Experimental radio-osteonecrosis in Rhesus macaque jaws; therapeutic irradiation dose effect on dental extraction wound healing.код для вставкиСкачать
Experimental Radio-osteonecrosis in Rhesus Macaque Jcrws; Therapeutic Irradiation Dose Effect on Dental Extraction Wound Healing ’ LEO ZACH, GERSON COHEN, IRWIN SCOPP AND GUSTAVE KAPLAN Department o f Pathology, N e w Y o r k University College of Dentistry, Dental Department, Veterans Administration Hospital, N e w Y o r k , Dental Department, Veterans Administration Hospital, N e w Y o r k , Department of Radiology, Veterans Administration Hospital, N e w Y o r k Varying degrees of osteonecrosis result from molar extractions or other oral surgical procedures in rhesus macaques before, during, or after the administration of 6000 rad (the equivalent of human therapeutic dose levels) via either 240 kVp x-ray or cobalt 60 irradiation to the jaw areas subjected to surgery. The effects of various experimental time-dose-wound combinations on the level of impairment of wound-healing, interruption of osteogenesis, and the nature of the response of the irradiation-compromisedtissues are covered in this report. ABSTRACT The purpose of this investigation was to evaluate the possibly differential effects on surgically traumatized dental and oral tissues of traditional 240 kVp (orthovoltage) and cobalt 60 (megavoltage) delivered to selected jaw areas in adult rhesus macaques at full therapeutic irradiation level. This species was selected because of anatomic and physiologic similarities to man, relative longevity, and viability under animal room conditions. With the gradual phasing out in this country of 240 kVp irradiation a s a cancericidal therapeutic modality, the study emphasis shifted to concentration on the effects of the cobalt 60 beam and most particularly on the responses of irradiated oral tissues that had received, or were receiving, standard oral surgical procedures involving exposure of alveolar bone. The experiment was programmed to simulate a grave set of actual clinical situations in which irradiation therapy is used in palliation of, or as a n attempt to eradicate, oral malignant disease. Intraoral malignancy is essentially a disease of older males (see reference to work of J. J. Pindborg et al. in Gorlin and Goldman, ’70), having a three or four to one sex preponderance. Incidence corresponds closely with the peak years of serious, degenerative dental disease requiring surgical intervenAM. J. PHYS.ANTHROP.,38: 325-330. tion in the form of extractions for decay or irreversible periodontal breakdown. The time-coincidence of the need for surgical dental intervention and therapeutic irradiation poses serious problems for both the dentist and the radiotherapist. Surgically traumatized tissues, and especially bone, generally respond with a markedly diminished healing rate in the presence of ionizing radiation. Chronically infected tissues, such as are encountered in the oral cavities of large numbers of patients requirling irradiation for oral malignancy, tend to break down and ulcerate on irradiation much more frequently and with greater severity than do the intact tissues of younger patients. Mucosal ulceration exposes underlying bone, already compromised in its microvasculature by the energy-absorbing characteristics of bone. Partially devitalized osseous tissue and radiation-depressed marrow, in turn, undergo rapid and frequently devastating osteonecrosis when exposed to spreading infection that in normal tissues is competently tolerated or localized. According to Rubin and Casarett (’68), “there is a complex interplay between radiation effect and intraoral disease.” 1 Supported by United States Public Health Service grant DE 2293, Institutes of Health, National Instltute of Dental Research. 325 326 L. ZACH, G. COHEN, I. SCOPP A N D G. KAPLAN The controversy regarding prophylactic extractions of all carious or impaired teeth in the radiation field remains unresolved. As recently as 1965, Roswit recommended prophylactic extraction of all such teeth, particularly molars, rongeuring of the alveolar crests, removal of bone spicules, and surgical closing of sockets before irradiation; radiotherapy is then to be instituted at once. Others (Wildermuth and Cantril, ’53) suggest that a wiser course is to wait 15 days before starting irradiation. Many recommendations of this type of clinical programming are made in response to the intense and rapid cervical caries that is an almost invariable post-240 kVp irradiation sequel. The bone and tooth “sparing” characteristics of cobalt 60 radiation therapy have reopened the discussion of whether it is necessary for the patient scheduled for cobalt 60 therapy to undergo mutilating, multiple extractions. These clinical problems led to the design of this study. STUDY DESIGN Thirty-four experimental rhesus macaque monkeys received irradiation through mandibular portals before, during, and after intraoral surgical procedures. The animals, all adults with full permanent dentition, received a fractionated dose of 333 rads thrice weekly for a total dosage of 6000 rads over a six-week period. Dosage was administered at the rate of 35 rads/minute through two 5 X 7 cm treatment ports with both 240 kVp and cobalt 60 technique. With orthovoltage, a n HVL of 3.5 mm Cu was used at a TSD3 of 50 cm. With megavoltage, SSD was 55 cm. At varying positions on the time grid, the following oral surgical procedures were performed on the experimental animals. 