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H D Thames

Publications and source records attributed to H D Thames.

At least 91 records · Page 5Linked to original sources
PubMed1991

Changes in TCD50 as a measure of clonogen doubling time in irradiated and unirradiated tumors.

Dose-cure experiments have been carried out on a moderately well differentiated murine mammary carcinoma, designated MCA-4, at different stages of growth after tumor-cell inoculation or after 8 mm established tumors had been exposed to 60 Gy. TCD50 assays were performed at 1, 3, 7, 14, or 21 days after tumor cell inoculation, or when tumors reached a size of 6 or 8 mm. Likewise, TCD50 assays were performed at 0.25, 1, 3, 5, 8, 12, 16, or 21 days after 8 mm tumors had been exposed to a 60 Gy priming dose, or when the recurrent tumors reached 6 or 8 mm. All irradiations were performed under hypoxic conditions. The TCD50 (95% confidence limits) was 64.0 (61.7-68.3) Gy for the 6-mm and 71.9 (70.1-73.9) Gy for the 8 mm tumors, and these values were unaffected by preirradiation. Direct analysis was used for the simultaneous estimation of D0, clonogen number, and clonogen doubling time from the pooled data. There was no significant difference between D0 estimates for the preirradiated and control tumors, and the pooled estimate was 10.6 (9.6-11.8) Gy for tumors assayed at specified time points where the size was unknown. This is clearly higher than in tumors of known size [estimate for 6- and 8-mm tumors: D0 = 5.4 (4.5-6.6) Gy] owing to size and other heterogeneity. The clonogen doubling times (Tclon) were 3.4 (3.0-4.0) days in the preirradiated tumors and 5.8 (4.9-7.1) days in the unirradiated tumors. It is not unreasonable to assume that the systematic error due to heterogeneity was approximately the same for D0 and Tclon (since variable clonogen number is likely the predominant source of heterogeneity), and thus the ratio of D0 for tumors of unknown sizes (10.6 Gy) and D0 for tumors of known sizes (5.4 Gy) can be used to "correct" the Tclon estimates, with the result that Tclon (preirradiated) = 1.7 days and Tclon (unirradiated) = 3.0 days. We conclude that the clonogen doubling time was shorter in tumors exposed to a single high-dose irradiation than in unirradiated controls, which implies the existence of faster cell repopulation in irradiated tumors.

Animals↗
PubMed1991

Direct analyses of in vivo colony survival after single and fractionated doses of radiation.

Several methods are described for analysing the results of in vivo colony assays using the statistical procedure called maximum-likelihood analysis. The methods differ in the way in which they take into account possible sources of variability in the data. The methods described here for analysing microcolony data are direct methods, in that they use the observed colony counts rather than transformed (e.g. Poisson-corrected) data. Each method can be used to estimate the average number of surviving cells per tissue structure (e.g. per jejunal crypt) in a single dose group, together with 95% confidence intervals, or to fit cell-survival models to data from a range of dose groups (e.g. to obtain estimates of D0 or of the linear-quadratic parameters alpha and beta). Experimental microcolony data from murine jejunum, colon, and hair follicles irradiated in anagen (proliferative) or telogen (resting) phase have been analysed. Estimates of D0 have been derived from single-dose data and estimates of alpha, beta, and the initial number of clonogenic cells per structure have been derived from fractionation data. For hair follicles, the half-time of repair of sublethal radiation injury has also been derived from fractionation data.

Animals↗
PubMed1990

Fractionation sensitivity and latency of telangiectasia after postmastectomy radiotherapy: a graded-response analysis.

Latent time and dose-fractionation characteristics for telangiectasia are estimated in a series of 401 treatment fields in 335 patients treated with postoperative radiotherapy at the Department of Oncology in Gothenburg. To this end an extension of the mixture model to include graded-response data is proposed. In addition, a method for non-parametric estimation of median latent time is presented. Severity of telangiectasia was scored on an arbitrary 4-point scale ranging from no reaction to severe telangiectasia. The estimated number of tissue-rescuing units for the three grades of telangiectasia increased with increasing grade of reaction. The average length of time to expression of 90% of the ultimately expected damage was estimated at 6.6 years, 9.1 years and 14.8 years for grades greater than or equal to 1, greater than or equal to 2 and equal to 3, respectively. Thus increasing grades of telangiectasia occurred at progressively longer follow-up times. A statistically significant correlation was found between the level of tissue injury and the latent period. Patients with a high probability of ultimately expressing a specific grade of telangiectasia had a shorter latent period the higher the level of injury.

