Biomedical subjects
Publications and source records attributed to H R Withers.
Two acutely-responding normal tissues, bone marrow and gastrointestinal epithelium, have been shown to exhibit a biphasic dose-latency response to radiation with both a dose-dependent and dose-independent component for expression of radiation injury.
This article distills from available data descriptions of typical human symptoms in reaction to prompt total-body ionizing radiation in the dose range 0.5 to 30 Gy midline body tissue. The symptoms are correlated with dose and time over the acute postexposure period of 6 wk. The purpose is to provide a symptomatology basis for assessing early functional impairment of individuals who may be involved in civil defense, emergency medical care and various military activities in the event of a nuclear attack. The dose range is divided into eight subranges associated with important pathophysiological events. For each subrange, signs and symptoms are designated including estimates of symptom onset, severity, duration and incidence.
In pathogen-free mice, but not standard conventionally housed laboratory rodents, two distinctly different modes of early radiation lethality can be identified by modifying the irradiation technique (total-body versus abdominal irradiation) or by therapeutic intervention such as rescue of total-body-irradiated mice with syngeneic bone marrow or spleen. While damage to the gastrointestinal tract is usually designated as the predominant cause of death occurring within 10 days of radiation exposure, it was demonstrated that damage to the hematopoietic/lymphopoietic system can result in animal lethality over the same period as the gastrointestinal syndrome and that this target cell population is more radiation-sensitive than the gastrointestinal epithelium.
The historical rationale for the start of neutron radiotherapy is critically reviewed. Although it is proven that the extent of hypoxia varies among even apparently similar tumors in man the importance of this effect on the outcome of conventional radiotherapy is unknown. Other effects controlling response are inherent radiosensitivity and cell cycle redistribution. For the first the response of tumour cells to 2 Gy of X-rays is claimed to be a reasonable predictor indicating the width of the dose effect shoulder and hence the repair capacity of the tissue. An important argument for optimizing fractionation is the difference between early and late responding tissues in the isoeffect curves for X-rays as a function of dose per fraction. According to this multiple small doses of X-rays should provide a therapeutic advantage. On the other hand there may be rapid acceleration of tumour clonogen repopulation during treatment causing a loss of therapeutic differential in case of too long protraction of treatment. No or very little fractionation effects accrue to neutrons which can therefore be administered in more comfortable schedules than X-rays. In view of these biological considerations the current U.S. neutron protocols involve rapid treatment using relatively large dose fractions. Finally the point is stressed that future emphasis must be on the development of techniques to forecast the radiation response of tumours and to select patients who benefit from neutron radiotherapy.
Radiobiology concepts relevant to radiotherapy have undergone continued revision, suggesting that a continuing skeptical if not completely contrarian view of current concepts is also warranted. Some such revisions are revisited, and some present applications of radiobiology to radiotherapy are discussed before they, too, require revision.
The response of the resting (fully formed) hair follicle to irradiation was studied using an arbitrary 6 unit scale of epilation as an endpoint. Dose-response curves for single and multifractionated irradiations were analyzed in terms of the dose that gave a certain response in 50% of the mice (HRD50). HRD50 values increased with decrease in dose per fraction even when changing from 1.6 Gy to 1.15 Gy per fraction. The plots of the reciprocal of isoeffective doses versus dose per fraction are nonlinear suggesting either inappropriateness of the linear-quadratic model over the whole range of doses, or incompleteness of repair given as they were, at 3-h intervals. Allowing for incomplete repair, estimates for the alpha/beta ratio were 3.1 Gy and 1.7 Gy for the complete data set or for doses less than 7 Gy, respectively. The steep slope of the isoeffect curve plotting total dose versus dose per fraction was comparable to late responding normal tissues like lung, kidney and spinal cord. Such a response is consistent with slow proliferation of the matrix cells of resting follicles. The same animals were kept to assess the effect of dose fractionation on lethal injury to the lung. Since epilation occurs well before death from lung injury, the data for the two responses were correlated to determine whether epilation might help in predicting the probability of the later development of lung injury: no association was found.
