Complicating issues in complication reporting.
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Data Interpretation, Statistical↗
Biomedical subjects
H R Withers
Publications and source records attributed to H R Withers.
Dose-response relationship for radiation therapy of subclinical disease.
PURPOSE: To determine the dose-response relationship for elective treatment of subclinical metastatic deposits and validate a model for metastatic tumor cell burden. METHODS AND MATERIALS: The incidence of overt metastases in electively irradiated potential sites of spread from carcinomas of the head and neck, breast, cervix, ovary, lung, and testis, and from melanomas and osteosarcomas, was compared with the incidence in patients not receiving elective irradiation. The reduction in incidence of metastases was analyzed as a function of radiation dose. RESULTS: The dose-response curve for control of subclinical metastases is linear and shallow, and extrapolates to a dose intercept not demonstrably different from zero. A small threshold may reflect growth of residual micrometastases between treatment for the primary and elective irradiation. The shallow linear dose response reflects interpatient heterogeneity in metastatic tumor cell burden, ranging from 1 to M cells, where M is the upper limit of clinical undetectability. While a dose of 50 Gy in 2 Gy fractions is necessary to achieve an overall 90% reduction in the incidence of metastases, the metastatic cell burden in a proportion of patients can be eliminated by low doses. Thus, worthwhile rates of control can still be achieved when "tolerance" dictates lower than optimal doses, evidenced by the linearity and lack of significant threshold in the dose-response curve. This is an important difference from treatment of gross disease. The biological effectiveness of elective treatment is measured directly by the percent reduction in failure rate. Although it depends upon the log cell kill, it relates only to that proportion of patients harboring subclinical disease, and, therefore, is not well described by the increase in the cure rate for the total patient population. The linear dose-response relationship for reduction in failure rate is independent of the "natural" (untreated) incidence of subclinical metastasis, and, therefore, of site, histology, growth rate, stage, or other characteristics of the tumor. Conversely, the clinical effectiveness of elective treatment is measured by increase in tumor control rate and depends upon the "natural" incidence of metastasis: the higher it is, the greater the absolute increase in cure rate from a constant biological effect (log cell kill). CONCLUSIONS: (a) High control rates for subclinical metastases require doses of about 50 Gy in 2 Gy fractions, but worthwhile benefits can be achieved by lower doses if necessitated by reduced tolerance; (b) elective treatment of subclinical metastases should be instituted close to the time of treatment of the primary; (c) the biological effectiveness of elective radiation (or chemotherapy) should be measured by the percentage decrease in metastasis, not by improvements in the rate of control; and (d) demonstration of success in clinical trials of adjuvant therapy is more likely the higher the incidence of metastases in untreated controls.
Dose-Response Relationship, Radiation↗
The effect of interleukin-1 beta or transforming growth factor-beta on radiation-impaired murine skin wound healing.
The ability of exogenous interleukin-1 beta (IL-1 beta) or transforming growth factor-beta (TGF-beta) to reverse radiation-induced defective wound healing was investigated. Mice were irradiated with 8.5 or 11 Gy to total body (TB), 12 or 16 Gy to hemibody (HB), or 20 or 26 Gy to skin alone immediately prior to surgical wounding in order to determine the effect of hematopoietic system depletion on cytokine action. A single dose of IL-1 beta or TGF-beta or vehicle control was applied to each wound. All radiation doses and types resulted in a deficit in wound healing when measured on Days 11 and 14. IL-1 beta enhanced wound tensile strength (WTS) in TB-irradiated mice, while TGF-beta enhanced WTS in HB-irradiated mice. Neither cytokine was effective at enhancing WTS in unirradiated or skin-only irradiated animals. In addition IL-1 beta and TGF-beta showed distinct differences in their effects on the kinetics of healing with time after wounding. The effects of TGF-beta appeared to be transient with compromise of the gain in WTS. The differences in the effects of these two cytokines in affecting wound healing reflect their involvement in different cellular events in the wound healing process.
Animals↗
Single-dose compared with fractionated-dose radiation of the OM431 choroidal melanoma cell line.
