The response of a transplantable tumor to fractionated irradiation. III. Fast neutrons plus the radiosensitizer Ro-07-0582.
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Biomedical subjects
Publications and source records attributed to S B Field.
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Between each fraction in radiotherapy, there is repair and recovery of both normal and neoplastic tissues. Several different types of repair have been identified. Some relate specifically to the effect of changing the number of fractions and others to the overall treatment time. Each will be discussed and particular attention will be paid to slow repair phenomena which have recently been the subject of much interest.
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A study is made of the relationship between early and late damage after irradiation of the feet or ears of rats. In one type of experiment in which large groups of animals were given the same dose, there was a good correlation between the early and late forms of damage. In another experiment, the relationship between these two forms of radiation damage was found to be unaltered by a single dose of X-rays given 8 months earlier. Thus, both types of experiment point to the early and late forms of reaction in the skin of rodents resulting from a common cause. Other relevant experimental data and their relationship to clinical observations are discussed.
The physical and radiobiological properties of two neutron beams have been compared. The beams were generated by deuterons of 16 MeV at Hammersmith Hospital and 42 MeV at Harwell, in both cases falling on a Be/Cu target. The dose-rate and depth-dose characteristics at the higher energy were found to be superior to those at the lower energy. Collimation and shielding at the higher energy are facilitated by the greater degree of forward-peaking and by the fact that a higher dose-rate allows longer collimators to be used. Attenuation in iron was found to be similar at the two energies. The radiobiological properties of the two neutron beams are very similar. There is a difference of about 20 per cent in RBE for effects on mammalian tissues for doses between 300 and 2,000 rad of neutrons. The OER and the sparing effect of two large fractions are the same for the two beams.
The LD/50 between 40 and 180 days after irradiation of the thorax has been taken as a measure of lung damage in mice. The method has been used to derive the relationship between total dose, number of fractions (N) and overall treatment time (T). For X rays the results fit an Ellis type of relationship, i.e. total dose alphaN0-25 T0-07. This only applies for more than 8 fractions, below which N0-39 becomes a good fit to the results. For neutrons, the best fit is total dose alphaT0-07. Various possible explanations for the T factor are discussed, but for lung damage we attribute it to a slow repair process which possibly may only be observed in slowly proliferating tissues. Slow repair is about 100 times less rapid than Elkind-type of repair of sublethal damage and whereas Elkind repair is greatly reduced for irradiation with fast neutrons, relative to X rays, slow repair is not.
The treatment of cancer using fast neutrons was first attempted from 1938 to 1942, only a few years after the identification of the particle in 1932. The radiobiological information which was available at that time was both inadequate and contradictory, and provided no definite rationale for using neutrons in preference to X-rays. The doses given were often too high, causing many patients to suffer severe late reactions. As a result, further attempts to use fast neutrons in radiotherapy were abandoned for nearly 30 years. Interest in the use of fast neutrons was stimulated again by the elucidation of the oxygen effect and the discovery that it was less for neutrons than for X-rays. Thus tumours containing hypoxic cells would be less protected against neutrons. Also the reduced repair of sublethal damage with neutrons provided at least a partial explanation of the miscalculation of dose in the early trial. This was confirmed by means of a series of experiments on pig skin, from which it was also concluded that late damage was not more severe after neutrons, compared with X-rays for a given degree of early damage. A new clinical trial began in 1966, and the results so far are encouraging. In order to relate radiotherapy experience with X-rays to neutrons, it is necessary to measure the relative biological effectiveness (RBE) of neutrons. This has been done for skin of man, pig, mouse and rat. Because of the smaller recovery from sublethal damage after neutrons, the RBE increases as the dose per fraction decreases, but the relationship between RBE and dose per fraction is the same for all four species. Similar information, but only for rodents, has been obtained for a variety of other normal tissues with both cyclotron-produced and monoenergetic 14 or 15 meV neutrons. Experiments with animal tumours have indicated that there might be a wide variation in RBE from tumour to tumour due both to the presence of hypoxic cells and to differences in their capacities to recover from sublethal damage after X-rays and neutrons. The largest series of experiments on one tumour shows that whereas certain fractionation techniques with X-rays may produce a poor tumour response for a given level of normal tissue damage, all the neutron regimes produced a similar, close to optimum result. There is no evidence from which to expect any special dangers from neutron irradiation, and their likely advantage is that they may provide a more reliable method of radiotherapy as well as sterilizing some tumours which are normally resistant to X-rays.
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The relative biological effectiveness (RBE) for damage to mouse lung was measured for single doses and up to 30 fractions of 8 MV x rays and fast neutrons, relative to 250 kVp x rays. With 8 MV x rays the RBE was 0.87 and did not vary with dose per fraction between 150 and 1200 rad. With fast neutrons the RBE did not vary from 1.5 at 1200 rad of x rays, which is about 30% lower than that for skin, to 3.7 at 150 rad of x rays, which is about 10% less than that for skin. The implications for treatment of the lung with fast neutrons are discussed.
Lewis lung tumor cells were irradiated with 60Co gamma-rays or cyclotron-produced neutrons in situ as solid s.c. tumors or in vitro as single cell suspensions. Cell survival was assayed by colony formation both in vitro in soft agar and in the lungs of isogeneic recipient mice. Survival curve characteristics measured in vitro were: Do = 111 rads, Dq = 342 rads, n = 22 for gamma-rays, and Do = 61 rads, Dq = 46 rads, n = 2 for neutrons. In situ, the hypoxic fraction was 0.36. Irradiation in situ gave, for the hypoxic subpopulation, Do = 315 rads for gamma-rays and Do = 91 rads for neutrons. The oxygen-enhancement ratio for gamma-rays was 2.8 and for neutrons was 1.5. Using the split-dose technique, in which two equal doses were administered, separated by 4 hr chronically hypoxic tumor cells repaired sublethal damage, assayed by leaving tumor cells in situ up to 24 hr posttreatment, could not be detected after neutrons, but after gamma-rays it was observed as a 3- to 6-fold increase in survival. The repair of potentially lethal damage increased the relative biological effectiveness of neutrons from 3.7 at a survival level of 5% when assayed immediately after treatment to 4.7 when assayed 6 to 24 hr after treatment. These observations, primarily limited to the chronically hypoxic subpopulation of tumor cells, suggest that decreased repair of potentially lethal damage as well as sublethal damage may be an important radiobiological difference between the effects of high and low linear energy transfer radiation.
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