Late Radiation Changes Research Articles

Recovery of the Intestinal Mucosa in the Rat after X-Irradiation of the Exteriorized Intestine

We have previously reported on the effect of irradiating an exteriorized loop of rat intestine with a dose of 1000 R (1). Our observations extended to 72 hours after irradiation, when the damage to the epithelial cells lining the jejunal crypts and villi was severe with complete loss of the villous structures. We therefore decided to study the recovery process after this dose of radiation to assess when it took place and whether evidence of residual damage could be observed. There is considerable variation on these points in the literature. One group of workers found that after a dose of 900 R to an exteriorized loop of rat intestine only transitory changes were present initially, with no residual damage at a later period (2). On the other hand, another group found that after a dose of 1000 R to an exteriorized loop of rat intestine there was gross damage at 5 days, which gave rise to late radiation changes (3). The interpretation of the effects of irradiation is complicated by our inability to differentiate between the consequences of damage to the gut and the changes that result from repair processes. Though both processes no doubt occur concurrently, only the predominant one at a given moment is cited in this study, as this simplification is considered justifiable under present circumstances.

Effect of Total-Body Irradiation on the Response of Transplanted Mouse Tumors to Fractionated Local Radiotherapy

The ability of small doses of total-body irradiation to increase the amount of oncolysis produced by local radiation exposures of transplanted mouse tumors was originally reported by Hollcroft and her co-workers (3–5). Some time ago this phenomenon was confirmed in our laboratory (Wayne State University College of Medicine) and was further extended to other tumor-host systems (14). The obvious differences between the single exposures used in these earlier studies and the series of treatments employed in clinical practice led us to perform additional studies with several combinations of local fractionated exposures and total-body radiation to determine whether the enhancing effect was present. In the first paper of this series (15), we reported a substantial enhancement of effect when a portion of the local fractionated doses to the L-1 lymphosarcoma was replaced by small doses of whole-body irradiation. The effect seemed to be independent of the magnitude of the total-body dose, in accord with our previous experiences using single exposures, and was found to be valid for tumor regression, median survival time, late radiation changes, and the development of gross metastases. A lesser enhancement of effect by whole-body irradiation was found in a similar series of experiments with the Ehrlich carcinoma. The tissues obtained at autopsy of the mice used in previous experiments were subjected to detailed histologic study. In the present report, we shall present a deanalysis of these data to examine the effect of fractionation and concomitant whole-body radiation exposure on the development of metastases. Methods The experimental design and methods have been described in detail previously (15) and will be repeated here only in summary. The L-1 lymphosarcoma and the Ehrlich were removed from mice in which they were actively growing as solid tumors, and small fragments were implanted by trocar into the lower thigh of recipient animals. Seven experimental and one untreated control group of approximately 20 animals each were randomly formed from those mice whose tumors most closely approximated the average tumor size for the eight groups (7 mm). The relatively few animals with smaller or larger tumors were discarded. As indicated in Table I (which is a condensation of a more detailed table presented in the previous paper), the first experiment with the lymphosarcoma (L-l) included three groups which received 333 R per exposure three times a week. One of these groups received local exposure only. A second group was given 283 R to the tumor plus 50 R whole-body irradiation on one day, and 333 R local exposure on the other two days.

