaluated for engraftment. Rejection later occurred in four of these 14 patients, who then underwent successful regrafting. One of these patients, who was conditioned with CY alone at the first grafting, underwent successful regrafting after a conditioning regimen of CY and TBI. In the other three patients, irradiation was performed twice as the conditioning regimen. Thus, 14 of 15 patients underwent successful BMT and are alive with restored hematopoietic function. From the above results, the combination of TLI or TBI and CY was considered to be very useful as a conditioning regimen for BMT in patients with SAA.     

Lung dose rate and interstitial pneumonitis in total body irradiation for bone marrow transplantation.

The effect of dose rate to the lungs and development of interstitial pneumonitis (IP) was evaluated in 114 bone marrow transplant patients receiving fractionated total body irradiation (TBI) (1200 rads TD in 6 fractions twice daily over 3 days) as part of their pre-conditioning regimen. The tumour dose (TD) was calculated as the mean lung dose as previously described (1). A 6MV linear accelerator at a mid-line dose rate of 7.5 rads/minute was used between March 1981 and June 1985 and a Co-60 source at 5 rads/minute thereafter. This resulted in a range of dose rates to the lung of between 6.9 and 8.9 rads/minute and 2.9 and 6.5 rads/minute respectively. In the majority of patients the aetiology of IP was investigated by lung biopsy with histology and culture. There was no statistically significant difference in the incidence of IP over the two sets of dose rates. Our study suggest that the incidence of IP using fractionated TBI is not influenced by dose rates below 8.9 rads per minute.     

Fractionated homogeneous whole body irradiation prior to bone marrow transplantation

At the University of Kiel, myeloid and acute lymphatic leukemia is treated since 1983 by total-body irradiation applied prior to bone marrow transplantation. Dose deviations in the midplane caused by the irregular surface and tissue inhomogeneities of the patient are reduced down to +/- 3.5% compared to the central ray, with the help of CT-based individual compensators. This method prevents above all an excessive dose to the lungs. The radiobiologic advantages of fractionated irradiation have been employed for all patients treated hitherto (n = 9). At present, a total body dose of 12 Gy in six fractions is applied within three days. There were no undesired acute radiogenic reactions except a mild acute mucositis found in all patients. Chronic side effects, especially in the lungs, were not demonstrated, too. However, the average follow-up time of 149 days has been rather short. One patient died from relapse of leukemia after a total dose of 10 Gy, another patient died because the transplanted bone marrow was rejected, and a third died from catheter sepsis. Six out of nine patients are in complete remission with a maximum index of Karnofsky. The limited experiences gained hitherto show that the homogenous accelerated-fractionated total-body irradiation offers essential advantages compared to non-compensated single dose irradiation with respect to the prevention of undesired radiogenic effects in sound tissues and that its therapeutic efficacy is at least the same.     

The incidence of interstitial pneumonitis: comparison of total body irradiation schedules for allogenic bone marrow transplantation

Interstitial pneumonitis (IP) is one of the major causes of death following bone marrow transplantation (BMT). This report deals with a comparison between data compiled from six centers concerning the essential factors responsible for the development of IP. Special concern has been paid to the idiopathic form of disease where TBI is thought to be the most important factor in its pathogenesis. Our own experience using different TBI modalities shows that the instantaneous dose rate seems to be an important factor in the development of IIP. Comparing the data from various centers it is not possible at the present time to recommend one optimal modality.     

CT analysis of lung density changes in patients undergoing total body irradiation prior to bone marrow transplantation

Sequential changes in lung density measured by CT are potentially sensitive and convenient monitors of lung abnormalities following total body irradiation (TBI). Methods have been developed to compare pre- and post-TBI CT of lung. The average local features of a cross-sectional lung slice are extracted from three peripheral regions of interest in the anterior, posterior, and lateral portions of the CT image. Also, density profiles across a specific region may be obtained. These may be compared first for verification of patient position and breathing status and then for changes between pre- and post-TBI. These may also be compared with radiation dose profiles through the lung. A preliminary study on 21 leukemia patients undergoing total body irradiation indicates the following: (a) Density gradients of patients' lungs in the antero-posterior direction show a marked heterogeneity before and after transplantation compared with normal lungs. The patients with departures from normal density gradients pre-TBI correlate with later pulmonary complications. (b) Measurements of average peripheral lung densities have demonstrated that the average lung density in the younger age group is substantially higher: pre-TBI, the average CT number (1,000 scale) is -638 +/- 39 Hounsfield unit (HU) for 0-10 years old and -739 +/- 53 HU for 21-40 years old. (c) Density profiles showed no post-TBI regional changes in lung density corresponding to the dose profile across the lung, so no differentiation of a radiation-specific effect has yet been possible. Computed tomographic density profiles in the antero-posterior direction are successfully used to verify positioning of the CT slice and the breathing level of the lung.     

Whole-body irradiation for bone marrow transplantation

High dose total body irradiation is widely used in conditioning regimens to treat patients undergoing bone marrow transplantation. Radiation-related complications observed in 67 patients who received total body irradiation and their correlation with physiopathological mechanism of clinical manifestations are discussed. Interstitial pneumonitis occurred in 9 patients in our study (14%); the relationship between the incidence of interstitial pneumonitis and many factors such as irradiation treatment techniques, pre-graft chemotherapy, bone marrow malignant as well hereditary diseases, are discussed and related to a detailed literature review. Radiation techniques are different in leukemic and thalassemic patients.     

Total body irradiation in the preparation of leukemic patients for bone marrow transplantation

Total body irradiation is today the main conditioning method for patients who have bone marrow transplantation. The most diffuse procedure, as proposed at the Fred Hutchinson Cancer Research Center of Seattle, has been employed in this study. Our clinical material comprises 16 patients; 5 with acute lymphoid leukemia; 5 with acute myeloid leukemia; 4 with chronic myeloid leukemia in accelerated fase; and 2 in blastic crisis. Clinical results and toxicity are discussed, with emphasis to interstitial pneumonia.     

Total body irradiation and bone marrow transplant

Any malignancy, mainly hematological, may be sensitive (with complete remission) to high-dose chemo and/or radiotherapy. The dose of most antineoplastic agents is limited by the toxicity to the normal marrow. The availability of marrow for transplantation (allogenic, syngenic or autologous), and the capability of reconstituting hematopoietic function, makes it possible to administer chemoradiotherapy in supralethal doses in an effort to kill a greater fraction of the malignant cells. Total Body Irradiation is used both to eradicate the malignant cells and to suppress host immune reactivity enough to prevent rejection of allogenic marrow. The transplanted allogenic marrow can also exert an antitumor effect. A survey of radiobiological studies undertaken is presented and preliminary results of a series of patients treated with TBI at ISSR are discussed.