PURPOSE: To compare single-dose and fractionated-dose radiotherapeutic effects on choroidal melanoma cells. METHODS: We determined the effects of gamma radiation on OM431 cell survival by exposing cells to either a single 9-Gy dose or two 4.5-Gy fractionated doses at intervals of 20 minutes to eight hours. The effects of single dosing and fractionated dosing at six hours were compared at doses of 2 to 12 Gy. RESULTS: Tumor cell repair was most rapid during the first two hours. Maximum repair had occurred by six hours after radiation. Cell survival curves showed doses greater than 3 Gy of single-dose gamma radiation resulted in a greater number of cells killed than did equivalent fractionated doses. CONCLUSIONS: Ocular melanoma in vitro is relatively radioresistant to low-dose fractionated radiotherapy. High single-dose radiotherapy would be more effective but would also result in more damage to normal tissue unless more focused modalities of radiotherapy are used.
Cell Survival↗
Effects of gamma radiation on the OM431 human ocular melanoma cell line.
In order to determine the dose responsiveness to radiation of ocular melanoma, we conducted an in vitro dose-response study on a monolayer cell culture using a clonogenic assay. The effects on cell survival were determined relative to unirradiated controls. A human epithelioid ocular melanoma cell line, OM431, was maintained in tissue culture and serial dilutions of viable cells were plated in flasks, allowed to settle and attach for 48 h, and subsequently irradiated with 1-10 Gy in single fractions. After 2 weeks, the number of reproducing clones (forming colonies with greater than 32 cells or five generations) were counted. The surviving fractions of cells were plotted on a cell survival curve using the linear quadratic model. The survival curve showed a large initial shoulder followed by an exponential decline in growth. Our data suggest that the OM431 ocular melanoma cell line responds to irradiation in a manner similar to other melanoma cell lines and is relatively radioresistant especially at lower doses.
Cell Survival↗
Postoperative irradiation impairs or enhances wound strength depending on time of administration.
Irradiation can complicate surgical wound healing, yet little is known of the importance of the time between surgery and irradiation on this process. This study investigated the impact of postoperative irradiation on gain in would tensile strength in a murine skin model. Irradiation on the same day as wounding or to 2-day-old wounds reduced wound tensile strength. In contrast, postoperative irradiation delivered at 7, 9 and 14 days transiently enhanced wound tensile strength, as measured 3 but not 4 or 5 weeks later. This effect was independent of the inclusion (hemibody) or exclusion (skin alone) of the hematopoietic system in the field of irradiation. Radiation-enhanced wound tensile strength was greater and occurred earlier after higher radiation doses. Even though the effect of irradiation in enhancing wound tensile strength is transitory, it could be important in assisting early wound healing.
Animals↗
Radiobiology of subclinical disease.
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Dose-Response Relationship, Radiation↗
The effect of fractionated doses of radiation on mouse spinal cord.
PURPOSE: To determine: (a) the dose-response relationship and latent time to paralysis following fractionated doses of radiation in mice, (b) the values of parameters for isoeffect curves, and (c) whether these parameters depend on the size of dose per fraction and the severity of injury. METHODS AND MATERIALS: The spinal cords (T9-L5) of 608 C3Hf/Sed/Kam mice were irradiated with fractionated doses of x-radiation. Three levels of neurological damage were used to grade the spinal cord response. Animals which did not develop paralysis were observed for at least 18 months after irradiation. The fractionated schedules consisted of either 2, 3, 4, 6, 10, or 20 fractions in addition to single doses. For the fractionated regimes the daily fraction size ranged from 2 Gy to 24 Gy, and for single doses the range was 12 Gy to 52 Gy. Both the latent time to paralysis and the incidence of paralysis were considered as endpoints. For analysis of the sparing associated with fractionation, the dose points were divided into two groups: a "low damage" group consisting of doses of near or less than the ED50 at 450 days and a "high damage" group consisting of doses much larger than the ED50 at 450 days in which there was 100% incidence of paralysis. RESULTS: The latent time depended on the radiation dose; for each fixed fraction number the latent period became progressively shorter with higher total doses. Differences in histology in fractionation sensitivity are observed between the two groups. The low damage data in each fractionation treatment are the important data in the analysis of long-term incidence of paralysis. On the other hand, the high damage data were emphasized for the analysis of latency. Three statistical methods (mixture model, Cox model, and Fe-plot) were used to fit the linear-quadratic dose response model and the "Nominal Standard Dose" (NSD) model. The values of the parameters of these two models depended on the effect evaluated; the latent interval from the high damage region being not very fractionation-dependent, whereas, the incidence of paralysis from the low damage fractionation regimens was strongly dependent on dose per fraction. Specifically, the alpha/beta ratios for latency were large (e.g., 17 to 57 Gy) when fractionation schemes in the high damage region were emphasized. If data from the fractionation schemes in the lower damage region with fraction size less than 15 Gy were emphasized, the alpha/beta ratios for incidence of paralysis were 3.3 (1.8, 6.0, 95% C.I.), 4.1 (2.8, 5.5), and 4.4 Gy derived by the mixture, Cox, and Fe-plot models, respectively. These "low damage" alpha/beta ratios were similar for all levels of injury from mild to complete paralysis, and are those which are more relevant to clinical radiotherapy. The coefficients for the "Nominal Standard Dose" formula in the present study were 0.33 +/- 0.01 (s.e.) (by the Strandqvist-type plot), 0.38 (the Cox model), or 0.40 (the mixture model) for level 2 injury at 450 days. CONCLUSION: The values of parameters in the isoeffect models were different when the data analyzed were derived from regimens using fractionated low or high damage doses.