Effect of L-Triiodothyronine on Post-Irradiation Fibrosis

The first reports of radiation dermatitis followed shortly after the discovery of x-rays by Roentgen in 1895 (1). Wolbach (2) described the histopathology of radiation changes in 1909. These appear to be related to early inflammatory injury of the vascular and lymphatic structures and of connective-tissue elements, with increase in collagen. The vascular effect produces a greatly narrowed or completely occluded lumen, and thrombosis is common. An increase in the amount as well as a change in the type of collagen in irradiated tissue has been demonstrated by histologic, histochemical, and biochemical technics. These changes have been considered the major factors in the inability of irradiated tissue to heal normally and in the production of subsequent breakdown. During the past twenty years much attention has been given to describing and modifying radiation injuries produced in living cells, tissues, and whole organisms (3, 4), with particular concentration on the period immediately before, during, and after irradiation. The general conclusion has been that any modifying agent must be present during the act of irradiation if it is to reduce injury or to foster repair. An outstanding exception was initially thought to be the administration of bone marrow or splenic cells after irradiation. But it is now accepted that the major, if not the sole, mechanism involved here is one of grafting bone-marrow cells, i.e., a replacement mechanism (5). Our group at Memorial Center demonstrated that pharmacologic doses of L-triiodothyronine (T-3) produce significant improvement in late radiation damage (6). Of 75 patients with radiation injuries of two to thirty years duration, approximately two-thirds, with ulcers and fibrosis, showed good to excellent results. It was appreciated, however, that great difficulties are involved in the clinical evaluation of late radiation changes, despite attempts at objectivity, detachment, and a double-blind technic. Objective laboratory procedures were therefore developed which could quantitatively evaluate the efficacy of thyroid analogues in late radiation changes. This study covers some of the biological effects of a standard x-ray exposure and the effects of exogenous thyroid hormone on these changes. Methods Adult male rats weighing approximately 350 to 400 gm. 3,000 rads to the right hind limb in a single exposure from a 250-kevp x-ray generator, h.v.l. 1 mm. Cu, T.S.D. 21.5 cm., at a dose rate of 840 r per minute. The remainder of the animal was shielded from irradiation. The dose delivered to tissues outside of the direct beam was less than 5 per cent of that received by the right limb. Animals were randomly assigned to control groups and to a group started on L-triiodothyronine eight weeks after irradiation. Because L-triiodothyronine was found to be stable in drinking water at room temperature for more than three days, it was given in water.

LATE IRRADIATION CHANGES IN VAGINAL CYTOLOGY

Summary 1. One hundred and thirty-nine smears obtained with use of the Papanicolaou technique from postirradiated patients 6 months to 25 years after therapy were reviewed. 2. Findings were noted consistent with protracted effects of radiation in 72 percent of the cases studied; these were classified as showing good or mild late radiation change. These changes were seen as long as 25 years after therapy. 3. Twenty-six per cent of the smears displayed good late radiation change, of which 44 percent showed severe cellular atypism. All of the patients were clinically free of recurrent or persistent tumor. 4. One hundred and twenty-seve n duplicate smears studied by means of the fluorescent staining technique were also reviewed. Findings were noted which were suggestive of, though not considered to be specific for, late radiation change. Significant differences in interpretation between smears studied by means of this technique and the Papanicolaou technique were apparent. 5. The knowledge of prior pelvic irradiation must be taken into consideration when vaginal smears are evaluated, and when severe cellular atypism is noted this must be differentiated from that seen with carcinoma. 6. Clinical evaluation is still the most important factor in determining the presence of recurrent or persistent pelvic carcinoma.

Late irradiation changes in vaginal cytology

Summary 1. One hundred and thirty-nine smears obtained with use of the Papanicolaou technique from postirradiated patients 6 months to 25 years after therapy were reviewed. 2. Findings were noted consistent with protracted effects of radiation in 72 percent of the cases studied; these were classified as showing good or mild late radiation change. These changes were seen as long as 25 years after therapy. 3. Twenty-six per cent of the smears displayed good late radiation change, of which 44 percent showed severe cellular atypism. All of the patients were clinically free of recurrent or persistent tumor. 4. One hundred and twenty-seve n duplicate smears studied by means of the fluorescent staining technique were also reviewed. Findings were noted which were suggestive of, though not considered to be specific for, late radiation change. Significant differences in interpretation between smears studied by means of this technique and the Papanicolaou technique were apparent. 5. The knowledge of prior pelvic irradiation must be taken into consideration when vaginal smears are evaluated, and when severe cellular atypism is noted this must be differentiated from that seen with carcinoma. 6. Clinical evaluation is still the most important factor in determining the presence of recurrent or persistent pelvic carcinoma.

