Osteosarcoma

Norman Jaffe, MD, DSc*

ETIOLOGY
The questions below should help
focus the reading of this article.
Although the etiology of osteosar- EDUCATIONAL OBJECTIVE
coma is unknown, certain associa-
1. What age group has the highest 22. The pediatrician should have
tions have been established. The
peak incidence of osteosarcoma? knowledge to make an appropri-
disease frequently occurs in long
2. What are the most frequent sites ate evaluation of a high school
bones, and its early predominance
and portions of bones in which os- football player with enlargement
after the age of 13 years suggests
teosarcoma occurs? of his left upper leg and accom-
an association with rapid bone
panying pain, differentiating
3. What are the clinical signs ob- growth. It also occurs more com-
in osteosarcoma? among osteosarcoma, Ewing sar-
served monly in taller teenage individuals
coma, juxtacortical osteosar-
4. What diagnostic procedures and young adults. This is compara-
coma, chondrosarcoma, fibro-
should be performed and what criti- ble with the increased incidence of
cal information must be obtained osteosarcoma in larger breeds of sarcoma, malignant fibrous
from these procedures? histiocytoma, giant cell tumor of
dogs (such as St Bernards, Great
the bone, eosinophilic granuloma
5. What other types of malignant Danes, and German shepherds)
of the bone with a pathologic
and benign tumors should be in- over the incidence in smaller
fracture, aneurysmal bone cyst,
cluded in the differential diagnosis? breeds. Approximately 4% of cases
simple bone cyst, osteoblastoma,
6. What treatment modalities are are associated with prior therapeutic
stress fracture, hematoma, and
currently in use for osteosarcoma? radiation to bone and exposure to
radioactive substances. An associa- chronic osteomyelitis, and be
able to develop an appropriate
tion with retinoblastoma is also well
plan for management. (Topics,
recognized. Under these circum-
90/91)
Malignant tumors of bone and stances, the tumor may occur in a
cartilage constitute less than 1% of previously radiated bone (the skull
all malignant neoplasms and ac- or mandible) in addition to a site re-
count for a mortality rate of 1.87 per mote from the radiated area. of pain and swelling at the tumor
million children less than 14 years of Although history of trauma fre- site. Lower extremity tumors usually
age. Osteosarcomas represent 60% quently brings the tumor to the at- also are associated with a limp. The
of all bone tumors in children and tention of the patient, trauma is not amount of time symptoms endure
adolescents. The incidence in pa- considered an etiologic factor. The varies, and not infrequently the
tients less than 20 years of age is bone probably is weakened by the symptoms may be ascribed to a
3.36 per million in whites and 2.88 presence of the tumor and therefore sprain, arthritis, or “growing pains.”
per million in blacks. The peak oc- more vulnerable to minor injury. Ex- Occasionally, the pain or swelling
curs between the ages of 15 and 25 posure to repeated trauma does not may be extremely severe. Relief
years. Before and during early ado- appear to increase risk for osteosar- may be obtained by various maneu-
lescence, the frequency of occur- coma, however. Retrovirus has been vers, including drawing up the legs
rence is the same for boys and girls, shown to induce bone sarcomas in in the case of distal extremity tu-
whereas the male-to-female ratio is animals. Cultures of human tumors mors, thereby relaxing the muscles
1.6:1 during late adolescence and have been found to contain C-type overlying a taut periosteum.
adulthood. virus particles, but a viral etiology Physical examination usually re-
has not been established. Finally, veals a mass, with a localized in-
DEFINITION AND approximately 10% of patients with crease in temperature over the
NOMENCLATURE long-standing Paget disease devel- tumor site. Limitation of movement
op osteosarcoma. This disease is of the joints proximal and distal to
Osteosarcoma is defined as a rare in children and adolescents, the tumor usually is encountered. In
bone tumor comprising anaplastic however. advanced cases, vessels frequently
spindle-shaped cells and malignant surface over the tumor. The draining
osteoid or bone. The eponym “os- lymph glands are involved rarely.
teosarcoma” is used by the World CLINICAL MANIFESTATIONS
Systemic symptoms are usually ab-
Health Organization and is prefer- Osteosarcoma most frequently sent unless the tumor is far ad-
red to the alternate “osteogenic sar- develops in the distal femur, then in vanced with widespread metas-
coma.” the proximal tibia and proximal hu- tases.
merus. These sites account for 60% Clinical evaluation should consist
of all cases. Ninety percent of the of a complete history and full physi-
tumors occur in the metaphysis and cal examination. Specific inquiry
*fpartment of Pediatrics, The University of 10% in the diaphysis. However, any should be made regarding anteced-
Texas, M. D. Anderson Cancer Center, 1515 part of the skeleton can be affected. ent trauma or infection. Although
Holcombe Boulevard, Houston, Texas 77030. The majority of patients complain there is no evidence that either may

