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Biomedical subjects

H D Thames

Publications and source records attributed to H D Thames.

At least 109 records · Page 6Linked to original sources
PubMed1989

Fractionation sensitivity of a functional endpoint: impaired shoulder movement after post-mastectomy radiotherapy.

A clinical radiobiological study of the fractionation sensitivity of impaired shoulder movement after postmastectomy radiotherapy is presented. From 1978 to 1980, 163 breast cancer patients received postmastectomy irradiation delivered in 12 fractions, 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 midaxilla. From 1981 to 1982, 66 patients received a minimum target dose of 40.92 Gy in 22 fractions with 5 fractions per week over a period of 29 to 35 days. The treatment technique remained essentially unchanged during the whole period of 1978 to 1982. Maximal flexion and abduction of the arm were measured with unfixed scapula. A relative score, indicating the grade of impaired shoulder movement on a nominal scale from 0-3, was established by comparison with the mobility of the contralateral arm. In addition, working ability and pain at movement and at rest were evaluated. These performance parameters significantly correlated with the grade of impaired shoulder movement. The occurrence of moderately or severely impaired shoulder movement was analyzed using a mixture model incorporating dose-fractionation, latency, and predisposing clinical factors. The risk of shoulder problems was significantly higher among patients above 60 years of age. The analysis pointed to subcutaneous fibrosis as a disposing factor and indicates that postoperative physical exercise programs are beneficial. Arm edema had no statistically significant influence on shoulder performance. The alpha/beta ratio was estimated at 3.5 Gy with 95% confidence limits (c.l.) [0.7, 6.2] Gy. The length of time to expression of 90% of the ultimate frequency of moderate and severe shoulder impairment was estimated at 3.9 years with 95% confidence limits [3.1, 4.6] years. The nominal standard dose (NSD) formalism failed to produce isoeffective total doses with respect to impaired shoulder movement in the two fractionation schedules. Although the deleterious effects of larger-than-conventional dose fractions have been documented in a number of clinical series, this study represents the first quantitation of the fractionation sensitivity of a functional clinical endpoint.

Adult↗
PubMed1989

The effect of patient-to-patient variability on the accuracy of predictive assays of tumor response to radiotherapy: a theoretical evaluation.

Mathematical modeling was used to investigate the relative accuracy that might be expected from predictive assays of tumor response to radiotherapy based on one of the following four tumor characteristics: intrinsic tumor-cell radiosensitivity, doubling time of the clonogenic tumor cells, number of clonogens in the tumor at the start of treatment, and extent of hypoxia in the tumor. In particular, the influence of inter-tumor heterogeneity on predictive accuracy was investigated. Wide patient-to-patient variability in a tumor characteristic contributing to treatment response adds to the accuracy of a predictive assay based on that characteristic, but variability from patient to patient in factors influencing response, but not measured by the assay, has a confounding effect and reduces predictive accuracy. The results of this theoretical study suggest that predictive assays based on intrinsic tumor-cell radiosensitivity are much more likely to be correlated with clinical outcome than are assays based on clonogen doubling time, hypoxic fraction, or clonogen number, since individual differences in tumor radiosensitivity can seriously confound assays based on the other factors. It is concluded that it may be necessary to correct for individual differences in intrinsic radiosensitivity before predictive assays based on other tumor characteristics, such as potential doubling time, might have any detectable clinical significance.

Colony-Forming Units Assay↗
PubMed1989

Definitive radiotherapy for squamous cell carcinoma of the tonsillar fossa.