Breast Neoplasms↗
PubMed1990

Time-dose factors in radiotherapy: a review of the human data.

The values for alpha/beta (fractionation sensitivity, or recovery capacity) for early and late reactions in human normal tissues are consistent with results from experimental animals. For breast treatments direct analysis indicates that for early reactions alpha/beta is in the range 7 to 11 Gy, while for late effects it is in the range 2 to 4 Gy. Data on recovery kinetics in human tissues is limited but these indicate that recovery may be slower in humans than in rodents. For early skin reactions the halftime of recovery is about 1 h, while for late telangiectasia it is more than 3 h. alpha/beta values for human tumors are more variable than in rodents: some are high (head and neck, lung, skin, cervix) and similar to those for early reacting normal tissues. Others are low, including melanomas, where alpha/beta was estimated at 0.6 (-1.1, 2.5) Gy, and liposarcomas, where direct analysis of cases surveyed from the literature suggested that alpha/beta = 0.4 (-1.4, 5.4) Gy. Repopulation kinetics is faster in the mucosa of the soft palate and faucial pillars (1.8 Gy/day) than in head and neck tumors (up to 1 Gy/day).

Animals↗
PubMed1990

The response of two human tumor xenografts to fractionated irradiation. The derivation of alpha/beta ratios from growth delay, tumor control, and in vitro cell survival assays.

A series of growth delay experiments was performed to derive alpha/beta ratios for two human neoplasms growing as xenografts in the hind limbs of NCr/Sed nude mice. The tumors were irradiated at 6 mm mean diameter under clamp-hypoxic conditions in one, two, four, or eight fractions, 2 fractions per day with a minimum intertreatment interval of 4 hr and a maximum overall treatment time of 3 days. The alpha/beta ratios derived for the high grade glioma U87 and the pharyngeal squamous carcinoma FaDu were 38 and 20 Gy, respectively. Comparably high values were derived from the same two tumors in a reanalysis of fractionated TCD50 data. The alpha/beta ratios were similarly high whether the TCD50 data were analyzed using the Full Effect plot or the Direct Method. For comparison, cell survival assays were performed on U87 and FaDu irradiated in vitro under plateau-phase, aerobic conditions. The alpha/beta ratios obtained were 9.2 and 15.0 Gy, respectively. Such high alpha/beta values suggest a therapeutic gain could result from the use of small doses per fraction.

Animals↗
PubMed1990

Fractionation sensitivity and immunological status in radiation treated murine sarcomas.

The fractionation sensitivity of a strongly immunogenic murine fibrosarcoma (FSa1) was tested in highly immunosuppressed (18 Gy whole body irradiation, 10 fractions, 4 days and bone marrow salvage) and control mice (C3Hf/Sed). Radiation was delivered to extremity-transplanted tumors after reaching a volume of 250 mm3. Two, 4 and 10 fractions were used, delivering the radiation treatments to uniformly hypoxic tumors (by extremity clamping). Doses needed to attain a 10 day tumor-growth delay (TGD) over the volume range 250 mm3 to 1000 mm3, and doses necessary to reach a tumor-control probability of 50% (TCD50), were calculated for the three fractionation schedules. Immunosuppression influenced the TCD50 values profoundly: 56.2, 71.5, and 101.4 Gy in control mice versus 76.6, 104.2, and 141.1 Gy in immunosuppressed mice for 2, 4, and 10 fractions, respectively. The alpha/beta ratios estimated by reciprocal-dose analysis using the TGD and TCD50 assays were not significantly different, nor were the alpha/beta ratios of tumors grown in immunosuppressed mice (TGD 5.7 Gy; TCD50 5.3 Gy) as compared with tumors in control recipients (TGD 3.5 Gy; TCD50 4.9 Gy). In addition, direct analysis was used with the fractionated TCD50 data from control and immunosuppressed animals to calculate a immunity-related-cell-kill factor. For 250 mm3 tumors a 1.29 [0.99 . . . 1.59, 95% confidence interval] log10-kill factor was obtained.