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Osteosarcoma

be implicated in the cause, tumors nated multifocal sclerosing osteo-

occasionally have given rise to sarcoma and has a poor prognosis.
symptoms typical of osteomyelitis. Pain and swelling are usually evi-
Knowledge of the duration of symp- dent at the different sites of bony in-
toms may help estimate the rate of volvement.
tumor growth. Clinical examination
should record the size and location
RADIOGRAPHIC EVALUATION
of the tumor, signs of local inflamma-
tion, possible involvement of region- High-quality radiographs of the
al lymph nodes, and any functional entire affected bone should be ob-
disorder of the affected limb. tamed. Variable radiographic ap-
pearances may be encountered and
PATHOLOGIC VARIETIES OF represent a summation of changes
OSTEOSARCOMA dependent on the type of tumor, ex-
tent of intramedullary and soft tissue
Osteosarcoma usually originates invasion, and potential for new bone
in the medullary region of the bone. formation. Appearances range from
Several varieties have been de- intensely blastic to lytic lesions.
scribed and are designated by the However, the majority are mixtures
preponderance of matrix within the of both, with poorly defined margins
tumor. There are four major types: (Fig 1, parts A and B). Early cortical
osteoblastic, chondroblastic, f i- destruction and extension into the
broblastic, and telangiectatic. In the soft tissues usually are observed.
telangiectatic variety, numerous Characteristically, spicules of neo-
blood-filled spaces are observed to plastic tissue arise perpendicular to
be interspersed with osteoclasts or the cortex of the bone and extend
neoplastic multinucleated giant outward from the center to create a
cells. A more recently described en- “sunburst” appearance. An eleva-
tity is small-cell osteosarcoma, tion of the peniosteum adjacent to
which has features similar to those the tumor is designated the “Cod-
of a Ewing sarcoma. Rarely, osteo- man triangle.” The sunburst appear-
sarcoma also may arise in soft tis- ance and the Codman triangle are
sue. characteristic but not patho-
Several additional variants of os- gnomonic findings.
teosarcoma determined by radio- Radiographic evaluation should
graphic examination have been de- include anterior, posterior, lateral,
scribed also. These comprise the and two oblique views of the entire
so-called surface osteosarcomas of affected bone. This should be fol-
which there are two varieties, par- lowed by computerized tomographic
osteal (or juxtacortical) and pen- scans to determine the exact extent
osteal. By definition, these varieties of mntramedullary invasion. This in-
do not involve the medullary cavity, formation is critical in the case of pa-
are usually (although not invariably) tients considered eligible for limb
of low malignant potential, and often salvage (see below). Not infre-
can be treated by wide local exci- quently, information obtained by
sion. The parosteal variety not infre- computerized tomographic scans
quently occurs at the distal posterior can be supplemented by that from
end of the femur and is seen more magnetic resonance imaging. Occa- Fig 1. A, osteoblastic osteosarcoma affect-
commonly in girls; in contrast, the ing distal end of right femur. The radiograph
sionally, in the case of surface le-
demonstrates an osteoblastic tumor infiltrat-
peniosteal form occurs more com- sions, laminagrams of the bone also ing metaphyseal end of right femur with pene-
monly in the tibia and is charac- may be useful to determine the ex- tration of cortex, producing a sunburst ap-
terized by an abundant proliferation act extent of tumor invasion into the pearance. A soft tissue mass with osteoid and
of cartilage. Specific radiographic medullany cavity or cortex. new bone formation is also present. The tumor
has also permeated a major section of the
and angiognaphic studies should be
metaphysis. Reproduced from Jaffe et a!.
performed to determine their malig- Control of primary osteosarcoma with chemo-
DIFFERENTIAL DIAGNOSIS OF
nancy and the extent of invasion therapy. Cancer. 1985;56:461-466. B, large
MALIGNANT BONE TUMORS
into the medulla; surface osteosar- predominantly osteolytic osteosarcoma of dis-
coma tend to have low-grade malig- A variety of malignant and benign tal end of femur with a fracture transversing
tumor (arrows). Reproduced from Jaffe et a!.
nancy and no invasion. A rare form conditions may be entertained as Pathologic fracture in osteosarcoma. Impact
of osteosarcoma, appearing in mul- possible causes for pain and swell- of chemotherapy on primary tumor and surviv-
tiple sites in the skeleton, is desig- ing in the extremity of a child on ado- al. Cancer. 1987;59:701-709.

