Accuracy and precision of absorbed dose measurements for neutron therapy.

The occurrence of normal tissue complications and probability of tumor control are steep functions of absorbed dose. Consequently the delivery of the dose to the patient should be performed with a precision better than +/- 2% and an overall uncertainty less than +/- 5%. The sequence of dosimetry procedures to deliver the absorbed dose to the patient is analyzed with emphasis on the physical parameters involved in neutron dosimetry; the results of neutron dosimetry intercomparisons are summarized. The protocols for neutron dosimetry formulated by European and American physicists differ in a number of aspects, including the choice of the phantom material. For the treatment of a specific lesion, e.g., a tumor of the floor of the mouth, different treatment plannings have been suggested. Regarding the determination of total absorbed dose at a reference point in a phantom, the required overall uncertainty can be achieved for neutron energies up to 20 MeV. Because of differences in size, shape and composition between the phantom and the patient, somewhat larger uncertainties are to be anticipated for the actual treatment. Further experimental and theoretical studies are needed to obtain more reliable values for kerma in different elements and neutron sensitivity of the photon dosimeters for neutron energies in excess of 20 MeV.

Oestrogen receptors in rat mammary tissue and plasma concentrations of prolactin during mammary carcinogenesis induced by oestrogen and ionizing radiation.

Female-Sprague-Dawley rats received a subcutaneous implant containing 2 mg oestradiol at the age of 7 weeks. One week later half of the rats treated with oestrogen and half of the rats in an untreated control group were irradiated with 2 Gy (200 rad) of X-rays. The content of oestrogen receptor of the mammary tissue and the concentration of prolactin in the plasma were studied at intervals of 2 months for a period of 14 months after this treatment. Oestrogen treatment resulted in a decrease in the content of oestrogen receptors in the mammary tissue of both irradiated and non-irradiated rats. In oestrogen-treated rats, plasma prolactin was raised 10-50 times and pituitary tumours were observed. Radiation had no additional effect on the oestrogen-receptor content of mammary tissue or the concentration of plasma prolactin. The changes in the oestrogen-receptor content of mammary tissue and the prolactin concentration of plasma preceded the development of mammary tumours. It is suggested that the synergistic action of oestrogen and radiation on rat mammary tumour development is the result of a stimulation by oestrogen and/or prolactin of the sensitivity of the mammary gland to ionizing radiation.

Total body irradiation for treatment of haematological diseases.

The present status of total body irradiation (TBI) as a part of the treatment of haematological diseases was discussed during a separate symposium at the 5th Annual ESTRO meeting at Baden-Baden. The experimental techniques applied in Europe, the dosimetry for TBI, the radiobiological aspects and the late effects after TBI have been reviewed. For specific geometries, precautions have to be taken to avoid increased dose contributions at the skin due to electrons scattered from the wall behind the patient. CT data can be useful for the individualization of the exposure regimen of patients with extreme variations in lung anatomy or lung density. An appreciable number of centres apply in vivo dosimetry, however, special care is needed for the correct interpretation of the dosimeter readings. A number of late effects, including induction of cataract and secondary tumours has been observed after TBI. The techniques applied for TBI at the various centres and the temporal administration of the dose show wide variations. At present, the patient material is too heterogeneous to draw any conclusion about an optimum schedule for a TBI regimen. Further cooperation between clinicians, radiobiologists and radiation physicists has to be established to achieve consistency and further improvement of the results after TBI.

Late effects of total body irradiation in correlation with physical parameters.

Clear and complete documentation of the physical parameters of total body irradiation (TBI) is one of the essential requirements for the evaluation and improvement of the clinical results of TBI. Concerning the dosimetric aspects of TBI, a number of recommendations have been formulated with emphasis on basic dosimetry, patient dosimetry and dose specification. The dosimeters should be calibrated regularly with reference to the absorbed dose in water. Depth dose measurements should be performed in water equivalent phantoms of specified dimensions. It has been strongly suggested to measure the absorbed dose at the surface of the patient at 8 different regions at the entry and exit of the beam under TBI conditions. The reference dose to the patient should be specified as the total dose to mid abdomen at the height of the umbilicus. As an independent parameter, the lung dose should be specified as the mean dose in the central region of the shielded part of both lungs. Recent, more complete, information on the physical and dosimetric aspects of TBI will be incorporated in the registry of the European Bone Marrow Transplant Group (EBMT). A cooperation has been established between the EBMT and the European Late Effects Project Group (EULEP) to study the development of late effects in man caused by ionising radiation.

Techniques applied for total body irradiation.