1. Extraction of right mandibular first molar with forceps and elevators; no suture, hemostatic agent, or socket dressing. 2. Buccal gingivectomy to expose alveolar crestal bone from distal aspect of right cuspid tooth to mesial aspect of right second molar extending 1.5 to 2.0 cm from the free margin apically. 3 . Extirpation of the pulp of the maxillary right central incisor via a lingual cavity, insertion of a gutta percha root canal filling, and a zinc oxide-eugenol seal. These three challenges to the reparative potential of the irradiated oral tissues simulate actual clinical situations of loss of a tooth, gingival disease, and a n attempt to retain a tooth with pulpal involvement, respectively. Bone was exposed and traumatized, and direct bacterial pathways opened. Animals were given 200,000 units of penicillin-streptomycin preoperatively, and this dosage was continued for 14 days. Nonetheless, several specimens died of pneumonia before the planned time of sacrifice, with losses occurring both before and after starting irradiation. The surgical procedures were performed on the 34 experimental animals either before (or at the beginning of) irradiation, intercurrent with irradiation (after 3000 rads), or after completion of the full course (6000 rads) of radiation. As a control, one additional animal received a full course of irradiation with no oral surgical procedures; and a n additional control underwent the surgical steps, but received no irradiation. In the course of the study, a total of 35 rhesus macaques were irradiated. In table 1, the section called “Matchings” lists together specimens having identical or closely comparable experimental records. Comparisons between the orthovoltage-megavoltage members of each pair or group of specimens offer a fair possibility of demonstrating distinctive characteristics of the response of injured/healing tissues to the two types of irradiation. Some specimens receiving one type of irradiation could not be matched for experiences with any receiving the other type; they are listed under the heading “Unique” and are useful for evaluating tissue response to the surgery-irradiation circumstances described. OBSERVATIONS Early in the course of the continued irradiation procedures, it became apparent that 6000 rad delivered to one jaw site of rhesus macaques, via either 240 kVp or cobalt, constituted a n over-taxing dosage. Accordingly, after treatment of the 2 HVL, half-value layer produced by a 3.5 mm-thick copper filter. 3 TSD, tube to surface (or skin) distance. 4 SSD, source to surface (or skin) distance. RADIO-OSTEONECROSIS IN MACAQUE JAWS 327 TABLE 1 Comparison of specimens receiving megavoltage a n d orthovoltage Irradiation experimental sequence Animal numbers M2-M31-09 M3-010-041 M4-016 M5-M39-M47-02-05 M8-038 M16-0 10-0 16 M22-07 M26-041 M27-030-04-07 M30-030 M36-036 M44-026 M45-031 M48-048 08011- 0220381 Matchings 1 Died shortly after full course of irradiation; no surgery. Surgery before irradiation; sacrifice one to two months after full course. Surgery two months after irradiation; sacrifice six months after surgery. Surgery five months after irradiation; sacrifice one month after surgery. Surgery intercurrent with irradiation; sacrifice two months after full course. Surgery two months before irradiation; sacrifice two to six months after full course. Surgery two months after irradiation; sacrifice two to three months after surgery. Surgery at start of irradiation; sacrifice one to two months after full course. Surgery one to two months after irradiation; sacrifice one to two months after surgery. Surgery two months after irradiation; sacrifice one month after surgery. Surgery one to two months before irradiation; sacrifice two months after full course. Surgery one to two months after irradiation; sacrifice one to two months after surgery. Surgery one month after irradiation; sacrifice 1 1 to 1 2 months after surgery. Full course of irradiation only; no surgery; sacrifice 1 1 months after irradiation. Unique Surgery intercurrent with irradiation; sacrifice ten months after full course. Surgery not performed; irradiation halted when the specimen developed progressive sloughing a n d osteoradionecrosis after 3000 rad; specimen died five months thereafter. Surgery performed at 3 0 0 0 rad level; full course continued a n d completed. Animal died one month thereafter of fulminating osteoradionecrosis. Same treatment as 022; specimen survived three months post-irradiation. M , animals receiving cobalt 60 irradiation (megavoltage). 