Hypotheses regarding tissue organization and radiation response were described and, on the basis of simple modeling, tentative conclusions were drawn regarding the influence on "tolerance" doses of tissue organization and the volume of an organ irradiated. (1) A functional subunit (FSU) may be defined structurally (e.g. as in a nephron), or only functionally, as the largest unit of cells capable of being regenerated from a surviving clonogenic cell without loss of the specified function. (2) Functional subunits may be arranged in parallel or in series: in parallel they give rise to graded dose responses, whereas in series, they give rise to threshold binary, or quantum responses. (3) Tolerance doses are a function of the number and radiosensitivity of target cells in an FSU, tissue organization and the functional reserve (i.e. the proportion of functional subunits necessary for adequate organ function). (4) An influence of treatment volume on "tolerance" doses is more likely to depend upon tissue organization than upon differences in cellular radiosensitivity. (5) The volume of tissue irradiated would be expected to be irrelevant to the "tolerance" of tissues showing a graded dose response (e.g. skin desquamation), except when the injury becomes severe, when tolerance for a large severe wound is likely to be less than for a small volume of injury, for non-radiobiological reasons. (6) Tissues with FSU's arranged in series, for example, spinal cord or peritoneal sheath along small bowel, should show a threshold-binary response. Sigmoid dose response curves should have a lower threshold and be steeper the larger the treatment volume. The effect of increase in volume is greatest with changes in small volumes: once a large number of FSU's are being irradiated, a further increase in volume has little effect on the position or slope of the probability curve for such complications. (7) Because their sigmoid dose-response curves are step, threshold-binary tissues are sensitive to small increases in "biologically effective" dose. For example, when the spinal cord is treated with large dose fractions the biological effectiveness per unit of dose increases sharply. Thus, using a large volume together with large dose fractions, as could happen in palliative prescriptions, could augment the danger of myelitis.(ABSTRACT TRUNCATED AT 400 WORDS)
A mathematical model is presented to describe the regenerative response of mouse gut epithelal cells to radiation. The model, derived from radiobiological principles, predicts the cellular surviving fraction following any irradiation regimen. There are three basic elements to the model (a) a single dose survival curve, either the linear-quadratic or the two-component model, (b) a part to incorporate the regenerative response, either a Gompertzian or a logistic growth and (c) a part to accomodate the delayed onset of regeneration, including either a mitotic delay, a fixed time delay, both, or neither. The models are similar in spirit, but different in detail to the model proposed by Cohen. The various models are evaluated on three large datasets, where the response is cell survival in the jejunum or the colon measured using the crypt colony assay. The models were fit and the parameter estimates and standard errors were obtained from the raw observations using non-linear least squares. It is concluded that Gompertzian growth gives a better fit to the data than logistic growth; the delayed onset of regeneration in these tissues can be best accounted for by a mitotic delay or a mitotic delay plus a fixed time delay, and there is little to choose between the linear-quadratic and the two-component model. There was a strong relationship between the tissue cell cycle time and the regenerative response, the mitotic delay being longer and the rate of regeneration slower for the colon than for the jejunum.
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When analysis of results of radiotherapy for nearly 500 patients with oropharyngeal cancer showed evidence for rapid tumor regrowth during extensions of treatment from about 5 weeks to about 8 weeks, we searched the literature on radiotherapy for head and neck cancer to determine whether it revealed similar evidence of accelerated tumor regrowth. Estimates of doses to achieve local control in 50% of cases (TCD50) were made from published local control rates, and the dependence of these doses on overall treatment duration was evaluated. In parallel, published scattergrams were analyzed to estimate the rate of tumor regrowth over the period of 4-10 weeks from initiation of therapy. Both analyses suggested that, on average, clonogen repopulation in squamous cell carcinomas of the head and neck accelerates only after a lag period of the order of 4 +/- 1 weeks after initiation of radiotherapy and that a dose increment of about 0.6 Gy per day is required to compensate for this repopulation. Such a dose increment is consistent with a 4-day clonogen doubling rate, compared with a median of about 60 days in published reports of unperturbed tumor growth rates. The values presented here are average values for a large number of patients: it is necessary, not only to verify the results of these retrospective analyses in prospective studies, but also to develop methods to predict the time of onset and rate of accelerated tumor clonogen repopulation in the individual patient.