In this review, different techniques of total body irradiation are discussed with special attention to their advantages and disadvantages. The results of an EBMT questionnaire, which was sent out to the European TBI centres, are also presented. It turned out that there exists a great variety in techniques, total doses, and fractionation schedules used all over Europe. It was also clear that the documentation concerning dosimetry and the time factor in TBI still has some deficiencies. Therefore, a proposal is now made for reporting the technical and dosimetric aspects used in total body irradiation in an unambiguous manner.

Assessment of a carcinogenic risk for treatment of Graves' ophthalmopathy in dependence on age and irradiation geometry.

In view of the probable carcinogenic risk due to the irradiation of Graves' ophthalmopathy in young patients the effective dose was assessed for two geometries. Adjusting the field to the conical outline of the orbit resulted in appreciable reduction in dose to uninvolved areas such as brain and bone marrow. In Leiden and in Essen the initial target dose was 20 Gy in 10 fractions of 2 Gy. Since 1996 the target dose in Essen was lowered to 10 fractions of 1.6 Gy with equal positive results. The combined effect of field optimization and 20% reduction in target dose has lowered the effective dose from 65 to 34 mSv. The attributable lifetime risk for fatal malignancies of 0.3% as a population average will be considerably reduced when the exposure occurs at older age.

The carcinogenic risk of high dose total body irradiation in non-human primates.

PURPOSE: High dose total body irradiation (TBI) in combination with chemotherapy, followed by rescue with bone marrow transplantation (BMT), is increasingly used for the treatment of haematological malignancies. With the increasing success of this treatment and its current introduction for treating refractory autoimmune diseases the risk of radiation carcinogenesis is of growing concern. Studies on tumour induction in non-human primates are of relevance in this context since the response of this species to radiation does not differ much from that in man. MATERIALS AND METHODS: Since the early sixties, studies have been performed on acute effects in Rhesus monkeys and the protective action of bone marrow transplantation after irradiation with X-rays (average total body dose 6.8 Gy) and fission neutrons (average dose 3.4 Gy). Of those monkeys, which were irradiated and reconstituted with autologous bone marrow, 20 animals in the X-irradiated group and nine animals in the neutron group survived more than 3 years. A group of 21 non-irradiated Rhesus monkeys of a comparable age distribution served as controls. All animals were regularly screened for the occurrence of neoplasms. Complete necropsies were performed after natural death or euthanasia. RESULTS: At post-irradiation intervals of 4-21 years an appreciable number of tumours was observed. In the neutron irradiated group eight out of nine animals died with one or more malignant tumours. In the X-irradiated group this fraction was 10 out of 20. The tumours in the control group, in seven out of the 21 animals, appeared at much older age compared with those in the irradiated cohorts. The histogenesis of the tumours was diverse with a preponderance of renal carcinoma, sarcomas among which osteosarcomas, and malignant glomus tumours in the irradiated groups. CONCLUSIONS: When corrected for competing risks, the carcinogenic risk of TBI in the Rhesus monkeys is similar to that derived from the studies of the Japanese atomic bomb survivors. The increase of the risk by a factor of 8, observed in the monkeys, indicates that patients are likely to develop malignancies more frequently and much earlier in life after TBI than non-exposed individuals. This finding underlines the necessity of regular screening of long-term surviving patients subjected to TBI and BMT.

Probable risk of tumour induction after retro-orbital irradiation for Graves' ophthalmopathy.

Retrobulbar irradiation for Graves' ophthalmopathy is considered as a safe treatment and has recently been recommended as the initial treatment for patients with moderately severe eye problems. However, calculations using risk factors presently known reveal a theoretical risk of radiation-induced cancer of 1.2%. Therefore, the authors suggest that this treatment should be reserved for the elderly patient, for example above the age of 40-50 years.

Effects of total-body irradiation on growth, thyroid and pituitary gland in rhesus monkeys.

