Canine Osteosarcoma: A Review and an Experimental Treatment Regime

Johnson, Philip; Runyon, C.; and Grier, R. L. (1981) "Canine Osteosarcoma: A Review and an Experimental Treatment Regime," Iowa State University Veterinarian: Vol. 43: Iss. 1, Article 4. Available  


Osteosarcoma,   the  major   form  of  bone
cancer  in  dogs,  is  reviewed.   Incidence  rates
relative  to  breed,  age,  and  sex characteristics
are outlined.  Prediliction sites are also stated.
The  clinical,  radiographic,  and  metasta-
tic   characteristics   of   osteosarcoma   are   ex-
Theories  on  etiology  including  work  by
Brodey,   Wolke   and   Nielson   are   discussed.
Alternate treatment regiments  are examined,
including  an  indepth  look  at  a  case  at  the
Iowa    State    University    Clinic    which    was
treated using a combination of ostectomy and
allograft, local hyperthermia,  bleomycin, and

A  Review of Osteosarcoma
Osteosarcoma  is  the  major  form  of  bone
cancer  seen  in  the  dog. 6,10,16,22,30  One  study
showed that 85%  of the primary bone tumors
seen    in    dogs.  were    osteosarcoma,    while
chondrosarcomas,  the  second  most  common
primary  bone  tumor,  occurred  only  10%  of
the   time.6
Canine   osteosarcoma   is   nearly
always  malignant,   as   compared   to   a   50%
malignancy   rate   in   cats   and   a   generally
benign situation in cattle and in horses. 22
Several surveys have shown that large and
giant breeds have a much higher incidence of
osteosarcoma    and    are    at    a    significantly

greater  risk  of devleoping osteosarcoma  than
smaller breeds. 5,6,10,19,29,30 Among giant  dogs
the  risk of bone  sarcoma  is  estimated  to  be  5
to  30  times  the  risk of any other  cancer.  The
excess  risk  of  bone  sarcoma   appears  to   be
characteristic  of large  breeds  as  a  group  and
not of one or several particular breeds.29
The  incidence  of  osteosarcoma  increases
in  middle  aged  and  older  dogs.6,7,10,19  Giant
dogs  with  osteosarcoma  seem  to  be  slightly
younger  at  the  time  of  disease  development
than   those   in   other   weight   groups.19   The
average  age  in  a  survey  of  194  osteosarcoma
cases  was  7.7  years 6,  while  in  another  survey
of 65 cases the median age was 6.0 years.5
Most surveys of osteosarcoma indicate that
the    incidence    is    higher    in    males    than
females5,6,19  but  at  least  one  survey  failed  to
note  a  difference  in  incidence  rate  between
the sexes.10 The surveys stating a higher male
to    female    ratio    varied    slightly    in    their
numbers with ratios of 1.2:1.06 ,3.0:2.05,  and
1.7:1.019 being reported.
Most  cases  of  osteosarcoma  occur  in  the
appendicular  skeleton,  primarily  in  the  long
bones.6,7,16,17,30 There was a  higher incidence
in   the   pectoral   limbs   than   in   the   pelvic
limbs.6,30   A   study   of   Wolke   and   Nielson
showed  47%   of  the  total  cases  of  osteosar-
coma  occurring  in  the  pectoral  limbs,  while
29%  of the  cases occurred in the  pelvic limb.
This     figures     out     to     a     1.6: 1.0     ratio,
corresponding     to     the     ratio     of    weight
distribution between front and rear legs.3o
Six sites in the long bones have the highest
incidence    of    osteosarcoma     development.