0,animals receiving 240kVp x-radiation (orthovoltage ). first few animals, split portals were used and the subsequent radiation delivered via both right and left mandibular portals. Several specimens, however, mostly those given orthovoltage, died after a fraction of the proposed dose had been delivered; they are not included in the results, although histologic sections were prepared. GENERAL RESULTS OF IRRADIATION 1. Epilation. Facial epilation appeared in the orthovoltage-irradiated specimens, generally after three 333-rad treatments, or after approximately 1000 rad. The de- gree of loss varied, but was usually moderate. Epilation rarely was a feature of the cobalt-irradiated specimens and was mild when noted; it was not generally evident until 3000 to 5000 rad had been delivered. Some regrowth of facial fur occurred in the orthovoltage specimens that survived the irradiation for several months. 2. Radiodermatitis. Ali orthovoltage specimens showed markedly reddened, edematous skin within the beam areas after 1000 rad. The dermatitis frequently was severe, with swelling of the cheek 328 L. ZACH, G . COHEN, I. SCOPP A N D G. KAPLAN and infraorbital areas. Cobalt specimens showed a lesser degree of facial edema and hyperemia. 3 . Radiogingiuitis. All orthovoltage specimens displayed gingivitis, manifested by edema, hyperemia, and occasional ulceration resembling acute necrotising ulcerative gingivitis, at the fifth treatment (1600 rad level). Marginal sloughing was noted; and occasionally the posterior teeth, where the gingivitis was most severe, were mobile. Orthovoltage animals generally lost weight and had difficulty in feeding during the later stages of the irradiation, regardless of time of extraction. Megavoltage specimens showed less gingivitis, except for two (M2 and M 3 1 ) in which gingivitis led to slough with extensive exposure first of alveolar crestal bone and eventual broad bony exposure. Both specimens died before extractions. In all instances when osteoradionecrosis was severe, under both irradiation modalities, it was preceded by extensive gingival sloughing. RESULTS OF SURGICAL PROCEDURES 1. Surgery before irradiation. None of the specimens with extractions done before the irradiation course died before the planned sacrifice time; in these animals, for both irradiation modes healing response was generally less impaired than in the experimental animals that had extractions during or after irradiation. The orthovoltage response was uniformly more severe than the cobalt, however, with much-delayed epithelial bridging of the socket wound and retention of non-viable spicules of necrotic alveolar bone seeding the loose granulation tissue. With orthovoltage, scalloped erosions of adjacent roots, together with edema and inflammation of peridental ligaments, were consistently observed. The amount of the filling-in tissue, a t whatever time after irradiation it was examined, greatly lagged behind that in the non-irradiated control. Collagen maturation was delayed, with broad bundles appearing about one month after their appearance in the control. Collagen was fibrillar, rather than fibrous; and ground substance accetped a lesser quantity of eosin, appearing pale and myxom atous. In the specimens sacrificed at the longer post-irradiation intervals, microfistulae extended into the socket, frequently deep to surface; but the outward migration of miniature sequestra was very slow. Gingival biopsy areas eventually epithelized, but crestal erosion was noted in the orthovoltage specimens. Periapical response to pulp extirpation was essentially normal. Cervical caries and enamel erosion were noted in the orthovoltage specimens; none in the megavoltage. 2. Surgery during irradiation. This sequence produced the most severe impairment to normal healing of any of the modes studied, particularly when 240 kVp was the irradiation source. Two of the orthovoltage animals died of massive mandibular osteoradionecrosis. In these specimens, roots of adjacent teeth were totally exposed to the apices; bone was broadly exposed, friable, and crumbly. Masseter and temporalis muscles and overlying skin sloughed; edema in surrounding facial areas was severe, particularly in the tongue. Extensive lingual edema pressed the tongue against the remaining teeth, producing deep scalloping and ulceration of the beam-facing lateral border. Severe hemorrhaging into the sinuses, attributable to vascular wall erosion, was evident. Specimens which survived this challenge fared poorly, responding with sloughing socket walls after the extraction, exposure and erosion of adjacent roots, and a much enlarged socket wound. The alveolar socket filled slowly from the base, with thin and slow surface epithelization. Loose granulation tissue was filled with portions of non-viable bone, which lacked the epithelial downgrowths of the specimens irradiated at other times relative to extraction. Collagen appeared late in the healing; and ossification, even after six months, was scanty and inadequate. Epithelium, when it eventually bridged the defect, lacked a sawtooth basal attachment to underlying submucosa. Cobalt-irradiated specimens showed a lesser degree of gross disturbance in healing; all survived. Overlying muscle showed