Animals↗
PubMed1990

Does variation in the in vitro cellular radiosensitivity explain the shallow clinical dose-control curve for malignant melanoma?

In radiotherapy, clinical dose-control curves are generally more shallow than what should be expected from in vitro dose-survival curves for human cells of the same histology. One possible explanation is that a considerable inter-tumor heterogeneity in radiosensitivity flattens out the presumably steep individual dose-control curves. This paper compares dose-control curves for malignant melanomas derived from clinical data with curves derived from in vitro cell-survival experiments. Although inter-tumour variability in the in vitro dose and fractionation sensitivity may explain parts of the discrepancy between the steepness of clinical and in vitro dose-control curves, the present calculation indicates that a considerable additional variability, undetected by current in vitro assays, must be assumed to exist in order to resolve the discrepancy.

Cell Survival↗
PubMed1990

A generalized formulation of the 'incomplete-repair' model for cell survival and tissue response to fractionated low dose-rate irradiation.

A generalized equation for cell survival or tissue effects after fractionated low dose-rate irradiations, when there is incomplete repair between fractions and significant repair during fractions, is derived in terms of the h- and g-functions of the 'incomplete-repair' (IR) model. This model was developed originally from the concept of 'dose equivalent of incomplete repair', assuming that the repair of radiation damage is an exponential function of time and that the cell survival curve can be described adequately by the linear quadratic (LQ) formalism. The generalized incomplete-repair equation is shown to be equivalent to an expression derived by Dale et al. (1988) for analysis of tissue effects of fractionated irradiations at varying dose rates. The model is critically dependent on alpha/beta, repair half-time, treatment time and interfraction interval, and should therefore be regarded primarily as a tool for the analysis of fractionation and dose-rate effects in carefully designed radiobiological experiments, although it should also be useful in exploring, in a general way, the feasibility of clinical treatment protocols using fractionated low dose-rate treatments.

Cell Survival↗
PubMed1990

How well is the probability of tumor cure after fractionated irradiation described by Poisson statistics?

The probability of tumor cure in a homogeneous population of tumors exposed to fractionated radiotherapy was modeled using numerical simulations and compared with the predictions of Poisson statistics, assuming exact knowledge of the relevant tumor parameters (clonogen number, radiosensitivity, and growth kinetics). The results show that although Poisson statistics (based on exact knowledge of all parameters) accurately describes the probability of tumor cure when no proliferation occurs during treatment, it underestimates the cure rate when proliferation does occur. In practice, however, the inaccuracy is not likely to be more than about 10%. When the tumor parameters are unknown and are estimated by fitting an empirical Poisson model to tumor-cure data from a homogeneous population of proliferative tumors, the resulting estimates of tumor growth rate and radiosensitivity accurately reflect the true values, but the estimate of initial clonogen number is biased downward. A new formula that is more accurate than Poisson statistics in predicting the probability of tumor cure when proliferation occurs during treatment is discussed.

Animals↗
PubMed1989

Clinical radiobiology of malignant melanoma.