These  sites  are  the  proximal  humerus,  distal
radius,  proximal and  distal femur,  and  prox-
imal  and  distal tib~a.6,7,I6,I7,30In  the  Wolke
and  Nielson  survey,  the  distal  metaphysis  of
the  radius  was  the  most  common  site,  with
23%    of   the    total    cases.    The    proximal
metaphysis  of the  humerus  was  second in  in-
cidence, with 19% of the cases.30
In  some  circumstances  osteosarcoma  may
originate  in  tissues  other  than  bone.  It  has
been reported in  the  esophagus of a  dog,  ad-
jacent  to  a  chronic  lesion  produced  by  the
spirurid   worm,   Spirocerca   lupi.   A   second
extra-osseous  site  is  in  a  mixed  tumor  of  the
mammary gland. 26
One  of the  first  clinical  signs  of osteosar-
coma  in  the  metaphyseal   region  of  a   long
bqne is lameness.  One to two weeks later there
is  generally  a  cool,  palpable  swelling  in th
area of the lesion.  Eventually there is a visible
enlargement  at  the  site  of  the  lesion  that  is
warm  and  painful  due  to  stretching  of  the
periosteum. 22
Radiographically,   this   tumor   is   usually
found  at  the  extremity  of  a  long  bone  and
produces a radiolucent enlargement arising in
the  metaphysis  which  erodes  the  pre-existing
calcified bone of the cortex.26
The destructive process may be  restricted to  the  medulla,  but usually involves the cortex as well,  by the time the tumor is manifested clinically. 27
In     addition     to     cortical     destruction,
another  type of radiographic  change that  oc-
curs with osteosarcoma  is periosteal response.
The degree of periosteal reaction does not de-
pend  on  the  degree  of cortical  destruction.I7
This  periosteal  response  can  lead  to  a  large
soft  tissue  mass  contiguous  to  the  bone.  This
soft  tissue  swelling  around  the  osteosarcoma
lesion is  also  related  to  reactive fibroplasia  in
the  subcutaneous  and  intramuscular  tissues,
which   leads   to   impaired   circulation   and
All    osteosarcomas    are    collagenoblastic
tumors   in   which   the   collagen   fibers    are
organized  into  varying  amounts  of  osteoid,
bone,  and cartilage. 22 Depending on which of
these  components  is  dominant,   three  major
subtypes     are      recognized:      osteoblastic,
fibroblastic,  and chondroblastic. 12
The  critical,  identifying  characteristic  of
cells  of  osteosarcQma  is  their  ability  to  pro-
duce   ostedid.26
Osteoid   is   the   collagenous matrix  of  bone,  the  primary  product  of  the metabolic     activity    of    osteoblasts,     which

possesses  the  specific   bOinding  sites  of  bone
mineral. 11
In   primary   bone   neoplasms,   when   the
neoplastic bone cells have retained the  ability
to  produce  osteoid,  it is  laid  down  in  grossly
anomalous    patterns.    Mineralization    takes
place  as long as there  is blood supply and  the
retention ·of  the  basic  molecular  character-
istics of new collagen.  A characteristic feature
of   neoplastic   bone   is   the   inconsistency   or
nonuniformiiy  of  the  osteoid,  reflecting  the
degree  of  undifferentiation  of  the  cells  that
form iLII
As the  tumor grows by this process of lay-
ing down osteoid,  bone,  and/or cartilage,  the
periosteum  in  tne  area  of tumor  growth  can
be  elevated.  This  elevation  causes  a  triangle
to  be  formed  where  it  joins  normal  cortex,
known    as    Codman's    triangle. 17    This    is
another   distinctive   radiographic   feature   of
osteosarcoma    and    is    a    valuable    aid    to
Osteosarcoma does not often invade  adja-
cent bone (i.e. in distal end of radius or tibia),
but  this has  been reported.23
More often,  the adjacent    bones    may    show    radiographic evidence of periosteal reaction to the tumor. 17
This reaction causes new bone to be laid down
and gives  the  bone  a  rough  appearance,  sug-
gesting involvement with the tumor.
The  metastatic  route  of  osteosarcoma  is
typically   hematogenous.21,23  The   lungs   are
the'most  common  site  of  metastasis.6,17,23,27
Other    sites   of   metastases    are    the    liver,
kidneys,  amputation  stump6  and,  on rare oc-
casion,  to adjacent bones.
Neoplastic  cells  may  embolize  from   the
site    of    origin    without    unusual    trauma.
Manipulative  trauma  definitely  increases  the
number  of  cancer  cells  in  circulating  blood.
Both  surgical  and  non-surgical  trauma  pro-
bably  play  a  role  in  disseminating  these  cells
into  the  circulating  blood.  It  has  been  sug-
gested that biopsy of malignant tumors of the
extemities should be performed under tourni-
quet  whenever  possible,  and  when  indicated,
definitive,   ablative  opertions  should  be  car-
ried out without releasing the tourniquet.21
The etiology of osteosarcoma is unknown,
but  there  have  been  several  theories  put  for-
ward,  all  supported  by  at  least  some  clinical
evidence.  Brodey advances the theory that the
occurance  of osteosarcoma  can  be  correlated
with   the   high  growth  potentials  of  various
metaphyses of bones.6
For example,  the distal