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 ONCOLOGY

lescent. Expert radiologic opinion remarkable tendency to encircle the Giant Cell Tumor
frequently assists in differentiating shaft and is demonstrated best by
the possible causes but, in most in- computerized tomographic scans. This condition most commonly oc-
stances, a biopsy will be required. There are two types: parosteal and curs during the second decade of
Two methods of biopsy are avail- periosteal osteosarcoma. Medullary life and predominates in girls. Most
able: open and closed. An open bi- involvement ordinarily does not oc- giant cell tumors are found in the
opsy generally is obtained in the op- cur except in long-standing cases. epiphyses of long bones. Pain of
erating room with the patient under The tumor may be confused occa- variable severity is almost always
general anesthesia. At the M. D. An- sionally with heterotopic bone, the predominating symptom. Radio-
derson Cancer Center, closed biop- which is characteristic of myositis graphically, an expanding zone of
sy is practiced using a core trucut ossificans. radiolucency situated eccentrically
needle. The closed biopsy is ob- in the long end of a bone usually is
tained under general anesthesia in observed.
Chondrosarcoma
children and under local anesthesia
in older patients. This biopsy per- Local swelling and pain, alone or Aneurysmal Bone Cyst
mits a definitive diagnosis within 24 in combination, are the usual initial
This condition rarely is found in
hours and facilitates early planning symptoms of chondrosarcoma. Ra-
children. Pain and swelling are im-
of therapy. Core needle biopsies are diographs often afford patho-
gnomonic evidence of the tumor. portant features, and they vary in
accompanied generally by cytology duration from weeks to a few years.
examinations of aspirate, which may Osseous destruction combined with
The lesion often has a characteristic
permit an immediate diagnosis be- mottled densities due to calcification
radiographic appearance with a
fore processing the core of tissue for and ossification (“popcorn” appear-
zone of rarefaction, which usually is
pathologic examination. All needle ance) is the usual finding.
well circumscribed and eccentric.
biopsies should be interpreted with Telangiectatic osteosancoma can
the assistance of good quality radio- Fibrosarcoma and Malignant
simulate aneurysmal bone cyst oc-
graphs. Fibrous Histiocytoma
casionally.
The following conditions form part In the case of these tumors, pain-
of the differentialdiagnosis of malig- ful swelling usually is found unless Unicameral Bone Cyst
nant bone tumors. the tumor is covered by a thick layer A simple bone cyst may cause lo-
of uninvolved tissue. The tumor may
calized pain but, in most cases, it
MALIGNANT NEOPLASTIC occur primarily in bone or as a often comes to attention only after a
metastasis to the skeleton. There
TUMORS pathologic fracture has occurred.
are no roentgenographic features
Occasionally, there is swelling in the
Ewing Sarcoma that distinguish fibrosarcoma of region. Radiographically, there may
bone from osteolytic osteosarcoma.
be fusiform widening of the bone
This kind of tumor comprises be-
due to slight expansion of the cyst.
tween 7% and 15% of all malignant Rhabdomyosarcoma or Malignant
bone tumors. It occurs more fre- Soft Tissue Sarcoma
quently in boys and most commonly Osteoblastoma
in adolescents. The tumor origi- Pain, swelling, and discomfort are
symptoms of nhabdomyosarcoma The typical lesion found in cases
nates in the shaft of the bone, and of osteoblastoma occurs markedly
the earliest radiographic findings and malignancy of soft tissue sar-
coma. The tumor may erode into the more frequently in boys and more
may appear as a roughening of the frequently during adolescence than
peniosteum, which may be confused adjacent underlying bone or infil-
childhood. Pain is the cardinal
with osteomyelitis. Eventually, a trate into it. In most cases, a large
symptom. Lesions in the lower ex-
Ewing sarcoma tends to be exten- soft tissue mass with or without un-
tremity may result in a limp. Radio-
sive, sometimes involving the entire derlying reactive bone is seen.
graphically, one may observe bone
shaft of the long bone. Lytic destruc- destruction that is fairly circum-
tion is the most common finding, but BENIGN NEOPLASTIC TUMORS scribed but not always suggestive of
there may be regions of density with a benign process.
new bone formation. As the tumor Langerhan Cell Histiocytosis
bursts through the cortex, it often el- Osteochondroma
Patients with the localized form
evates the peniosteum, gradually
producing multiple layers of sub- (previously designated eosinophilic Osteochondroma is the most
peniosteal reactive new bone to give granuloma) have a solitary painful common benign bone tumor. It gen-
an “onion skin” appearance. focus and occasionally a palpable erally affects the ends of long
mass. The defect in the bone usu- bones, particularly the distal femur,
ally is defined discretely. Peniosteal proximal tibia, and proximal hu-
Juxtacortical Osteosarcoma
reaction may be present if the cortex merus. It may cause significant pain
This tumor is one of the patholog- becomes eroded or if a pathologic due to pressure on neovascular
ic varieties of osteosarcoma. It has a fracture has occurred. structures.