Between July 1968 and December 1983, 150 patients with previously untreated squamous cell carcinomas of the tonsillar fossa received megavoltage external beam irradiation with curative intent at U.T.M.D. Anderson Cancer Center. These patients were treated following a series of patients who had received radiotherapy between 1954 and May 1968. One hundred and thirty-seven patients were treated with conventional fractionation, the mean doses to the primary being 64.3 Gy, 67.8 Gy, 70.2 Gy, and 72.6 Gy for T1, T2, T3, and T4 lesions respectively. Thirteen patients were treated by altered fractionation schedules, 7 by hyperfractionation, and 6 by a concomitant boost to the primary. Elective bilateral neck irradiation was routine in all patients. A planned neck dissection was performed in 26 patients. The 5-year actuarial overall and disease-specific survival rates were 47% and 70%, respectively. Absolute local control rates with a minimum of 2 years follow-up after irradiation were 94%, 79%, 58%, and 50% for patients with T1, T2, T3, and T4 disease respectively. A total of 37 patients had local treatment failure; in 5 of 18 surgical salvage was successful. Only 4 patients with primary disease control developed failure in the neck and none of those with N0 or N1 disease did so when the primary was controlled. Twelve patients developed transient self-limited bone exposure, 7 developed osteoradionecrosis of the mandible, all requiring surgical resection. Most severe late complications occurred in patients with T3 and T4 lesions whose dose to the primary exceeded 67.5 Gy.

Adult↗
PubMed1989

Direct estimation of latent time for radiation injury in late-responding normal tissues: gut, lung, and spinal cord.

Mixture models are proposed for simultaneous analysis of the latency and fractionation characteristics of radiation injury in late-responding normal tissues. The method is an extension of the direct analysis for quantal response data. Conceptually, the application of the mixture model is based on the biological observation that over a wide range of doses a proportion of the irradiated subjects will never express damage. Mixture models allow the time of occurrence to be utilized in the analysis. Furthermore, this type of model takes time-censored observations into account in a natural way and provides an adequate framework for modelling and analysis of effect-dependent latency. Mixture models with complete and incomplete repair are applied to dose-incidence data for four late endpoints in rodents: death from radiation-induced pneumonitis, leg paralysis after spinal-cord irradiation, and radiation-induced rectal stenosis and anal discharge. Radiation-induced pneumonitis had an effect-dependent latency. The modelling of this phenomenon correlates well with the results of histologic studies. Interestingly, the ratio of hazard rates was not constant for this endpoint. The dominating feature in the latency of radiation injury to the spinal cord was a strong dependency on dose per fraction. After correction for this effect a tendency towards a longer latent time for lower effect levels was observed. For the rectal complications, there was no difference between latency with radiation only vs. radiation combined with cis-platin.

Animals↗
PubMed1989

Fractionation parameters for human tissues and tumors.

Time-dose factors such as fractionation sensitivity (alpha/beta) can sometimes be estimated from clinical data, when there is a wide variation in dose, fraction size, treatment time, etc. This report summarizes estimates of fractionation parameters derived from clinical results. Consistent with the animal data, alpha/beta is higher for acutely responding than for late-responding normal tissues. While many human tumors seem to be characterized by high alpha/beta values, there are exceptions (e.g. melanomas). Repair kinetics may be slower in human than in rodent skin and mucosa, but there are no hard and fast estimates of the repair halftime. Regeneration in head and neck tumors is equivalent to a daily dose of 1 Gy or less, while in the mucosa it is equivalent to approximately 1.8 Gy/day.

DNA Repair↗
PubMed1989

Response of plateau-phase C3H 10T1/2 cells to radiation and concurrent administration of bleomycin.

The mode and extent of interaction between bleomycin and radiation were assessed in contact-inhibited cultures of C3H 10T1/2 cells, which in confluent monolayers display a low turnover rate and behave more like late-responding normal tissues in vivo with respect to response to fractionated radiotherapy (i.e., having a low alpha/beta value). Plateau-phase C3H 10T1/2 cultures were exposed to gamma rays delivered in 1, 2, 5, or 10 fractions. The radiation doses administered ranged from 2 Gy in one exposure to 26 Gy in 10 fractions. Half of the cultures were also treated with 1 micrograms/ml of bleomycin for 5 days during which radiation was also given. It was found that 1 micrograms/ml of bleomycin sterilized approximately 40% of the C3H 10T1/2 cells in the cultures. The radiation dose-survival curves of various fractionation schedules (1, 2, 5, and 10 fractions) plus bleomycin were displaced downward (i.e., to lower survival levels) but not modified in shape. The alpha/beta ratios, parameters of the linear-quadratic model of cell survival, were 2.6 (2.2-3.1) and 2.4 (1.8-3.1) Gy for radiation only and radiation plus bleomycin, respectively. This observation indicates that the effect of combining irradiation and bleomycin on C3H 10T1/2 cells in monolayers was additive.