radius  has  a  much  higher  growth  potential
than   the  proximal  radius  and  also  has  the
higher  incidence  of osteosarcoma  of the  two.
A  similar  situation  exists  with  the  proximal
humerus,   which   exceeds   both   the   growth
potential  and  osteosarcoma  incidence  of  the
distal  humerus.   Brodey  continues  with   the
correlation by showing that the proximal and
distal femur and the proximal and distal tibia
have  nearly  equal  growth  potentials  and   a
nearly equal incidence of osteosarcoma.
Brodey  hypothesizes  this  rapid,  maximal
growth  at  the  metaphysis in giant breed  dogs
leaves  behind  small  foci  of  retained  hyaline
cartilage.  These  foci  have  not  been  seen  in
smaller dogs.  These  foci  may  serve  as  sites of
origin for later tumor growth. 6
Wolke  and  Nielson  consider other factors
to  be  involved  in  the  etiology.  They  suggest
that weight bearing stresses on the metaphysis
of the  long  bones  lead  to  the  development  of
osteosarcoma. They suggest that the re
higher  incidence  in  the  pectoral  limbs  versus
the pelvic limbs is directly proportional to the
relative weight distribution  between the front
and back legs.  They also site the increased in-
cidence  in  heavier  dogs  as  further  proof  of
their  weight-bearing  stress  theory.30  Another
study basically agrees with this theory,  stating
that  repeated  trauma  to  the  growth  plates in
young  giant  breed   dogs  (caused   by  weight
bearing  stresses),   may  partly  be  responsible
for the development of osteosarcomas at these
sites in later life. 14
Another  theory  concerns  the  relationship
of  healed   fractures   to   the   development   of
osteosarcoma.  Bennett,  Campbell and Brown
suggest  that  cartilage  cells  produced  during
the   healing  of  a   fracture   may  persist  long
after  the  fracture  is healed,  potentially form-
ing a  focus  for  neoplastic  development. 4 This
is  similar  to  the   Brodey  theory  of  retained
hyaline  cartilage  cells  providing  the  foci  for
tumor  growth,  differing only in  the  origin  of
the cartilaginous cells.

There  have  been  reports  of dogs  and  cats
that   have   developed   tumors   after   metallic
surgical   implants   were   used   to   treat   bone
fractures. 2
,25 Implanted metals may form cor-
rosive  products  such  as  metallic  salts  or  fine
particles.  The  animal's  response  to  metallic
implants   can   vary   from   inflammation   to
allergic  reaction  to  tumorogenesis.14
A  study of  S   clinical   cases   strongly   supported  
this theory.  AIlS  cases of osteosarcoma arose mid-

shaft of a  long bone,  a  very atypical location,
and  were  in  close  proximity  to   a  corroded
metallic  implant. 25  Obviously,  not  every  dog
that  develops  osteosarcoma  has  had  a  frac-
tured   bone   and/or   a   metallic   implant,   so
these  last  two  theories  are  not  the  definitive
answer  to  the  etiology  of  osteosarcoma,  but
they may eventually help to find that answer.
Successful  treatment  of osteosarcoma  has
advanced  about  as much  as  the search for  its
cause.     Amputation,     irradiation     therapy,
chemotherapy,   immunotherapy  and  a  com-
bination  of  these  and  other  modalities  have
been attempted with little success thus far. 5, 15
It  is  felt  that  early  diagnosis  is  the  key  to  the
success     of     any     attempted     therapeutic
regime. 17  Unfortunately  this  presents  a  very
early stumbling block in the battle against the
disease.   By   the   nature   of  the   disease,   the
tumor  may  already  be  metastasized  before  it
is  clinically  recognized.  In  addition,  clinical
recognition is often slow due  to such things as
blaming  early lameness on  other minor  trau-
matic  episodes,  radiographs  not  being  taken
or  poorly interpreted,  or  possibly even  an  in-
adequate   biopsy   being   taken,   missing   the
diagnostic area of the lesion. 17
To  overcome these problems of diagnosis,
all  dogs  with  lamenesses-  involving  high  in-
cidence  sites,   particularly  in  large  or  giant
breeds  greater  than  two  years  old,  should  be
thoroughly examined.  Radiographs should be
taken  of the  leg and  carefully evaluated.  If a
biopsy  is  to  be  performed,  it  should  be  done
with  the  aid  of two  radiographic  views of the
suspected  area.   Broad  areas  of  dense  bone
should be avoided and  a punch biopsy or a 2-
3mm slice of tissue should be taken.  The
cortex  should  be  completely  penetrated  and
the  medullary  cavity  entered.  Post-operative
radiographs  should  be  taken  to  evaluate  the
success of the procedure. 17