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Osteosarcoma

Chondroblastoma studies will reveal the soft tissue tection of (early) bone lesions that
mass or underlying peniosteal eleva- are silent and located in other parts
This tumor arises most frequently tion. The diagnosis may be sus- of the skeleton. Many medical cen-
during the second decade of life pected from the history. tens also obtain a routine skeletal
from cartilage located in the epi- Treatment of the above conditions survey to complement the radio-
physeal area. The tumor causes requires individual consideration. In nuclide bone scan.
pain. Radiographically, it appears as general, surgery is utilized as defini-
a central region of destruction de- tive treatment of primary tumors.
limited from the surrounding normal Ewing sarcoma may be treated with BIOLOGIC BEHAVIOR OF
bone. surgery, radiation therapy, or both. OSTEOSARCOMA
Most malignant neoplasms are also
Chondromyxoid Fibroma treated with chemotherapy. Lo- The biologic behavior of osteosar-
calized Langerhans cell histi- coma suggests that silent pulmo-
This disease is found most com- nary micrometastases are present
monly in people between the ages of ocytosis may be treated with intra-
cavitary hydrocortisone, surgical in approximately 80% to 90% of pa-
10 and 30 years. The tumor usually tients at the time of diagnosis (Fig
is located in the metaphyseal re- curettage, or (rarely) radiation thera-
py. Osteomyelitis is treated with anti- 2). These metastases are visible nei-
gion; pain is by far the most com- then on conventional radiograph nor
mon symptom exhibited. Radio- biotics and surgery if required. Mus-
cle and subpeniosteal hematomas computerized tomographic scans of
graphically, it is manifested as an the chest. However, in the absence
eccentric sharply circumscribed are treated with rest and analgesia.
of effective treatment, they become
zone of rarefaction that occasionally radiographically apparent in 6 to 9
causes expansion of the bone. METASTATIC SURVEILLANCE
months and are eventually responsi-
Once the diagnosis of a malignant ble for the patient’s demise. In opti-
NONNEOPLASTIC CONDITIONS bone tumor is established, a search mal circumstances, without the po-
for metastases is initiated. A chest tential benefit of postoperative
Stress Fracture radiograph is obtained routinely; if chemotherapy, only 10% to 20% of
this is normal, or if only a few meta- patients will survive after treatment
A stress fracture may cause pain stases are noted, a computerized to- with amputation. Approximately
and swelling at the site of the lesion mographic scan of the lungs should 10% to 20% of patients have overt
and be accompanied by a large de- be obtained. Occasionally, chest flu- pulmonary metastases at the time of
gree of callus. Careful radiographic oroscopy or tomograms of the chest initial examination. The skeleton,
study will reveal the presence of the in certain circumstances may be pleura, penicardium, lymph nodes,
fracture. Occasionally, laminagrams helpful. kidney, and brain later are involved.
or computerized axial tomography Radionuclide studies have be- A knowledge of the biologic behav-
may be required for this purpose. come routine for investigation of ior is essential to provide a rational
bone tumor. These may permit de- form of treatment.
Osteomyelitis
Alterations in the appearance of a
bone may result from an acute or
chronic infection, which may pro-
duce roentgenographic changes 0-12