Animals↗
PubMed1988

Effect of continuous infusion of bleomycin on the time for completion of repair of sublethal radiation damage in mouse lip mucosa during fractionated irradiation.

The influence of a simultaneous continuous infusion of bleomycin on the time necessary for repair of sublethal radiation damage during fractionated irradiation of mouse lip mucosa was studied. Although there are strong indications that bleomycin interferes with the accumulation and repair of sublethal radiation damage, no significant change in the time course of these repair processes could be demonstrated following various analyses of the experimental results. An interval of at most 4 h between successive irradiations was sufficient to allow for a similar amount of repair of sublethal damage as compared with either 24 h (2 fractions) or 6 h (10 fractions), whether or not radiation was combined with bleomycin infusion.

Animals↗
PubMed1988

Chemoresistance is not a cause of the apparent failure of adjuvant chemotherapy in postmenopausal women.

Chemotherapeutic regimens used for the adjuvant treatment of breast carcinoma are less effective when applied to postmenopausal women than when applied to premenopausal women. Differences in growth fraction or altered chemosensitivity of tumors are potential causes of the differential effects of chemotherapy in younger and older patients. We have attempted to identify the presence of these putative causes by measuring size of clonogenic cell fraction and drug sensitivity of progenitor cells on the tumors from pre- and postmenopausal women. We found that the chemosensitivity of tumors was similar for patients of all ages. We further observed that the clonogenic cell fraction of tumors from women older than 65 years tended to be smaller compared to those of all other patients, while the hormone-sensitivity of tumors from these patients was higher. Our observations thus suggest that drug resistance related to inherent metabolic characteristics of tumor cells may not be a major contributing cause of failure of adjuvant chemotherapy in the treatment of postmenopausal women.

Adult↗
PubMed1988

Does incomplete repair explain the apparent failure of the basic LQ model to predict spinal cord and kidney responses to low doses per fraction?

Recent evidence indicates that isoeffect doses for spinal cord and kidney may be overestimated for fraction sizes as small as 1 or 2 Gy when calculated from a linear-quadratic (LQ) model fitted to data obtained for fraction sizes larger than 2 Gy. Reasons for this are unknown, but possible interpretations include exhaustion of repair capacity and incomplete repair in experiments designed to study the response to these small doses. The latter interpretation is motivated by the relatively short intervals between multiple daily doses given to the spinal cord (4 h) and kidney (5 h) when fraction sizes were small. The possibility that overestimation of isoeffect dose could be explained by incomplete repair during short intervals between doses was assessed by fitting experimental data to the incomplete-repair model. For the spinal cord the data could be interpreted by assuming that a repair process with a half-time of 1.7 h was incomplete; this half-time is negligibly different from the estimate obtained from repair-kinetics experiments with larger doses per fraction. The deviation from the (complete-repair) LQ model could be interpreted for the kidney in terms of a half-time of repair of 2.8 h (a negligibly different fit was obtained with the value 1.5 h). The clinical implication could be that multiple-fractions-per-day treatment would benefit from use of the longest feasible interfraction interval when late reactions are dose limiting.

Animals↗
PubMed1988

Early fractionation methods and the origins of the NSD concept.