The  thorax  should  also  be  radiographed
when a malignant bone tumor is suspected.  If
metastasis  to  the  lungs  has  already occurred,
amputation is merely  palliative and  probably
should not not be done.  Radiotherapy can be
used  in  these  cases  to  ease  pain  and  to  slow
tumor growth. 5 Radiotherapy has been shown
to   be   of little   benefit in other phases of
osteosarcoma treatment.It has failed to
resolve the primary tumor, to    prevent
pulmonary metastasis   and   has undesirable
side  effects  on  normal  tisuses.  Radiotherapy
may have also caused an increase incidence of

side  effects  from  cytotoxic  drugs  in  combina-
tion therapy. 15
Amputation of the diseased limb has been
the  treatment  of choice  for  several years,  but
even   with   amputation   the   survival   rate   is
poor.   Brodey   points   out   that   there   is   no
baseline  data  for  long-term  survival  of  dogs
with   osteosarcoma   that   were   not   treated.
There   are   known   cases   where   dogs   with
osteosarcoma  did  survive  without  treatment,
and it is therefore concluded that not all long-
time survival can be credited to the treatment
under  consideration,   as  some  of  those  dogs
may have lived anyway.5
Chemotherapy    and     immunostimulants
have  been  recent  developments  in  the  fight
against  osteosarcoma.  Methotrexate,  vincris-
tine sulfate,  doxorubicin,  cyclophosphamide,
and bleomycin are some of the many different
chemotherapeutic  agents  that  have  been  or
are being tested.  Thus far  there is insufficient
data to determine if these drugs will be useful
or not.
The   same   observation   is   true   for   im-
munomodulators    such    as    BCG    (bacillus
Calmette-Guerin)    vaccine    and    levamisole.
There is some evidence that  BCG vaccine will
help  delay  metastasis  following  amputation
by   activating   macrophages   non-specifically
and  causing  them  to  recognize  and  destroy
malignant cells. 15.
2o However,  it has also been
demonstrated that BCG vaccine treatment,  at
best,  only  delays  and  does  not  cure  osteosar-
coma.  More specific immunotherapy needs to
be developed.
Thus,  even with therapy,  the prognosis for
a  dog with  osteosarcoma  is  very  poor.  In  one
study of 194 cases of osteosarcoma  85 %
were dead by 8 months,  and of the other 15%, only
one  dog  was  considered  cured. 6
In  another survey  of  65   cases  the   results  were 
similar, with  only  10.7%  of  the  cases  surviving  one
year past the time of diagnosis. 5 There is some
hope  that  combination  therapy  and  earlier
diagnosis will help to improve these figures.


Case Report-No. 582704-
An Experimental Treatment Regime
On June  24,  1980 a  7 year old,  80 pound,
mixed  (Collie-Shepherd)  spayed  female  dog
was  presented   to   the  Iowa  State  University
Small   Animal   Hospital   with   a   history   of
lameness in the left front leg of two days dura-
tion.  The  dog  had  been  in  a  kennel  for  10
days  and  had  not  been  lame  prior  to  board-