simulating a bone tumor. Anti- MONTH$

FATAL
microbial therapy sometimes atten- 80-90%
uates the infection to the degree
that normal radiographic pro-
gression of the disease is distorted,
thereby increasing the likelihood of
mistaking an infection for a bone
neoplasm. The patient usually com-
plains of pain and discomfort and, #{149}
CURED
occasionally, swelling precipitated 20%
by excessive exercise.

Hematoma
A hematoma into a muscle or sub-
peniosteal region may occur as a
Fig 2. Biologic behavior of osteosarcoma. Microscopic disease in lungs is present in 80% to
consequence of trauma or exces- 90% of patients at initial examination and appears on conventional radiographs 9 to 12 months
sive exercise. It causes localized after amputation (upper diagram). In optimum circumstances, only 20% of patients will be cured
pain and discomfort. Radiographic following amputation (lower diagram).

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 ONCOLOGY

TREATMENT OF THE PRIMARY limb salvage with functional restona- nametens. These comprise a reduc-
LESION tion. Initial trials were conducted in tion in pain and swelling, a reduction
the early 1970s with preoperative in soft tissue mass, nevisualization
Treatment is designed with cura- chemotherapy utilized to contain the of tissue planes between muscle
tive intent unless the disease is fain- primary tumor pending manufacture bundles, healing of the peniosteurn
ly extensive, when palliation be- of a custom-made endoprosthesis. and pathologic fractures, and orga-
comes the major consideration. (In Concurrently, it was contemplated nized deposition of calcium.5 An-
newly diagnosed patients, apprecia- that micrometastases would also be giognaphically, responses are mani-
ble palliation and, occasionally, cure destroyed. fested by reduction and disappear-
can also be obtained by treating Conceptually, preoperative che- ance of tumor neovasculanity and
with “curative intent”.) mothenapy appeared to offer several stain.6 Tumor response may be visu-
The primary tumor constitutes an advantages: enhanced opportunity alized also by radionuclide imaging.
uninhibited source of metastases for tumor-free margins and im- Ultimately, the efficacy of chemo-
and must be removed to achieve proved safety of the surgical pro- therapy is assessed by pathologic
cure. Traditionally, extirpation of the cedure, which involved limited examination of the extirpated tumor.
primary tumor has been accom- tumor resection; early systemic The criteria and grading of patholog-
pushed by surgical amputation. The
treatment to destroy (pulmonary) mi- ic responses utilized by the pediatric
affected bone usually is sectioned at crometastases; and identification of department at the M. D. Anderson
least 3 inches above the proximal an effective systemic agent (on corn- Cancer Center is outlined in Table 1.
limit of the intramedullary extent of bination of agents) for postoperative The use of preoperative chemo-
tumor visible on the computerized adjuvant therapy. The latter was de- therapy for treatment of the primary
tomographic scan. For lesions in the termined by the degree of necrosis tumor has been marked by contno-
proximal femur or humerus, a disar- versy. It has been suggested that a
induced in the primary tumor. These
ticulation may be preferred. A hemi- concepts are applicable to patients delay in the implementation of pni-
pelvectomy is performed for tumors undergoing limb salvage or amputa- mary definitive (surgical) treatment
of the innominate bone. If the lesion could jeopardize survival if satisfac-
tion and have been incorporated
is close to the hip on shoulder joint, a into the treatment program utilized tory and early response to chemo-
modified hemipelvectomy or fore- at the M. D. Anderson Cancer Cen- therapy is not achieved. Conceiva-
quarter amputation may be consid- ter. This is illustrated in Figure 3, bly, in the absence of an adequate
ered to ensure tumor-free margins. and an example of a response of the response, a tumor would remain in
If the tibia or fibula is affected, an primary tumor to initial treatment situ for a critical period during which
above-the-knee amputation usually with intra-artenial cis-iarnminedichlo- seeding of pulmonary micro-
is performed. Lesions of the foot re- roplatinum II (CDP) is presented in metastases could ensue if this had
quine below-the-knee amputation. Figures 4 and 5. not occurred already. This ultimately
Several medical centers have in- Responses to preoperative treat- could affect survival in patients who
troduced the practice of fitting the ment of the primary tumor may be were nonmetastatic at diagnosis.
patient with a prosthesis imme- assessed by clinical, radiographic, Further, because of tumor hetero-
diately following amputation of the geneity, it was uncertain if chemo-
angiognaphic, and pathologic pa-
leg. This consists of a rigid dressing
pylon and a foot-ankle assembly.
This intermediate prosthesis per-
mits early ambulation and improves
the psychologic outlook. A definitive
prosthesis usually can be fitted ap-
+ clx
proximately 8 weeks later.