Modification of late radiation injury with L-triiodothyronine.

In 1895, Roentgen reported a new form of radiation. In 1896 Becquerel discovered radioactivity. In 1896 also the first cases of radiation dermatitis and epilation were observed (1). By 1902 radiation-induced cancer was reported (2). By 1910 the histopathology of late radiation changes had been documented (3). Each organ or tissue has been shown to have a characteristic pattern of structural and functional alterations which are produced as a late effect of exposure to ionizing radiation (4). These changes appear to be related to early injury to the vascular structures and to connective-tissue elements. This in itself may produce secondary changes in the parenchymal cell of the organ in question. In addition, the parenchymal cell may be injured directly by the ionizing radiation. The interplay of these two mechanisms, and doubtless others as yet unappreciated, results in altered structure and altered ability to perform a normal role in the economy of the body. These changes do not appear to reach a static state even at times far removed from the initial injury. It would appear, therefore, that the process is a dynamic one. Attempts to understand its mechanisms may lead to methods capable of perturbing the balance. Obviously, as clinicians we are interested in exploiting those methods which would result in a return to or toward normal. Attempts to alter the damage produced by ionizing radiation at the time it is initiated have included measures taken before and during irradiation. Attempts to modify established damage have for the most part been confined to a period of thirty days after exposure. With the exception of splenic and bone marrow transplants and their variants, no agent as yet has been found which, if given after irradiation, will modify radiation damage materially. The presence of such agents as cysteine, glutathione, cystamine, and AET at the time of irradiation appears to be necessary (5). There is some evidence that most of these protect against only one facet of the postirradiation syndrome, i.e., the causes of death from the ninth to the thirtieth day. Mice so protected may have a decreased life span. Renal pathology appears to be the most frequent cause of death in these initially protected animals (6). Attempts to alter established damage in patients have been sporadic and frustrating. Supportive measures such as transfusion for aplastic anemia or removal of severely damaged skin and underlying tissues followed by skin grafting are fairly routine. ACTH and cortisone were studied at one time because of their known suppressive effect on connective-tissue reaction to other injurious stimuli, with the hope that this effect might also be seen after irradiation. Unfortunately neither the animal experiments of Karnofsky (7) nor the human studies of Chu et al. (8) afforded any detectable evidence of beneficial effect.

A study of late radiation necrosis following therapy of skin cancer.

The utilization of roentgen rays in cancer therapy obviously is dependent upon their capacity to destroy malignant growth without producing destruction of surrounding normal tissue. However, in basal- and squamous-cell cancer of skin, margin of difference between what is generally regarded as the tumor lethal dose and that which will produce permanent destruction (necrosis) of normal skin and subcutaneous tissues, is a somewhat narrow one. It should not be surprising, therefore, that if normal tissue tolerance were for any reason slightly lowered, it might approach that of tumor lethal dose. Consequently, surrounding tissue, as well as tumor, might be destroyed. Although these basic principles have been known for years, there appears to be a tendency to associate phenomenon of tissue necrosis solely with excessive overdosage. The late radiation changes resulting from total dosages far in

LATE RADIATION EFFECTS IN ROENTGEN THERAPY FOR HYPERTHYROIDISM

Their Possible Bearing on the Use of Radioactive Iodine To the Editor:— Radioactive iodine, especially the isotope of 8 day half-life, I131, has been employed in the treatment of hyperthyroidism in several clinics during recent years, a total of several hundred patients probably having received the material. The question of the possibility of late radiation changes leading to malignant degeneration has been raised and cannot be disregarded. Serious sequelae to radiation therapy usually appear several years after the treatment; hence such damage from radioiodine would not be expected for some time. If it is to be feared that this will be a serious hazard, the use of the material ought to be very sharply restricted until sufficient time has elapsed to ascertain the late results in persons already treated. On the other hand, if any pertinent evidence can be obtained from the already large experience with roentgen rays, it