ing.   At   the   time   of   admission   there   was
palpable   swelling  of  the   distal   left   radius.
Radiographs   strongly   suggested   a   primary
bone   tumor   such   as   osteosarcoma.   At   this
time    the    lungs    showed    no    evidence    of
A  bone  biopsy  was  taken  and  frozen  sec-
tions  indicated  osteogenic  sarcoma.  Paraffin
sections  confirmed  this  diagnosis.  The  owner
emphasized   that   he   did   not   want   the   left
forelimb  amputated  and  it  was  decided  that
the  dog  would  be  released  to  return  to  the
clinic     once     a     treatment     protocol     was
The dog returned to the clinic on July 14,
1980     and     the     left     radius     was     again
radiographed.   It   was   originally   hoped   to
debulk  the  tumor  since  at  the  time  of  first
presentation  it  had  not  invaded  the  opposite
cortex.      However,      the     second     set     of
radiographs revealed rapid progression of the
osteosarcoma  in  the  radius  and  marked  in-
volvement  of  the  opposite  cortex.  There  was
still   no   evidence   of  pulmonary   metastasis.
The soft tissue swelling was not very extensive.
Clinical     pathology     showed     an     elevated
alkaline  phosphatase  of  105.9  lUll  (normal
10-80 lUll) which suggested bone cell activity
probably related to the osteogenic sarcoma.





The   protocol  for   treatment   was   agreed
upon  (Table  1).  The  regimen called for  local
excision of the  tumor,  bleomycin chemother-
apy, levamisole immunomodulation and local

The  distal  one  third  to  one  half  of  the
radius,  including the  distal  epiphysis  and  ar-
ticular surface,  were  removed.  Frozen section
histopathology   revealed   that   the   proximal
end  of the  excised  bone  segment  was  free  of
the  tumor.  Two  screws  were  placed  through
the  proximal  radius  into  the  ulna   to  tem-
porarily    stabilize    the    elbow    joint.    Two
Hemovac  tubes  were  inserted  in  the  incision
site  for  local  hyperthermia  treatment.   The
perforated portion of each tube was placed in
the    defect    where    the    distal    radius   had
previously been.  The rationale for  adjunctive
local   hyperthermia   was   the   possibility   of
tumor extension into soft tissues and proximal
to  the  excised  portion  of the  bone  as  well  as
the  fragmentation  of  the  neoplasm  that  oc-
curred at the time of excision.
The  dog  was  given  one  half  bolus,  92mg
or approximately 2.71 mg/kg, of levamisole 3
hours   prior   to   surgery.    Hyperthermia   by
hydrothermic  perfusion  followed   closure  of
the  wound,  synchronized with  10  units of in-
travenous  bleomycin.  The  log for  the  hyper-
thermia  treatment  can  be  found  in  Table  2.
In   the   course   of   the   procedure   the   ther-
mometer was postitioned too close to the skin
on    the   far    side   of   the   leg.    The    tissue
temperature was thought to be too low during
the first  part of the  procedure,  when actually
it  was  probably  too  high.   Consequently  the
tissue readings were in error and the possibili-
ty of thermal burn to the leg was high.

A lymphocyte transformation test was run
upon  admission  to  the  hospital  on  July  14,
1980.  This  test  was  used  to  measure  the  im-
mune  status  of the  dog,  and  it  indicated  she
was immunosuppressed.  (Table 4) This result
was  not  surprising  due  to  the  presence  of  a
well established neoplastic condition.
The   dog   was   sent   home   3   days   post-
operatively  with  a  surprisingly  small  area  of
thermal burn.
The  dog  was  re-admitted  one  week  post-
operatively for the second phase of treatment.
The  proximal  incision  was  draining  at  this
time,   and  Pseudomonas  was  cultured  from
the  wound.  The  dog  was  put  on  Tribrissena
therapy for  5  days.  The  lymphocyte transfor-
mation  test  showed  improvement  of  the  im-
mune  status.   (Table  4)  The  dog  was  then
given  her  second  hyperthermia  treatment  in
synchrony    with    10    units    of   intravenous
bleomycin.  At  the  end  of  the  procedure  the
tubes  were  removed.  The  log  for  the  second
hyperthermia   treatment   can   be   found   on
Table 3.  The area of the thermal burn on the
proximal  part  of  the  leg  was  extensive  after
the   second   hyperthermia   treatment.    The
burn  was  treated  topically  with  sulfamylon
and bandages. The dog was sent home for the
weekend two days post-operatively.

