Radiotherapy with three fractions per day for twelve consecutive days for tumors of the thorax, head and neck.
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Dose-Response Relationship, Radiation↗
Biomedical subjects
J Denekamp
Publications and source records attributed to J Denekamp.
Radiotherapy employing three fractions on each of twelve consecutive days.
In order to achieve the greatest advantage of accelerated hyperfractionated radiotherapy, treatment has been given 3 times each day for 12 consecutive days without a rest period. A total tumour dose of 50.4 Gy was well tolerated in a series of 38 patients with bronchial, head and neck and oesophageal carcinomas. A further 14 patients have now received an elevated dose of 54 Gy, again with satisfactory tolerance. The tumour responses at all these sites have been very promising and further work is proceeding.
Bronchial Neoplasms↗
Effect of anemia on tumor radiosensitivity under normo and hyperbaric conditions.
The effect of chronic anemia on tumor radiosensitivity in a murine tumor has been investigated. Anemia was induced by bilateral kidney irradiation given several months before tumor implantation. Anemic, anemic transfused, and normal non-anemic age-matched tumor bearing animals were irradiated with X rays (2 F/24 hr) either in air, air plus misonidazole, or under hyperbaric oxygen. The most resistant response was that of tumors grown in normal mice treated in air. Anemia produced an increase in radiosensitivity which was further enhanced by red blood cell replacement. The most sensitive overall response was seen in the anemic-transfused group treated with HBO.
Adenocarcinoma↗
The response of mouse epidermis to fractionated doses of pi mesons.
An extensive series of preclinical experiments are described in which the relative biological effectiveness (RBE) of pions from TRIUMF has been determined for mouse skin. To measure the RBE at both high and low doses per fraction, a range of fractionation schedules was used, with 1, 2, 4, 10, and 20 fractions. Because the pion dose rate is much lower than the dose rate of X or gamma-rays used in radiotherapy, two sets of reference X ray data were obtained: one at the same dose rate as the pions (15 cGy min-1), and another at the more conventional 150 cGy min-1. This allowed a "biophysical" RBE for equivalent dose rates and a "practical" RBE for preclinical evaluation to be calculated. The pion RBE was significantly higher for 20 small fractions than for fewer large doses. The absolute value of RBE depends upon the dose rate of the reference X ray treatments. The "practical" RBE increased from 1.05 at high doses to 1.45 at the smallest dose per fraction tested. The "biophysical" RBE for equivalent dose rates ranged from 1.20 at high doses to 1.5 for 20 fractions.
Animals↗
Stromal sensitivity to radiation and hyperthermia.
The influence on stroma of heat alone, X-rays alone or the combined treatment, has been studied using the tumour bed effect (TBE) as an assay. Ca NT cells have been implanted into previously treated subcutaneous sites as an angiogenic stimulus. The vascular damage is then assessed by the reduced tumour growth rate, which results from inadequate vascular proliferation. A range of X-ray doses was used and large alterations in latent period for growth to 2 mm diameter were followed by smaller alterations in the growth rate of established tumours. A dose response relationship was seen for latency (0-20 Gy) and for growth rate (0-16 Gy). A range of subcutaneous temperatures was obtained by immersion in a water bath for 60 minutes at 40 degrees, 41.5 degrees, 43 degrees or 44.5 degrees C. A slight retardation of tumour growth was seen after 41.5 degrees C, but an unexpected acceleration resulted from the highest heat treatment. Combined heat and X-ray treatments showed thermal sensitization of the X-ray induced TBE at 41.5 degrees C, with a reversal at higher temperatures. At 43 degrees C and 44.5 degrees C a mild thermal burn was induced and this appeared to elicit neovascularisation that could be utilized by the implanted tumour cells. Delayed implantation of tumour cells (at 4 weeks instead of 1 day) abolished this effect.
Adenocarcinoma↗
The effects of melphalan and misonidazole on the vasculature of a murine sarcoma.
A method for estimating both structural and functional vascular volumes in murine sarcomas is described. Intact vessels were demonstrated by the presence of laminin, a basement membrane-associated antigen, using an immunofluorescent technique, and functional vessels in the same sample by prior injection with the DNA binding dye Hoechst 33342. No significant vascular effects were seen after melphalan but a very pronounced decrease in both functional and structural vascular volume was seen after MISO. Combined chemotherapy of a murine sarcoma with melphalan and MISO induced a rapid decrease in the functional vascular volume, and there was a resumption of blood flow prior to measurable regrowth. The fully regrown tumour retained the vascular characteristics of untreated tumours of similar size.
Animals↗
Actinomycin D and radiation: effects on mouse lung.