Tumor-control probability (TCP) was analyzed in a series of 121 patients having 239 histologically proven recurrent or metastatic malignant melanomas. These were treated with fractionated radiotherapy with various doses per fraction, total doses, and overall times. Cutaneous lesions (127, 53%) were treated with electron beams, and more deeply seated tumors (112, 47%) with 60Co or 4-8 MV X-rays. The fraction size was highly variable, and this permitted determination of the alpha/beta ratio in the multifraction linear-quadratic model, which was estimated at 0.57 Gy with 95% confidence limits [-1.07, 2.5] Gy. Treatment time had no demonstrable influence on TCP. Thus this tumor exhibits the fractionation sensitivity characteristic of a late-responding normal tissue, suggesting that an adequate fractionation schedule for malignant melanomas would be characterized by larger-than-conventional doses per fraction, possibly about 6 Gy per fraction. This is consistent with the conclusions of other authors. Tumor size, evaluated as mean tumor diameter, S, had a major impact on TCP: the number of target cells increased as a power function of S with exponent 0.72 (95% confidence limits [0.49, 0.94]. In fact, a considerable amount of the heterogeneity in the dose-response data could be removed by accounting for size. Thus, the weak or absent dose response became highly significant. When a patient had multiple lesions, the responses of these to radiotherapy tended to be similar, thus implying that results were significantly influenced by a "hidden parameter" (such as inherent radiosensitivity or immunological status). A test of the predictive value of the TCP-model was performed in a different series of 183 cutaneous and lymph node malignant melanomas. The observed dose-response relationship in this data set was in good agreement with the model prediction. A chi-square test for goodness-of-fit showed that the variation between predicted and observed results could be explained by the binomial variation on quantal response data.

Cobalt Radioisotopes↗
PubMed1989

The effect of cis-diamminedichloroplatinum(II) on radiation damage in mouse rectum after fractionated irradiation.

The influence of cis-diamminedichloroplatinum(II) (c-DDP) on radiation injury in the rectum of mice was investigated after single dose and fractionated irradiation. Mice were exposed to single doses, or 2, 4 or 8 fractions of X-rays given daily (or twice a day for the 8 fractions) with or without 8 mg/kg of c-DDP. The incidence of rectal stenosis and of anal discharge were scored and a direct analysis of the data for linear-quadratic dose-dependence of damage was performed with correction for censoring. For each endpoint, c-DDP did not significantly change the dose-response curves after fractionated irradiation. Subtile modifications in the coefficients of the linear-quadratic relationship were observed. The drug appeared to increase the alpha term by a factor of 2.3 and the beta term by a factor of 1.5, but the differences did not reach statistical significance. For the rectal stenosis endpoint, the alpha/beta was 4.4 Gy after irradiation alone and 6.9 Gy after combination treatment. Again the differences were not significant. These data suggest that c-DDP did not reduce the repair capacity in the mouse rectum during fractionated irradiation. Combined modality therapy with c-DDP and radiation would therefore not be expected to cause an increase in late damage in the large bowel.

Animals↗
PubMed1989

Latent-time estimation for late cutaneous and subcutaneous radiation reactions in a single-follow-up clinical study.

In this paper, an analysis of the fractionation sensitivity and latency of subcutaneous fibrosis and telangiectasia in a clinical series is presented. The series comprised 163 breast cancer patients who, from 1978 to 1980, received postmastectomy irradiation delivered in 12 fractions, with 2 fractions per week over a period of 37 to 46 days. The total dose was specified either as a maximum absorbed dose of 51.36 Gy, or as a minimum target dose of 36.6 Gy specified at the level of the mid-axilla. From 1981 to 1982, 66 patients received a minimum target dose of 40.92 Gy in 22 fractions administered as 5 fractions per week over 29 to 35 days. Late complications were evaluated prospectively at a single follow-up after a minimum observation time of 16 months. The clinical endpoints analyzed were subcutaneous fibrosis and telangiectasia. The data were analyzed using a mixture model that incorporates both dose fractionation and latency effects. The length of time to expression of 90% of the ultimate frequency of moderate or severe complications was 3.2 years (95% confidence limits (c.l.) [2.3,3.9] years) and 4.7 years (95% c.l. [4.0,4.8] years) for fibrosis and telangiectasia respectively, while the alpha/beta ratios were 1.9 Gy (95% c.l. [0.8,3.0] Gy) and 3.7 Gy (95% c.l. [0.2,47] Gy), respectively. For subcutaneous fibrosis the time to reach a specific grade of reaction increases with the grade, thus being consistent with the clinical impression that fibrosis progresses in severity over time. If latency and censoring effects are unaccounted for, serious underestimates of the ultimate frequency of radiation complications in groups with incomplete follow-up may result.