PURPOSE: To investigate the effect of total-body irradiation (TBI) on growth, thyroid and pituitary gland in primates. METHODS AND MATERIALS: Thirty-seven rhesus monkeys (mean age 3.1+/-0.6 years) received either a low-dose (4-6 Gy) TBI (n = 26) or high-dose (7-12 Gy) TBI (n = 11) and were sacrificed together with 8 age-matched controls after a post-irradiation interval of 5.9+/-1.5 years. Anthropometric data were collected: thyroid and pituitary glands were examined; serum levels of thyroid stimulating hormone (TSH), free thyroxin (FT4), insulin-like growth factor-I (IGF-I) and its binding protein-3 (IGFBP-3) were measured. RESULTS: Decrease in final height due to irradiation could not be demonstrated. There was a dose-dependent decrease in body weight, ponderal index, skinfold thickness and thyroid weight. The latter was not accompanied by elevation of TSH or decrease in FT4. Structural changes in the thyroid gland were found in 50% of the irradiated animals. Levels of IGF-I and IGFBP-3 did not differ between the dose groups, but the high-dose group had a lower IGF-1/IGFBP-3 ratio. CONCLUSION: Total body irradiation had a negative effect on body fat. There was no evidence of (compensated) hypothyroidism, but dose-dependent decrease in thyroid weight and changes in follicular structure suggest some effect of TBI on the thyroid gland. The decreased IGF-I/IGFBP-3 ratio in the high-dose group can indicate that the somatotrophic axis was mildly affected by TBI. These results show that TBI can have an effect on the physical build and thyroid gland of primates even in the absence of cytostatic agents or immunosuppressive drugs.

Actuarial analysis of the hazard for mammary carcinogenesis in different rat strains after X- and neutron irradiation.

Mammary carcinogenesis in three different rat strains has been studied after single and fractionated irradiations with X-rays and monoenergetic neutrons of three energies. The aims of the programme are the investigation of the nature of the dose-effect relationships, and the determination of the relative biological effectiveness (RBE) of neutrons. Histopathological examinations of tumours has been completed and dose-effect relations are reported separately for the induction of benign and malignant lesions. Appropriate corrections have been made for competing risks in the tumour rate analysis. The probability curves for survival without evidence of tumours have been described by Weibull distributions. This continuous parametric failure-time model is used to derive the relative excess hazard for exposure to X-rays and neutrons. The different rat strains show considerable differences in susceptibility for the induction of cancer by radiation. In general linear dose-response curves have been observed for mammary tumourigenesis in the three rat strains for both X-rays and fast neutrons. Within the statistical precision of the data a dependence of the RBE on neutron dose cannot be recognised. The highest RBE values, varying between 7 and 15 for different types of tumours in the three rat strains have been observed for 0.5 MeV neutrons. These RBE values are lower in general than those observed by other groups for beams of comparable energy.

Effects of X-irradiation, ovariohysterectomy and estradiol-17 beta on incidence, benign/malignant ratio and multiplicity of rat mammary neoplasms--a preliminary report.

An overview is given of the effects of X-irradiation, ovariohysterectomy and estradiol-17 beta administration on mammary tumorigenesis in females of 3 rat strains, viz. the WAG/Rij, BN/BiRij and SD. The 3 rat strains differed significantly in their spontaneous mammary tumor incidence. Female SD rats had the highest incidence (47%) and female BN/BiRij rats the lowest (17%). Female WAG/Rij rats had an intermediate incidence of 29%. The benign/malignant ratio in female WAG/Rij, BN/BiRij and SD rats was 1.0, 2.0 and 7.3, respectively. The average number of mammary gland neoplasms per untreated tumor-bearing female was 1.2 in the WAG/Rij, 1.0 in the BN/BiRij and 1.6 in the SD, whereas the respective maximum numbers were 2, 1 and 5. Ovariohysterectomy almost entirely prevented mammary tumor formation in all 3 rat strains, whereas estrogen treatment enhanced it. In addition, estrogen treatment resulted in an increased number of mammary tumors per tumor-bearing female and changed the benign/malignant ratio into the direction of malignant. X-irradiation increased the mammary tumor incidence in all 3 rat strains, especially of the benign tumors. Estrogen potentiated the effect of irradiation. An effect of irradiation on mammary tumorigenesis was not observed in ovariohysterectomized females of all 3 rat strains.

The gene transfer-misrepair hypothesis of radiation carcinogenesis tested for induction of mammary tumours in rats.

Mammary tumour induction was studied in female WAG/Rij rats following exposure with single doses of 0.3 and 1.2 Gy gamma radiation and with the same total doses delivered in fractions of 2.5 and 10 mGy respectively at intervals of 12 h. All rats were implanted with pellets containing 2 mg of estradiol-17 beta prior to the irradiation. The occurrence of mammary carcinomas and of fibroadenomas was recorded. The relative excess hazard for tumour induction was lower for the fractionated regimens than for the single dose exposures. The results are compatible with the predictions of the gene transfer-misrepair hypothesis for radiation carcinogenesis.

Radiation exposure in standard and high-resolution chest CT scans.

It has been suggested that radiation doses due to high-resolution computed tomography (HRCT) of the chest are considerably higher than those from conventional CT. We compared the effective dose (E, mSv) in conventional chest CT (10-mm contiguous slices) and HRCT (1.5-mm slices, gap 10 mm). In our study, the effective dose from a HRCT (0.98 mSv) is about 6.5 times less than the effective dose from a standard CT scan (6.5 mSv), and only a factor 12 higher than from a conventional chest examination (0.085 mSv).