The concept of the time factor in radiotherapy originated in the controversy surrounding single-dose and fractionated treatments during the first 20 years of this century. The success of Coutard's fractionated treatments of larynx tumors was an important factor in the abandonment of single-dose treatments. There was considerable research afterwards into the influence of dose rate and overall time of treatment on the responses of normal tissues. Recovery was modeled in terms of the Schwarzschild law of photochemistry, as exemplified by the analysis of Strandqvist in log dose-log time coordinates. Different conventions were followed in defining the time for a single-dose treatment. Subsequently the concept arose that the slopes of isoeffect lines relating dose and treatment time for normal tissues and tumors were different and moreover that the effects of fraction number and overall time could be separated; these developments constituted the foundation of the Ellis NSD model. It had an important influence on clinical practice and was reasonably successful in predicting isoeffective regimens for acute effects. It failed to predict severe late effects after large dose fractions. The dissociation between acute and late effects with altered fractionation led to recognition of the importance of the ratio alpha/beta in characterizing the fractionation sensitivity of tissues.

Humans↗
PubMed1988

Accelerated fractionation in the radiation treatment of head and neck cancer. A critical comparison of different strategies.

There is strong clinical and radiobiological evidence that protraction of overall treatment time has an adverse influence on the radiocurability of certain human tumors. Overall treatment time can be reduced without recourse to large dose fractions by the use of accelerated fractionation, but in patients with head and neck cancer acute mucosal reactions limit the extent to which treatment can be accelerated. Three different prototypical schedules for accelerated fractionation have been devised to avoid exceeding acute mucosal tolerance. Type A consists of an intensive short course in which the overall duration of treatment is markedly decreased with a corresponding substantial reduction of total dose; type B achieves a modest decrease in overall time without reduction of total dose by using a split-course technique; type C also achieves a modest decrease in overall time without reduction of total dose by means of the concomitant boost technique. A hybrid schedule combining features of types B and C allows additional shortening of overall treatment time without reduction of total dose. Available radiobiological and clinical data suggest that schedules of types B or C which do not compromise total dose are generally preferable to those of type A in which there is a trade-off between total dose and overall time. For a given total dose and overall time, a continuous treatment of type C is likely to produce more cell kill than a split-course of type B, although the latter will be better tolerated. Because of the increased acute toxicity associated with all schedules of accelerated fractionation, rational selection of patients for such treatment is important. New techniques to measure the potential doubling time of human tumors in vivo offer this prospect.

Clinical Trials as Topic↗
PubMed1988

Proliferation kinetics of a murine fibrosarcoma during fractionated irradiation.

Accelerated growth of tumor clonogens during the course of fractionated irradiation has been considered one of the major causes of radiation treatment failure. Alterations in clonogen growth rate could occur through three basic mechanisms: changes in cell-loss factor, changes in cell-cycle time, and recruitment of previously quiescent cells into the proliferative pool. This study was designed to assess changes in the cell-cycle time of clonogens of a murine fibrosarcoma during fractionated irradiation using an artificial pulmonary micrometastasis model. Lung colonies of various ages (4 h, 1 day, or 4 days) were exposed to single doses of irradiation ranging from 5-13 Gy; the fraction of surviving colonies was used to determine the preirradiation growth kinetics. The growth kinetics during fractionated irradiation was derived from colony-survival data of 4-day-old micrometastasis exposed to single doses or to 2, 5, 9, and 15 fractions separated by 4, 12, or 24-h intervals. The size of dose fractions used ranged from 1.7 to 14 Gy. The estimated clonogen doubling times before irradiation and during overall treatment periods of up to 14 days were 0.71 and 1.1 days, respectively. This significant (P less than 0.0001) increase in the doubling time was most likely a consequence of lengthening of the overall cell-cycle time of the clonogens by radiation-induced division delay. This observation suggests that accelerated growth, when it occurs in some tumors during fractionated treatment, is the result of a decreased cell-loss factor or recruitment of quiescent cells, but not a shortening of the cell-cycle time of the clonogens.

Animals↗