Animals↗
Late effects of radiation on the lumbar spinal cord of guinea pigs: re-treatment tolerance.
PURPOSE: Using a guinea pig model of lumbar myelopathy, various factors affecting the tolerance of spinal cord to irradiation were assessed: (a) extent of initial injury (b) time interval between priming and test doses (c) animal age at the time of initial radiation treatment. METHODS AND MATERIALS: A 3 cm section of lumbar spinal cord of guinea pigs was irradiated with fractionated doses of 4.5 Gy gamma rays given as 9 fractions per week. Guinea pigs were primed with 9 x 4.5 Gy in 7 days which is 60% of the ED50 for a continuous course of treatment. After 28 or 40 weeks, animals were retreated with 6-14 fractions of 4.5 Gy. Animals were observed for 2 years following the priming dose and both the incidence and latency of myelopathy recorded. RESULTS: Young adult guinea pigs (8 wk old) showed both a decreased radiation tolerance and latency compared to old individuals (40 wk old). At 28 or 40 wk after 9 x 4.5 Gy, only about 8% of the initial injury was remembered in young adult guinea pigs. CONCLUSION: The amount of residual injury was dependent on the initial damage as a proportion of the tolerance dose. The spinal cord shows a greater capacity for long-term recovery than generally appreciated and re-treatment doses clinically prescribed may be lower than necessary.
Age Factors↗
Myelin-associated changes in mouse brain following irradiation.
The goals of this study were to quantify myelin-associated changes in the brain following single doses of radiation and to determine their relationship to the dose limits that this tissue can tolerate. Mice developed a transient loss of balance 1 month after 60 Gy doses 250 kVp X-rays to the brain and 3-4 months after 30-45 Gy radiation, but not after lower doses. The symptoms were transient and lasted approximately 1 month. The ED50/300 for radiation-induced brain death, which occurred large between 200 and 240 days, was 32.4 Gy (29.1, 35.5 Gy, 95% confidence limit of mean). At the time that animals developed neurological symptoms, 3-4 months after irradiation with doses of 30-45 Gy, biochemical assays of myelin-associated proteins showed decreases in 2',3'-cyclic nucleotide phosphohydrolase (CNPase) and myelin basic protein (MBP) levels that were not seen with lower radiation doses. By 120-180 days, further dose-dependent decreases in both CNPase and MBP levels were found after 20-45 Gy irradiation that preceded and correlated with death. The correlation of the decrease in CNPase and MBP levels with the incidence of transient neurological malfunction and animal death, together with histological evidence, suggests that demyelination is responsible for these phenomena.
2',3'-Cyclic-Nucleotide Phosphodiesterases↗
Radiation-induced astrocytic and microglial responses in mouse brain.
The aim of this study was to investigate the responses of astrocytes and microglia to whole brain irradiation. Levels of glial fibrillary acidic protein (GFAP), which is a marker for astrocytes, were measured by ELISA in irradiated brains taken at varying time points after irradiation. GFAP levels were increased between 120 and 180 days after single doses of 20-45 Gy radiation, but not after lower doses (2 or 8 Gy). The increases in GFAP levels were confirmed by Western blot analysis and immunohistochemical staining which showed that the number of GFAP-positive astrocytes was increased, as was their staining intensity. Coincidently with the increase in astrocyte staining, there was an increase in the number and the intensity of microglial cell staining for Mac I antigen. Autoradiography of brain tissue following in vivo administration of [3H]thymidine showed an increased number of labelled cells during the same time period. The radiation-induced astrocytic and microglial responses that follows brain irradiation is indicative of reactive gliosis and inflammation occurring during the latent period up to the onset of late radiation-induced injury. This gliosis increases with radiation dose. The possibility that gliosis may participate in modifying postirradiation injury in the brain is discussed.