intense edema, with perimysial stripping away from the fibers. Empty osteocytic lacunae were found even at considerable distance from the socketbordering bone. RADIO-OSTEONECROSIS IN MACAQUE JAWS 3. Surgery after irradiation. Tolerance to this time-sequence was surprisingly favorable, particularly after cobalt irradiation and to a lesser extent in specimens that had extractions several months after completion of the orthovoltage course. The largest number (20) of specimens were treated on this schedule in a n attempt to determine whether dental or oral surgical procedures were possible after irradiation, particularly in view of the anticipated sparing effect of the by now almost universally used cobalt 60 beam. Healing with both modalities, however, was slower and destruction greater than in specimens that had undergone surgery before irradiation. In one orthovoltage animal, even with surgery following irradiation by three months and sacrifice three months after surgery, no osteoblastic activity was found at the base of the sockets, which were filled with immature collagenous connective tissue. Epithelialization was thin and poor, with considerable down-dipping along the root walls of the adjacent bicuspid and molar teeth. In these adjacent teeth, resorptive nicking through the cementum and into the dentin was noted, with the scallops often filled with epithelial downgrowth, simulating the histology seen in advanced periodontitis. Opportunity to study the pulps of several unerupted third molars i n the radiation beam showed odontoblastic disruption with consequent derangement of dentin formation as a direct result of irradiation. Enamel caries was a fairly constant feature of the specimens. In addition, a direct erosive effect manifested by chalkiness and staining of enamel in the pathway of the beam, was noted. This response differed from the cervical caries customarily observed, a condition partially attributable to diminution of salivary flow. The observed erosions were on the buccal aspects of the teeth closest to the direct beam and on the lingual aspects of the contralateral teeth, i n all instances not i n the cervical area, but more occlusally, at the region of greatest diameter of the affected tooth. This response is thought to be a direct radiation effect on enamel hydroxyapatite crystal structure, not one mediated via bacterial action. Cobalt- irradiated animals showed more 329 rapid and more competent healing responses. After one month, bridging epithelium surfaced the socket wound. Early osteogenesis was noted at this time, with a fairly adequate network of spicules evident after three months. No extensive osteonecrosis was evident in any of the cobalt animals, which showed satisfactory (slow but adequate) healing after six months. CONCLUSION The study tends to confirm on a n experimental basis, the clinical findings a t Roswell Park of Solomon et al. ( ' 6 8 ) , who reported no instance of radio-osteonecrosis in 32 consecutive patients subjected to 48 dental operative procedures (in most instances including multiple extractions) performed after cancericidal doses of radiotherapy. Because of the time-span covered, it must be assumed that many of these patients received conventional orthovoltage therapy for their head and neck malignancies. The study also tends to indicate that even though healing is delayed, irradiated jaw structures may be subjected to oral surgical procedures, if performed judiciously and with antibiotic support. The wholesale extraction of healthy teeth, even those within the radiation beam, seems contraindicated. Close cooperation between dental and radiotherapy services is necessary to determine the state of oral health of patients scheduled for radiotherapy. Plans for the elimination of teeth hopelessly infected, whether through caries or periodontal disease, should be carried out as early as possible. The retention of sound dental structures, rapidly brought to as hygienic a state as possible, is then a distinct probability. Investigation of radiation caries should continue, both of the rampant, cervical type and of the direct enamel erosive-effect type observed in this work. Further, the comparative responses of rongeured and sutured tissues with those where extractions were performed with a minimum of surgical intervention require study. LITERATURE CITED Gorlin, R. J., and H. M. Goldman, eds. 1970 Thoma's Oral Pathology. Sixth ed. C. B. Mosby Co., St. Louis, Vol. 2, pp. 819-821. 330 L. ZACH, G. COHEN, I. SCOPP AND G. KAPLAN Roswit, B., S. J. Malsky and C. G. Amato 1965 In vivo radiation dosimetry for clinical and experimental radiation therapy. prog, in c1inical Cancer, 1: 96-126. Rubin, P., and G. W. Casarett 1968 Clinical radiation pathology as applied to curative radiotherapy. Cancer, 22: 767-778. Solomon, H., F. C. Marchetta, R. 0. Wilson, R. A. Miller and H. W. Detolla 1968 Extraction of teeth after cancericidal doses of radiotherapy of the head and neck. Amer. J. Surg., 1 1 5 : 349-35 1. Wildermuth, O., and S. T. Cantril 1953 Radiation necrosis of the mandible. Radiol., 61: 771-785.