The effect of actinomycin D (0.4 mg/kg) on radiation-induced lung damage in the mouse was investigated. The drug was administered either 4 weeks before, immediately after, or 16 weeks after single doses of 240 kV X-rays applied to the thorax of CBA mice. Lung damage was assessed by measuring respiration rate, with a whole body plethysmograph. Dose-response curves were obtained at 2-week intervals from 12 to 40 weeks after irradiation. Actinomycin D had no significant effect on respiration rate in this study. A summary of other experimental studies is included which shows conflicting results.
Animals↗
Pions and pig skin: preclinical evaluation of RBE for early and late damage.
The skin of 50 pigs has been irradiated with negative pi mesons and with X rays in order to determine the RBE for early epidermal and later dermal damage. Late fibrosis was not studied. Four, 7, 9 and 10 fractions were used. An estimate of the RBE was made from the reactions on each pig for both early and late damage so that interanimal variability would be avoided. The data were also averaged to obtain mean dose response curves. There was no tendency for higher RBE's for late than for early skin damage. These pig studies have demonstrated an RBE of about 1.5 for early epidermal reactions and a slightly lower RBE (approximately 1.4) for later dermal damage in the same animals. This indicates that at doses of about 2.0 to 3.5 Gy pions, the medium wave skin damage is unlikely to be more severe than would be predicted from the early skin reactions and the accumulated clinical experience with X rays. However, if the trend to a steeper slope for the RBE versus dose per fraction for late injury is correct, as indicated by other published studies a relative increase in the late injury might be expected if much lower doses per fraction are used. The present clinical studies at Vancouver using 15 X 2.1 Gy pions indicate that an RBE of 1.5 is appropriate for epithelia, brain and colorectum.
Animals↗
Response of human tumour xenografts to fractionated X-irradiation.
The response of two human tumour xenografts to single dose and fractionated X-rays has been tested using regrowth delay as the assay. The tumours were line transplanted cells from a moderately well-differentiated squamous carcinoma of the tonsillar fossa (XJ) and an undifferentiated carcinoma of the floor of the mouth (XR). Comparison of the dose response curves for single doses in air, clamped, or after misonidazole administration, led to estimates of the hypoxic fraction (approximately 15%) and the sensitizer enhancement ratio (less than or equal to 1.6). When 5 daily fractions were used, the effect of misonidazole (miso) was lost and reoxygenation appeared to be effective in both tumours. Comparison of single doses and 5 fractions in clamped tumours, and in those sensitized by miso, allowed the sparing effect of fractionation to be estimated. When analysed by the linear quadratic model the alpha/beta ratios were found to be in the range of 6.4-9.2 Gy and 6.8-16.0 Gy for the two tumours. These values are in good agreement with murine tumours (assayed in vivo or in vitro), with human tumour cells assayed in vitro, and with analyses of fractionated clinical data for skin cancer.
Animals↗
Fractionation studies with WR-2721: normal tissues and tumour.
We have studied the ability of WR-2721 to protect skin, kidney and an anaplastic murine tumour against single or fractionated X-ray treatments. Skin reactions, four different kidney assays, regrowth delay and local control of tumours have been used to construct dose-response curves from which the degree of radioprotection can be quantified as a protection factor. Low doses of WR-2721 (0.2-0.3 mg X g-1) were used before each of 1, 5 or 10 fractions. The degree of protection was similar in all three systems and it did not change significantly with fractionation.
Amifostine↗
Time-dependent recovery in the kidney.
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Animals↗
Evidence for a constant repair capacity over 20 fractions of X-rays.
The response of mouse skin to small X-ray doses (less than or equal to 4.5 Gy) has been studied using gross skin reactions to obtain dose response curves. In order to study such small doses without giving a very prolonged series of fractions, the 'top-up' or partial tolerance design of experiment has been used. Eight or twenty priming fractions of X-rays have been 'topped up' with graded single doses of 3 MeV neutrons to bring the sub-threshold X-ray damage into the measurable range. By this means the effect of the same dose could be studied, when given either 8 or 20 times. The data were analysed to see whether each fraction was equally effective in the long or short fractionation schedules. The effectiveness remained constant, showing no significant loss of the repair capacity as the fractionation schedule proceeded.
Animals↗
Cell kinetics and radiation biology.