TREATMENT OF THE PRIMARY

TUMOR WITH CHEMOTHERAPY
A major advance in the treatment
of osteosarcoma occurred with the
discovery that several chemo- EXPEMENTAL
therapeutic agents were effective in Uncon.ervsilon - QJP.ADR,CTX.MTW
the treatment of the disease.12 This
was demonstrated initially by the Fig 3. Treatment protocol (TIOS-lil) utilized at the M. D. Anderson Cancer Center. Patients
ability of the agents to eradicate pul- receive seven courses ofpreoperative intra-arterial cis-diamminedichloroplatinum-ll (CDP) every
monary metastases and to improve other week for 3 months. This is followed by a surgicalprocedure. Patients with tumors exhibit-
survival. As a consequence, new ing over 90% necrosis in the resected specimen (see Table 1) are treated with Adriamycin (ADR,
75 mg/M2 or 40 mg/M2 in combination with cyclophosphamide) for 6 months (cumulative dose
concepts in the treatment of the pri- 450 mg/M2). Patients with less than 90% tumor necrosis are treated with ADR and cyclo-
mary tumor were introduced.3’4 phosphamide (CTX, 600 mg/M2) for 1 year. Small cell osteosarcoma is treated with ADR, yin-
Principally, this involved preopera- cristine, Actinomycin D, and CTX (A-VAC) for 18 months. Patients who refuse surgical interven-
tive chemotherapy and attempts at tion are entered into an experimental program (limb conservation).

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Osteosarcoma

TABLE 1 Pathologic Categories

.

of Therapeutic Response
I. No effect or doubtful effect
A. No effect: most oftumor vi-
able; necrosis in up to 30%
of cases
B. Doubtful effect: most of
tumor viable; necrosis in up
to 40% of cases; may be
minimal evidence of fibro-
vascular regeneration
II. Partial tumor effect
A. 40% to 50% tumor destruc-
tion; definite evidence of fi-
bnovascular regeneration
B. 50% to 60% tumor destruc-
tion; fibnovascular regener-
ation
III. Definite tumor effect
A. 60% to 90% tumor destruc-
tion; possible viable tumor;
frank evidence of fibro-
vascular regenerative ac-
tivity
B. Greater than 90% tumor
destruction:complete
tumor effect; no viable or
minimally viable tumor; ma-
jor fibrovasculan regenera-
tion