Breast Neoplasms↗
PubMed1989

The high steepness of dose-response curves for late-responding normal tissues.

Values are calculated for the parameters alpha, beta, and the number of tissue-rescuing units (TRU), which together describe the location and the steepness of dose-incidence curves for functional injury in various normal tissues. The analysis is based on a Poisson model of the distribution of surviving TRUs. The steepness of the curves for early-responding tissues has been shown previously to be compatible with values of sensitivity for the target colony-forming cells in these tissues. We now show that the steepness of curves for late responses in spinal cord, lung, and kidney is higher by a factor of up to 3 than the steepness of curves for early responses in other tissues. Although the interpretation of this higher steepness is not fully understood, this observation is likely to be of importance for radiotherapy.

Animals↗
PubMed1989

Repair capacity and kinetics of human skin during fractionated radiotherapy: erythema, desquamation, and telangiectasia after 3 and 5 year's follow-up.

Prospective clinical fractionation studies on acute and late reactions in skin have been going on since 1972 at the Radiotherapy Department in Gothenburg. The clinical assay consisted of breast cancer patients irradiated postoperatively to the internal mammary nodes from unilateral or bilateral fields exposed to various dose schedules. 750 fields in 450 patients have been analysed. Schedules with 1, 2 or 5 fractions per week and 2 or 3 fractions per day were evaluated with erythema, desquamation and telangiectasia as endpoints. For some schedules a dose-response relationship was established in a limited dose range, but often there was only one dose group per schedule. These data are suited to analysis by the method of direct analysis of quantal response. This was used in the present analysis, along with the linear quadratic (LQ) model and its generalization, the incomplete repair (IR) model. The repair capacity was similar for erythema and desquamation, with alpha/beta ratios between 7.5 and 11.2 Gy. Unexpectedly, there was more significant time factor during radiotherapy courses up to 6 weeks for erythema and desquamation, but the repair capacity was changed after 4 weeks for both endpoints, and alpha/beta increased to between 18.3 and 34.5 Gy. The repair capacity for late telangiectasia differed significantly from that for erythema and desquamation, with alpha/beta values between 2.8 and 4.3 Gy. There was a significant time factor for telangiectasia with characteristic doubling time of about 16 days, when an exponential function for time was used. Concerning the repair kinetics in skin, there were insufficient data to obtain precise estimates, but there was a suggestion of two components of repair. This was inferred from higher-than-predicted recovery with 15-min intervals, when the data were fitted with the monoexponential model. The monoexponential fit gave t1/2 between 1.1 and 1.3 h for acute effects and 3.5 h for late effects. Recovery after 15-min fractionation intervals, if it resulted from a fast repair component, would be consistent with a half-time of 0.3-0.4 h. The time factor and the relative long half-time for repair for late effects have important implications for multiple-fraction-per-day treatment, and imply that interfraction intervals of 4 h or less, as commonly used, will be insufficient. Instead, intervals of 6 h or longer are recommended. Using accelerated fractionation with a significant reduction in overall treatment time a dose reduction is still necessary to take into account the time factor for late effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗
PubMed1989

Repair kinetics in tissues: alternative models.

Monoexponential repair kinetics is based on the assumption of a single, dose-independent rate of repair of sublethal injury in the target cells for tissue injury after exposure to ionizing radiation. Descriptions of the available data based on this assumption have proved fairly successful for both acutely responding (skin, lip mucosa, gut) and late-responding (lung, spinal cord) normal tissues. There are indications of biphasic exponential repair in both categories, however. Unfortunately, the data usually lack sufficient resolution to permit unambiguous determination of the repair rates. There are also indications that repair kinetics may depend on the size of the dose. The data are conflicting on this account, however, with suggestions of both faster and slower repair after larger doses. Indeed, experiments that have been explicitly designed to test this hypothesis show either no effect (gut, spinal cord), faster repair after higher doses (lung, kidney), or slower repair after higher doses (skin). Monoexponential repair appears to be a fairly accurate description that provides an approximation to a more complicated picture, the elucidation of whose details will, however, require very careful and extensive experimental study.

Animals↗