Animals↗
The number of clonogenic cells in a mouse jejunal crypt.
The near linearity of cellular dose-survival curves for neutrons facilities back-extrapolation to their origin at zero dose. This zero dose intercept is the number of clonogenic cells per circumference, from which the average number of clonogenic cells per crypt can be calculated. The average estimate of clonogenic cell number per crypt (k) from back-extrapolation of 11 single dose neutron survival curves to a common intercept was 100. Multifraction experiments provide an even better estimate of k because more complete dose survival curves can be constructed on the assumption of an equal effect per equal dose fraction. The short back-extrapolation of five such curves to a common intercept yields an estimated k value of 123 (108-140, 95% confidence interval) cells per crypt. These k values were higher than those estimated by Hendry's two-dose gamma-ray method.
Animals↗
Dose-survival curves, alpha/beta ratios, RBE values, and equal effect per fraction for neutron irradiation of jejunal crypt cells.
Jejunal crypt cell survival after regimens of one, two, three and five fractions was used to reconstruct composite single-dose survival curves for neutrons of five different energies. There is no obvious shoulder, but there is a gradual divergence from linearity that is most evident at low levels of cell survival (high doses). The effect of dose fractionation is relatively small, especially at the low doses characteristic of each treatment session in neutron radiotherapy. The alpha/beta values for the linear-quadratic survival curves range from 27 to 40 Gy. The curves for neutrons are different from the curves for gamma rays mainly in their alpha coefficients, as predicted by Kellerer and Rossi's theory of dual radiation action, but both alpha and beta values are higher the lower the mean neutron energy, which is not consistent with the theory. The ratio of alpha coefficients reported here for various neutron beams to those for gamma rays reported elsewhere ranges between 3.2 and 4.6. This range of values represents the maximum limits for RBEn/gamma values (at very low doses), and is sometimes referred to as RBEm. These values increase with decreasing neutron energy. The ratios of beta coefficients for neutron and gamma-ray survival curves were lower than the alpha ratios, ranging between 0.9 and 1.9, although not reliably distinguished from 1.0. Each of a series of equal dose fractions given at 3-h intervals produced a constant (logarithmic) decrease in cell survival as evidenced by the consistency of the estimate of cell survival from a certain single dose fraction, regardless of the level of cell survival (number of dose fractions) from which the estimate was made. Even more significant than the overlap of individual data points is the excellent fit of all the data to survival curves reconstructed on the assumption of an equal effect per fraction. An implication of these results is that, with neutrons, too little unrepaired injury persists at 3 h to influence the response to a subsequent exposure measurably.
Animals↗
The effect of local and systemic irradiation on impairment of wound healing in mice.
These experiments were designed to quantify the impact of local or systemic irradiation on the healing of full-thickness skin wounds in mice. Mice received total-body hemibody, or skin irradiations, prior to wounding. Wound tensile strength measured on day 14 was used as an end point. The dose to achieve an isoeffect of 40% of the tensile strength of the wounded controls was 13 Gy less for the total-body exposure than for local skin irradiation. Histological observation showed markedly fewer inflammatory cells in the wounded skin sections from total-body and hemibody-irradiated mice compared with those receiving only skin irradiation. These data demonstrate that the healing response in irradiated skin is dependent upon the extent of hematopoietic suppression and that at low doses this determines the outcome rather than damage to fixed target cells such as dermal fibroblasts, which are relatively resistant to radiation.
Animals↗
Biological basis of radiation therapy for cancer.
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Cell Division↗
The EORTC hyperfractionation trial.
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Clinical Trials as Topic↗
Dose-time factors in head and neck data.
This paper discusses two points regarding the interpretation of dose-time effects on tumor control in head and neck data. It is shown that the sample size in many clinical series will be too small to be able to statistically detect a dose-response relationship. The results from a non-parametric regression technique applied to control rate data from a large number of institutions suggest an influence of both dose and time on the control rate and qualitatively agree with a previous analysis of these data.
Algorithms↗