The effect of 150 kVp X irradiation on the healing of full depth surgical wounds in the lower dorsal skin of the mouse was assayed by measuring the wound strength of seven 2-mm-wide segments along each wound. The strength of unirradiated wounds increased with time in two phases: during the first 2 weeks it reached nearly half of the values recorded from unwounded skin, after which the rate of increase slowed for at least 2 weeks before beginning a second increase. By 150 days, the breaking strength of the wound was about 80% of that of unwounded skin. A single dose of 18 Gy prior to wounding reduced the strength of the wounds to about one-third to one-half that of an unirradiated wounds within the 3 months of follow-up. The effect of irradiation on wound strength did not change as the interval between exposure and wounding was increased to 2 months but decreased slightly when this interval was extended to 3 months. When the healing wound was irradiated within 5 days of surgery, the effect on healing was about the same as with preirradiation; if irradiation was delayed for 12 days after wounding the second phase of healing was only postponed and the wound strength ultimately approached the values recorded from unirradiated wounds. The wound strength of skin preirradiated by X rays and assayed 14 days after wounding showed a clear sigmoid dose response with a threshold between 8 and 10 Gy and a plateau at the maximum effect above 20 Gy. The persistence for at least 3 months of the effect of radiation on wound healing suggests that the tissues involved in the healing process are normally proliferating slowly. The accelerated expression of radiation injury through surgical wounding permits the early quantification of the radiation response of tissues that would normally be delayed in their expression of radiation damage.
One hundred five patients treated with potentially curative surgery and adjuvant postoperative radiotherapy for adenocarcinoma of the rectum and rectosigmoid from 1973 through 1981 were reviewed. Radiation therapy was given with 18-25 MeV X rays in doses of 40-50 Gy in 5 weeks (midline dose) using AP-PA fields in 97 patients. A boost of 6 to 10 Gy was directed to the area of maximum risk by anterior-posterior or perineal fields in 71 patients. Local failure occurred in 15 patients and was documented pathologically in 8 patients, or clinically or radiologically in 7 patients. The local recurrences according to the Modified Astler-Coller staging criteria were: B1: 0% (0/3); B2: 4% (1/24); B3: 31% (4/13); C1: 8% (1/12); C2: 18% (8/45); C3: 20% (1/5). Local failure after adjuvant radiotherapy versus surgery alone was compared. The comparison of local failure of combined treatment versus surgery alone, from our institution, is as follows: B2-4% vs 13%, B3-31% vs 26%, C2-18% vs 30%, and C3-20% vs 49%. Sixty-one patients (58.1%) have been followed for 5 years, with a median of 73 months and a minimum of 24 months. The actuarial 5-year survival (disease-free) for the entire group is 55% and is not statistically different for the groups with negative or positive nodes. Fourteen patients (13%) required surgery for small bowel complications; four others (4%) had symptomatic small bowel obstruction treated with conservative therapy only. Small bowel obstruction occurred in 4 of 16 (25%) treated with radiation fields above L5, whereas those treated below L5 had an 11% incidence. Postoperative adjuvant radiotherapy can increase local tumor control compared to surgery alone. The small bowel complication rate in this series most likely reflects AP-PA treatment technique and can be decreased by the use of multiple fields with maximum shielding of the small intestine.
This is a report of studies of time-dose relationships for post-irradiation leg contractures in mice. The isoeffect doses for various degrees of contracture, measured 250 days after irradiation, increased with the number of fractions, but not with the overall treatment times, throughout 30 days. The isoeffect curves relating the total doses for given levels of responses to the doses per fraction were steeper for leg contractures than for acute skin reactions. The alpha/beta ratios ranged from 1.4 to 5.0 Gy, depending on the degrees of contracture. They were less than the 7.5 to 50 Gy for acute skin reactions as determined in previous experiments using the same animals and irradiation systems. Thus, the data resembled those from other slowly-responding normal tissues such as the spinal cord, kidney and lung. The leg contracture consisted of dermatogenic, myogenic, and arthrogenic components; after the mice were sacrificed there was residual contracture following removal of the skin and muscle. Inhibition of bone growth accounted for only a small proportion of the contracture. The overall response reflected responses of several tissue types.