The   dog  was  re-admitted   the   following
Monday,   July   28,   1980.   The   left   leg  was
radiographed  and  the  ulna  had  fractured  at
the  distal screw due to excessive activity while
home.  Bleomycin  and  levamisole  treatments
were  continued  as  called for  by the  protocol.
The   wound   cultured   negative   for   Pseudo-
monas  on  two  cultures,   two  days  apart,   so
systemic   antibiotics   were   discontinued   and
the   burn   was   treated   topically.   The   lym-
phocyte   transformation   test   showed   some
deterioration in the immune status of the dog.
A  urinalysis  and  CBC  were  normal  and  the
alkaline  phosphatase  level  was  still  elevated
with  a  207  lUll.   The  dog  was  again  sent

home  with  the  leg  encased  in  a  Robert-Jones
dressing for protection and support.
On  August  1,  1980  a  whole  cortical  bone
allograft from  a  St.  Bernard  cross  donor  dog
was used to replace the distal one third to one
half of the  radius.  The  radiocarpal joint  was
arthrodesed  and- both  ends  of the  graft  were
stabilized  with  Dynamic  Compression  Plates.
A   cancellous   bone   graft   from   the   greater
tubercle  of  the  humerus  was  packed  at  the
ends    and     around     the     allograph.     The
alignment  was  considered  excellent  on  post·
operative radiographs.  The  thermal burns on
the  lateral  side  of the  leg were  debrided  and
sutured as much as possible.



The  dog was  placed on Ecotrinb for  a  few
days post-operatively to decrease discomfort.
On   August   4,    1980   the   wound   again
cultured positive for Pseudomonas with only a
slight    sensitivity    to    gentocin.     Beginning
August  5,  1980  the  dog  was  treated  daily on
an out·  patient basis.  By August 12,  1980 the
wound  over  the   proximal  entry  site  of  the
infusion tube was starting to granulate in and
the   dog  was   showing  steady  improvement.
Lymphocyte   transformation   tests  continued
to  demonstrate  immunosuppression.   (Table
4) The bleomycin and levamisole therapy was
continued as ordered in the protocol.
The   lymphocyte   transformation   test   of
August   26,    1980    revealed   the   continued
immunosuppression.   (Table   4)   The   dog   is
bearing  nearly full  weight on  the  leg and  the
wounds have nearly closed,  but due to licking
by   the   dog,   constant   bandaging   and   con-
tinued   Pseudomonas   infection,   the   healing
process is slower than normal.

The  lymphocyte  transformation  test  was
repeated on September29,  1980 and again on
November  18,  1980.  These  tests continued  to
show immunosuppression. (Table 4)
The   most   recent   radiographs   show   the
ulna fracture to be healed and the allograft in
proper   position   and   apparently   becoming
incorporated into the bone as of December 5,
1980.  There  is  no  evidence  of  recurrence  of
osteosarcoma at the primary,  distal radial site
and the lungs continue to be free of metastasis
and fibrosis.

The  approach  to  treatment of this case of
osteosarcoma  in  a  dog  was  an  experimental
one.  Part of the  reason  for  this approach was
the need to select a  route of therapy designed
to  preserve  the  limb,   as  the  owner  did  not
wish the leg to be amputated.  Another reason
was   Drs.    Grier's   and    Runyon's   desire   to
evaluate    combination    therapy    with    limb
preservation  in  mind,  as  described  in  recent
literature. 28
The particular combination of bleomycin,
local    hyperthermia    and     levamisole    was
derived with certain  advantages  in  mind  and
hopefully,    a    minimal    number    of   disad-
The    principle    reason    bleomycin    was
selected as the chemotherapeutic agent was its
synergistic  effect  with  local  hyperthermia. 18
Also,   in  mice  this  drug  has  been  found   to
concentrate   in   the   lungs,   along  with   skin,
kidneys,   peritoneum  and  lymphatics. I   Since
metastasis to the lungs is a major concern with
osteosarcoma,  it  was  hoped  to  use  this  to  an
advantage.    The    major    disadvantages    of
bleomycin were cost,  at $157.00  per 15  units,
and   the   possible   side   effect   of  pulmonary
fibrosis.  Thus  far  pulmonary  fibrosis  has  not
been detected on radiographs of this dog.
Local  hyperthermia  was  advantageous  in
several  ways.  As  noted  previously,  bleomycin
is  markedly  potentiated  when   administered
simultaneously with hyperthermia, suggesting
a   true  interaction.   Results  of  simultaneous
combination therapy in mice were better than
either  bleomycin  or  hyperthermia   alone  or
when  given  24  hours  apart.  The  main  disad-
vantage    is    that    bleomycin    is    enhanced
significantly  only  near  43°  C,  which  is  near
the top of the therapeutic range and leads to a
greater hazard of possible toxicity. 18