Center, the Pediatric Oncology

Group (a consortium of hospitals in-
vestigating the treatment of cancer
in children) currently advocates a
concurrent randomized trial utilizing
preoperative chemotherapy in one
group of patients and immediate
surgical intervention in the other.
Eligibility criteria for limb salvage
have been established. Patients
with lower extremity lesions should
have obtained maximum or near
maximum linear stature. This is
Fig 5. A, pretreatment subtraction angio- based on the reconstruction tech-
gram ofleft tibia in patient with osteosarcoma. nique. Tumor resection generally in-
Tumor neovascularity and stain are obvious. volves the knee epiphyses, which
B, posttreatment subtraction angiogram of
Fig 4. A, pretreatment osteolytic lesion in
Figure 5A. Following four courses of intra-arte-
precludes further growth. Alter-
distal femoral shaft. “Moth-eaten and per-
“
rial cis-diamminedichloroplatinum-ll, there is natively, if the predicted
leg length
meation patterns of bone destruction are pre-
dominant. Soft tissue swelling is also noted. complete disappearance of tumor neo- discrepancy exceeds 8 cm, amputa-
B, following three courses of intra-arterial cis- vascularity and stain. Figure 5 is reproduced tion using an exoprosthesis is pref-
diamminedichloroplatinum-Il, a dense rim of from Jaffe et a!. Osteosarcoma: intra-arterial erable. More recently, the Lewis Ex-
calcification has developed, best seen in prox- treatment of the primary tumor with cis-
diamminedichloroplatinum-l! (CDP), an- pandable Adjustable Prosthesis has
imal aspect of tumor. Solid periosteal new
bone is present on medial aspect of tumor, giographic, pathologic and pharmacologic been introduced as an investigation-
bridging area of previous cortical destruction. studies. Cancer. 1983;51: 402-407. al procedure for these patients. This
Reproduced with permission from Jaffe et al. permits periodic expansion of the
Chemotherapy for primary osteosarcoma by therapeutic effects observed in bulk prosthesis at regular intervals until a
intra-arteria! infusion. Review of the literature tumor were reproducible in micro- suitable height has been attained.
and comparison with results achieved by the
intravenous route. Cancer Bull. 1984; 36:37-
metastases. As a consequence, de- Patients with upper extremity le-
42. © by the MedicalArts Publishing Founda- parting from the treatment protocol sions receive more favorable con-
tion. used at the M. D. Anderson Cancer sideration.

PIR 338 pediatrics in review vol. 12 no. 11 may 1991

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 ONCOLOGY

The biopsy incision prior to limb iimb salvage require antibiotic coy- biologic reconstructive material
salvage also should be placed prop- enage for dental prophylaxis in a which, as opposed to a metal pros-
erly; an injudicious incision may ren- manner similar to that recom- thesis, is more likely to withstand
den a patient unsuitable. As mdi- mended for patients with congenital and adjust to mechanical strains
cated earlier, needle biopsies are heart disease. and stresses.
preferred at the M. D. Anderson
Cancer Center. Small tumors of the
PROSTHESIS
distal femur and minimal soft tissue
POSTOPERATIVE ADJUVANT
involvement are optimal. It is also Recent advances in limb salvage
TREATMENT
anticipated that surgery will be per- advocate the use of metal prosthetic
formed without sacrificing a major replacements. These are used for Postoperative adjuvant chemo-
vessel or nerve. defects following tumor resection therapy generally is administered to
The patient and family should also near major joints, especially the hip, most patients. The strategy is de-
be advised that limb salvage in knee, and shoulder. Allograft on au- signed to destroy pulmonary micro-
some medical centers is still consid- tograft replacement may be at- metastasis considered to be present
ered investigational. They should be tempted in some patients. At the M. in the majority of patients at the time
made to understand the nature of D. Anderson Cancer Center, selec- of diagnosis. A variety of chemo-
the disease and its treatment. Fail- tion of patients for allognafts is gov- therapeutic agents have been
ure to respond to chemotherapy (if erned by attempts to preserve the shown to be effective in osteosar-
administered preoperatively) may integrityand stabilityof the adjacent coma. These comprise high-dose
result in amputation and require joint. Patients selected for this form methotnexate with citnovonum factor
psychologic adjustment. Chemo- of biologic reconstruction must have rescue (MTXCF),1 Adniamycmn
therapy does not alter the need for lesions located in the metaphyseal (ADR),2 CDP,7 cyclophosphamide
an adequate cancer surgical pro- or diaphyseal region, permitting in- (CTX),8 ifosfamide (IFX),9 and phe-
cedure. In the absence of limb sal- tercalary resection. Patients requir- nylalanmne mustard.8 The mecha-
vage, tumor extirpation is performed ing osteoarticulan grafts are ex- nism of action and side effects of the
by amputation on disarticulation. cluded. There appears to be a principal agents are outlined in Ta-
Patients who have undergone number of advantages to the use of bIe2.