Relative biological effectiveness for neutron carcinogenesis in monkeys and rats.

The risks of total-body irradiation with large doses of X rays (average dose 6.7 Gy) and fission neutrons (average dose 3.4 Gy) were investigated by keeping a group of long-term surviving monkeys from an experiment on acute effects under continuous observation. On the basis of the number of animals developing tumors in each group as a function of the total observation period and the average absorbed dose, relative biological effectiveness (RBE) values between 4 and 5 have been derived at these high dose levels. In experiments on mammary carcinogenesis in rats the highest RBE values are observed for neutrons with energies of 0.43 to 1 MeV as produced by the p + T reaction or by the fission process. Based upon linear dose-response curves for neutrons and X rays, a maximum RBE value of 15 was observed for induction of adenocarcinomas in WAG/Rij rats. Appreciably higher RBE values would be obtained if the results of the gamma-ray exposure, indicating a nearly quadratic dose-response relationship, were used as a baseline. For radiation protection applications it should be realized, however, that such an increase will be caused by the lower efficiency of low-linear-energy-transfer radiation rather than by an increase in efficiency of the neutron irradiation at low doses.

Simulation of measurements of uptake of 123I-iodide in the thyroid of fetal chimpanzees.

The quantitative assessment of the uptake of 123I-iodide (123I-) in the fetal thyroid in vivo was simulated in phantom measurements. First, the relationship between the depth of the fetal thyroid phantom and the two-peak ratio, the ratio of the counts in the gamma-ray and the X-ray energy windows of the registered spectrum, was determined. Subsequently, the attenuation of the gamma-ray signal in relationship to the depth of the fetal thyroid phantom was determined. Finally, the relationship between the two-peak ratio and the attenuation of the gamma-ray signal was deduced. For a reliable correlation, the signal recorded from the radioactivity surrounding the fetal thyroid phantom has to be subtracted from that obtained with the fetal thyroid phantom present. A correction curve was generated to be applied to the in vivo measurements. It is concluded that with this method determination of uptake of 123I- in the fetal thyroid is feasible.

Protection of the maternal and fetal thyroid from radioactive contamination by the administration of stable iodide during pregnancy. An experimental evaluation in chimpanzees.

The safety and efficacy of the administration of stable iodide to protect the fetal thyroid from exposure to radioactive iodide were investigated in chimpanzees in weeks 19 to 21 of pregnancy. The mean 24-h uptake of iodide in the fetal thyroid, determined with 123I-, was 1.8%. Administration of stable potassium iodide (KI), 0.65, 1.95 or 6.5 mg per kg body weight, 1 h before tracer injection reduced the fetal uptake satisfactorily. Only the higher doses were effective after 20 h. Excess iodide may impair a child's thyroid status. However, adverse effects were not found during the 11 days the animals ingested these doses. Tracer concentrations in the amniotic fluid were 30- to 130-fold lower than in the urine. The dose to the fetus from radioactivity in the maternal bladder was estimated by computer simulation. The potential increment of the risk from this dose during the ingestion of stable iodide is smaller than the reduction of risk achieved by inhibiting the uptake of radioactive iodide by the fetal thyroid. The conclusion of the experiments is that stable iodide can be used safely and effectively to protect the fetal thyroid against contamination with radioactive iodine.

Protection of the infant thyroid from radioactive contamination by the administration of stable iodide. An experimental evaluation in chimpanzees.

Protection of the thyroid from radioactive contamination by the administration of stable iodide was investigated in chimpanzees aged 2 to 98 weeks. The uptake of iodide in the thyroid was measured with 123I-. The animals were subjected to a control measurement first, and subsequently the thyroid uptake of 123I- was determined twice; once at the start and once at the end of 11 days of ingestion of 0.5, 1.5 or 5.0 mg of stable iodide per kg body weight per day. The three doses of iodide reduced the control thyroid iodide uptake of 10 to 30% to lower than 1% when ingested 1 h before exposure to the tracer and to 2-4% when ingested 20 h before exposure. In the latter experiments 0.5 mg iodide/kg was less effective than doses of 1.5 mg/kg or higher. The physiological state of the thyroid of control infant chimpanzees does not differ from that of human infants. Incidentally, an increased level of TSH was found during the ingestion of iodide, but with unaltered thyroxine levels. Therefore, it is concluded that a daily dose of 1.5 mg stable iodide/kg body weight and higher offers optimal protection of the thyroid against exposure to radioactive iodine in infants and that, when used during 10 days, it leaves the thyroid unaffected.