Another   advantage   of   hyperthermia   is
that  it  has  been  shown  to  increase  the  im-
munogenicity of some tumor cells,  perhaps by
unburying  some  of  the  cell  surface  antigens
from surrounding lipids. 24
It  also  seems  relevant  that,  as compared
to  surgical  removal  (which  eliminates  poten-
tial    antigens);    and    radiotherapy,    chemo-
therapy,    and    whole    body    hyperthermia
(which  suppresses  antibody  formation),  local
hyperthermia may cause  a  slow release of an-
tigens  with  no  inhibition,  and  possibly  even
an increase, in antibody formation. 24
Problems possible with local hyperthermia
are  cardiac  arrhythmias,   hepatic  and  renal
dysfunction,  low grade  fever  due  to  necrosis,
and cutaneous burns. 24
Levamisole was used in  this  case in an  at-
tempt to help restore the immune responses of
a      predictably      immunosuppressed      dog.
Though the mechanism of action is unknown,
it  is  well  understood  that  the  best  results  are
obtained  in  immunodeficient  patients.   The
drug  modulates  immune  function  at  2  to  3
mg/kg  of  body  weight.   At  higher  doses,  it
may actually suppress immune function. 8
Though  the  mechanism  of  action  is  un-
known,   levamisole   in   vitro   and   levamisole
therapy  in  vivo  correct  defective  motility  in
phagocytic   cells.   The   drug   also   stimulates
phagocytosis in cultured monocytes.8
Some   immunodeficient   patients   do   not
improve with levamisole treatment.  It may be
due  to  the  inability  of the  individual  tp  pro-
duce levamisole-induced serum factor needed
to  increase  lymphocyte funciton. 8  If the  lym-
phocyte  transformation  test  is  accurate  in  its
assessment   of  the   animal's   immune   status,
then  the  results  of  the  levamisole  therapy  to
date  is  discouraging,  as  the  dog  continues  to
be immunosuppressed.
The reliability of the lymphocyte transfor-
mation  test  is  a  controversial  matter.   Some
feel  it  is  a  good  prognostic  test,  while  others
do not.
9 The work on this project has assumed
the  test to  be reliable  and  will continue  to  do
so.  There are very few good ways to assess im-
munostatus  in  such  a  quantified  manner  as
with this test.
To  close  this  report  no  definite  conclu-
sions can be drawn from  this one clinical,  ex-
perimental  case  that  has  yet  to  run  its  com-
plete  course.   Additional  cases  treated  using
this   therapeutic   protocol,    each   individual
drug  and  other drugs  as  well  as  controls,  are

needed  to  factually  evaluate  the  results.  This
will  take  a  great  deal  of  time,   energy  and
money  and  will  require  cooperation  among
many researchers involved in cancer work.