The cell cycle, the growth fraction and cell loss influence the response of cells to radiation in many ways. The variation in radiosensitivity around the cell cycle, and the extent of radiation-induced delay in cell cycle progression have both been clearly demonstrated in vitro. This translates into a variable time of expression of radiation injury in different normal tissues, ranging from a few days in intestine to weeks, months or even years in slowly proliferating tissues like lung, kidney, bladder and spinal cord. The radiosensitivity of tumours, to single doses, is dominated by hypoxic cells which arise from the imbalance between tumour cell production and the proliferation and branching of the blood vessels needed to bring oxygen and other nutrients to each cell. The response to fractionated radiation schedules is also influenced by the cell kinetic parameters of the cells comprising each tissue or tumour. This is described in terms of repair, redistribution, reoxygenation and repopulation. Slowly cycling cells show much more curved underlying cell survival curves, leading to more dramatic changes with fractionation, dose rate or l.e.t. Rapidly cycling cells redistribute around the cell cycle when the cells in sensitive phases have been killed, and experience less mitotic delay than slowly proliferating cells. Reoxygenation seems more effective in tumours with rapidly cycling cells and high natural cell loss rates. Compensatory repopulation within a treatment schedule may spare skin and mucosa but does not spare slowly proliferating tissues. Furthermore, tumour cell proliferation during fractionated radiotherapy may be an important factor limiting the overall success of treatment.
Animals↗
The use of 'top-up' experiments to investigate the effect of very small doses per fraction in mouse skin.
The partial tolerance type of 'top-up' experiment has been investigated to determine the resolution of this approach for studying the damage to mouse skin from very small doses of X-rays and neutrons. The effect of 20 fractions, each as small as 0.10 Gy of X-rays or of 0.05 Gy of neutrons, can be detected if 3 MeV neutrons are used as the 'top-up' reference radiation. This capability results from the almost linear underlying dose-response curve and highly reproducible dose-effect relationship for the low energy neutrons. The data fit the linear quadratic model of dose fractionation for X-rays down to fractional doses of 0.75 Gy, but at lower doses there is a trend towards an increase in the skin radiosensitivity. Modelling shows that this might be consistent with a sub-population of the cells showing an exceptional radiosensitivity, and a replenishment of this subpopulation occurring in the 8 h between small dose fractions. More experiments are needed at very low doses in order to confirm this hypothesis for skin and for other tissues.
Animals↗
Precipitation of latent renal radiation injury by unilateral nephrectomy.
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Anemia↗
The effect of small radiation doses on mouse skin.
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Animals↗
Differences in chemosensitivity between subcutaneous and pulmonary tumours.
The response of a murine tumour to cyclophosphamide has been studied in two sites (subcutis and lungs) over a wide range of tumour sizes. The site of tumour growth has been shown to have a marked influence on chemosensitivity for tumours of equivalent size. Pulmonary metastases are much more sensitive than subcutaneous implants. In the lung there is a simple decrease in curability as the tumour grows, presumably reflecting the increase in clonogenic cells per tumour. In the subcutis the pattern is more complex. An initial sensitivity is followed by a decline during the avascular phase of growth. As the vascular network develops the tumours regain their chemosensitivity. There is no correlation between volume doubling time and chemosensitivity. This study indicates that it is impossible to predict the response of pulmonary deposits from a study of subcutaneous implants.
Animals↗
A review of alpha/beta ratios for experimental tumors: implications for clinical studies of altered fractionation.
Clinical interest in the use of more and smaller dose fractions in radical radiotherapy has been stimulated by recent reviews of experimental results with normal tissues. It has been found that if the dose per fraction is reduced (i.e., in hyperfractionation) there is sparing of late responding normal tissues relative to those which respond early. This phenomenon can be understood in terms of the shapes of the underlying dose effect relationships, which can be described using the linear quadratic equation. The ratio (alpha/beta) of the linear (alpha) and quadratic (beta) terms is a useful measure of the curviness of such dose effect curves. Low alpha/beta values (1.5 to 5 Gy) have been observed for late responding normal tissues and indicate that radiation damage should be greatly spared by the use of dose fractions smaller than the 2 Gy used in conventional radiotherapy. By contrast the high alpha/beta values (6-14 Gy) observed for acutely responding normal tissues indicate that the response is relatively linear over the dose range of clinical interest. Hence less extra sparing effect is to be expected if lower doses per fraction are administered. If tumors respond in the same way as acutely responding normal tissues then hyperfractionation might confer a therapeutic gain relative to late responding normal tissues. We have reviewed published results for experimental tumors irradiated in situ and either assayed in situ or after excision. The alpha/beta ratios were usually at least as high as those for acutely responding normal tissues, and 36/48 tumors gave values greater than 8 Gy. Low values of less than 5 Gy were obtained for only 4/48 tumors. There are considerable technical problems in interpreting these experiments, but the results do suggest that hyperfractionation might confer therapeutic gain relative to late responding normal tissues on the basis of differences in repair capability. In clinical practice more efficient reoxygenation, cell cycle redistribution and decreased overall treatment time might also confer therapeutic gain.
Animals↗