The effects of fractionated gamma irradiation on induction of mammary carcinoma in normal and estrogen-treated rats.

The effects of dose fractionation on induction of mammary carcinoma were studied in normal and estrogen-treated female rats of the inbred WAG/Rij strain. Groups of 40 animals received total-body doses of 1 or 2 Gy of (137)Cs gamma radiation, administered in fractions of 2.5, 10 or 40 mGy with intervals of 12 h, or in fractions of 10 mGy with intervals of 2, 5 or 24 h. The irradiations were started at the age of 8 weeks. Estrogen treatment was accomplished by implantation of a pellet containing estrogen at the age of 6 weeks. All mammary tumors were resected and classified histologically as carcinoma or fibroadenoma. The age-specific incidence of mammary carcinoma was compared with that in control groups of unirradiated normal or estrogen-treated rats and was expressed as excess normalized risk, using lifetime statistical analysis with both parametric and nonparametric methods. The data were also compared to the results of single-dose experiments reported in previous papers. Fractionated irradiation increased the risk of mammary cancer in both normal and estrogen-treated rats compared to the corresponding unirradiated control group. The excess normalized risk per unit of total dose was approximately equal with or without estrogen treatment. Without estrogen treatment, the effects of the single-dose and fractionated irradiations were approximately equal. In estrogen-treated animals, however, single-dose irradiation was up to 15 times more carcinogenic than the fractionated exposures. This fractionation effect appeared to vanish for total doses below approximately 0.3 Gy. With estrogen treatment, the excess normalized risk was significantly higher for dose fractions of 40 mGy than for fractions of 10 mGy. The risk was also markedly higher for fractionation intervals of 2 or 5 h than for intervals of 12 or 24 h. The results of these experiments show that the effects of dose fractionation on the induction of mammary carcinoma may depend on hormonal status, the total dose delivered, the dose per fraction, and the fractionation interval.

Neoplastic transformation of C3H 10T1/2 cells: a study with fractionated doses of monoenergetic neutrons.

As most occupational and environmental exposures to ionizing radiation are at low dose rates or in small dose fractions, risk estimation requires that the effects of the temporal distribution of dose are taken into account. Previous in vitro studies of oncogenic transformation, as well as in vivo studies of carcinogenesis induced by high-LET radiation, yielded controversial results concerning the presence of an inverse dose-rate effect. The present study tested the influence of one scheme of dose fractionation of monoenergetic neutrons on neoplastic transformation of C3H 10T1/2 cells. Neutrons of 0.5, 1.0 and 6.0 MeV were used. Cells were exposed to doses of 0.25 and 0.5 Gy, given acutely or in five fractions at 2-h intervals. The acute and fractionated irradiations with each energy were done on the same day. No significant difference between the two irradiation modes was found for both cell inactivation and neoplastic transformation at all energies. These results are in agreement with our data for fractionated fission-spectrum neutrons from the RSV-TAPIRO reactor.

Induction of mammary tumors in rats by single-dose gamma irradiation at different ages.

The effect of age at exposure on induction of mammary tumors was studied in female rats of the inbred WAG/Rij strain. Groups of 40 animals were exposed to a single total-body dose of 1 or 2 Gy of 137Cs gamma radiation at ages of 8, 12, 16, 22, 36 or 64 weeks and were observed for life. Mammary tumors, identified as nodules persisting and growing for 6 weeks, were resected and classified histologically as carcinoma or fibroadenoma. The age-specific incidence of mammary carcinoma was compared with that in a group of 120 unirradiated control rats, using lifetime statistical analysis with both parametric and nonparametric methods. The excess normalized risk of carcinoma was 0.9 for 1 Gy and 2.2 for 2 Gy in age groups 8-36 weeks, with no significant differences between the age groups. However, irradiation at 64 weeks yielded fewer carcinomas than in the controls, the excess normalized risk being -0.7 and -0.3 for 1 and 2 Gy, respectively. The occurrence of one or more fibroadenomas did not influence the incidence of carcinoma. The present data agree closely with the results reported previously for rats irradiated at age 8 or 17 weeks with a dose of 1.2 Gy. The reduced risk of radiation exposure at midlife is consistent with the available epidemiological data for exposed women. Although our findings have been obtained with a single total-body dose that is several orders of magnitude higher than the multiple doses delivered to the mammary gland during mammography, it is suggested that radiological screening for mammary cancer after the age of menopause will not increase the normal incidence of breast cancer.