1.   Baker CE jr (publisher):  Physicians' Desk Reference,
34th  Edition.   Litton  Indust  Inc,   Oradell,   Nj,   pp.
706-707,  1980.
2.   Banks   WC,   Morris   E,   Herron   MR,   Green   RW:
Osteogenic~arcomaassociated with internal fixation
in two dogs. JAVMA  167:166-167, 1975.
3.   Barrett  jT:   Textbook  of Immunology.   CV  Mosby
Co, St Louis,  1970, p. 215.
4.   Bennett  D,  Campbell  jR,  Brown  P:  Osteosarcoma
associated  with  healed  fractures.  J  Sm  A nim  Pract
5.   Brodey RS,  AbtDA:  Results of surgical treatment in
65  dogs with osteosarcoma. JA VMA  168:1032-1035,
6.   Brodey   RS,   Riser   WH:   Canine  osteosarcoma-A
clinicopathologic study of 194 cases.  Clin  Ortho and
Related Res 62:54-64,1969.
7.   Brunner   Cj,   Muscoplat   CC:   Immunomodulatory
effects oflevamisole. JA VMA  176: 1159-1161, 1980.
9.   Cochran AJ:  In vitro testing of the immune response,
Immunological  Aspects  of  Cancer.   Castro  jE  (ed)
University   Park   Press,    Baltimore,    pp.    226-228,
10.  Dorn CR: Epidemiology of canine and feline tumors.
JAAHA  12-307-312,  1976.
11.   Feist  jH:  The biologic basis of radiologic findings in
bone disease. Radiol Clin N Amer8:183-205,  1970.
12.   Friel  jP  (publisher):  Dorland's  Illustrated  Medical
Dictionary,      25th      Edition.      WB      Saunders,
Philadelphia, p.  1379,  1974.
13.   Gold  jM,  Freedman  SO:  Diagnostic  tests in  clinical
immunology,   Clinical  Immunology,   Freedman  SA
and  Gold  P  (eds).   Harper  and  Row,   Hagerstown,
Md, p. 609,1976.
14.  Hardy   WD:   The   etiology   of   canine   and   feline
tumors. JAAHA  12:313-334, 1976.
15.   Henness  AM,  Theilen  GH,   Park  RD,   Buhles  WC:
Combination therapy for canine osteosarcoma. JA V-
MA  170:1076-1080, 1977.
16.   Knecht CD,  Priester W A:  Musculoskeletal tumors in dogs. JA VMA  172:72-74,  1978.
17.   Ling   GV,   Morgan   jP,   Pool   RR:   Primary   bone
tumors     in     the     dog:      A     combined     clinical,
radiographic    and    histologic    approach    to    early
diagnosis. JA VMA  165:55-67,1974.
18.   Marmor    jB:    Interactions   of   hyperthermia    and
chemotherapy     in      animals.      Cancer     Research
39:2269-2276, june 1979.
19.   Misdorp   W,   Hart   AAM:    Some   prognostic   and
epidemiologic factors in canine osteosarcomla. J  Natl
Cancer Inst 62:537-545,1979.

20.   Owen   LN,   Bostock   DE,   Lavelle   RB:   Studies  on
therapy of osteosarcoma in dogs using BCG vaccine.
J Am  Vet RadiolI8:27-29,  1977.

21.   Peterson   LFA,    jones   jM,   Kelly   Pj,    Pease   GL:
Isolation of osteosarcoma cells from peripheral blood
after biopsy. Mayo Clin Proc 35:443-447,1960.
22.   Pool  RR:  Tumors of bone and cartilage,  Tumors in
Domestic   Animals,    2nd    ed.    Moulton   jE    (ed),
Berkeley,  University of California Press,  pp.  89-149,
23.   Schneider   PR,   Stowater   jL:   Pathologic   fractures
associated with skeletal metastasis of osteosarcoma in
a dog. JAVMA  175:61-64, 1979.
24.   Short  jG:  Hyperthermia  and  cancer:  a  brief review.
(a  bulletin)  BSD  Corp,  Salt  Lake  City,  pp.   1-13,
25.   Sinibaldi   K,    Rosen   H,    Liu   SK,    DeAngelis   M:
Tumors    associated    with    metallic    implants    in
animals.   Clin   Ortho  and  Relat  Res  118:257-266,
26.   Smith    HA,    Jones,    TC,    Hunt    RD:    Neoplasia,
Veterz"nary Pathology,  4th Edition. Lea and Febiger,
Philadelphia, pp 197-201,1972.
27.   Theilen GH,  Madewell BR:  Tumors of the skeleton,
Veterz"nary   Cancer   Medz"cine.    Lea   and   Febiger,
Philadelphia, pp 289-306,1979.
28.   Theilen   GH,   Pool   RR,   Park   RD:   Treatment   of
canine   osteosarcoma   for   limb   preservation   using
osteotomy,        adjuvant       radiotherapy       and
chemotherapy.  VM/ SA C 72: 179-183,  1977.
29.   Tjalma   RA:   Canine  bone  sarcoma:   estimation  of
relative risk as a function of body size. ]  Natl Cancer
Inst36:1137-1150,  1966.
30.   Wolke  RE,   Nielson  SW:   Site  incidence  of  canine
osteosarcoma. ]  8m Anim Pract 7:489-492,  1966.

Share this article / Teilen Sie diesen Artikel