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Experimental radio-osteonecrosis in Rhesus macaque jaws; therapeutic irradiation dose effect on dental extraction wound healing.

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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.
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macaque, radio, dose, osteonecrosis, healing, irradiation, experimentov, effect, rhesus, extraction, jaws, dental, therapeutic, wounds
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