TABLE 2. Chemotherapeutic Agents

Route of
Agent Dosage Administration Toxicity
Actinomycin-D Dosages vary from 10 Intravenous Bone marrow depression, stornatitis, exacer-
Dactinomycin to 15 L/kg/dfor 7 or Avoid extravasation bation of radiation effect (“recall” phenorne-
(Cosmegen) 5 d, respectively non), acne, alopecia
Extravasation results in ulceration
Doxorubicin Variable dosage (gen- Intravenous Myelosuppression, nausea, vomiting, diar-
(Adriarnycin) erally 50-75 mg/rn2 Avoid extravasation rhea, mucositis; possibly exacerbated with
every 3 wk) hepatic dysfunction, alopecia, phlebitis, skin
rash, cardiac toxicity
Exacerbation of radiation effect
Excreted in urine (red color)
Cyclophosphamide 600 mg/rn2 Intravenous Myelosuppression, nausea, vomiting,
(Cytoxan, Endoxan) alopecia, hemorrhagic cystitis,
asperrnia
Possible oncogenic potential
Ifosfarnide 2 gm/rn2 with MESNA Intravenous Myelosuppression, nausea, vomiting,
(sodium 2-mercap- alopecia, hemorrhagic cystitis, aspermia
toethane sulfonate) Possible oncogenic potential
uroprotectant
cis-Diamminedichloro- 80-1 50 mg/rn2 given Intravenous or Nausea, vomiting, anaphylaxis, ototoxicity
platinum IIcisplatin as single dose or in intra-arterial proceeding to deafness, renal dysfunction,
(Platinol) several divided hypocalcernia, hypornagnesemia, periph-
doses eral neuropathy
Often accompanied
with mannitol di-
uresis
Methotnexate 12.5 g/m2 followed by Intravenous Myelosuppression, stomatitis, renal toxicity,
leucovorin rescue hepatic dysfunction, nausea, vomiting, skin
(eg, 15-100 mg ev- rash
eny3h untilserum
rnethotrexate level
<0.3mol/L)

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Osteosarcoma

TABLE 3. Adjuvant Chemotherapy in Osteosarcoma

Follow-up
(Stated,
Metastasis-Free Estimated, or
Chemotherapy Regimen Survival, % Calculated), mo Research Investigator
CDP, MTX-CF, ADRt 56 95 Jaffe et al, 1988 (USA)13
MD(-CF, CDP 66 (High-dose MTX) 50 Picci et al, 1988 (Italy)14
ADA, BCD 51 (Low-dose MTX)
MTX-CF, ADA 58 48 Winkler et al, 1988 (Germany)15
BCD, CDP (Study patients, 49)
Ifos (Control patients 68)
ADA, XRT (1 750 rad, 50 Eilber et al, 1 987 (USA)11
preoperative), MTX 15 (Control patients; no
ADA, BCD (postopera- postoperative adjuvant
tive) chemotherapy)
CDP, ADA 60 24 Epelman et al, 1 988 (Brazil)16
MTX-CF, BCD, ADA 61 24 Provisor et al, 1987 (USA)17
CDP (modeled on Ti 0
protocol)
MTX-CF, ADA, XAT 56 60 Takada et al, 1986 (Japan)18
MTX-CF, ADA 77 24 Weiner et al, 1986 (USA)19
MTX-CF, ADA, BCD, 89 20 Kalifa et al, 1985 (France)2#{176}
CDP (modeled on Ti 0)
MTX-CF, ADA, BCD, 68 30 Winkler et al, 1984 (Germany)21
CDP, interferon
(COSS-80 protocol)
MTX-CF, ADA, BCD, 77 60 (median) Rosen et al, 1982, 1985, 1986 (USA)22-24
CDP #{231}rio
protocol)
BCD, MTX-CF, ADA, 65 33 Link et al, 1986 (USA)12
CDP
MTX-CF vs MTX-CF, 48 24 Medical Research Council, 1 986 (United King-
ADA 27 60 dom)25
MTX-CF (Intensive) 58 108 Goorin et al, 1987 (USA)26
ADA (Study Ill)
*CDP ni-dimminAdinhlnrnnItinum:
_._. --.-. ..-. -,-.-. MTX-CF, high-dose methotrexate with citrovorum factor “rescue”; ADA, Ad-
riarnycin; BCD, Bleomycin, cyclophosphamide, Dactinomycin; XRT, radiation therapy; T1O Protocol, protocol devised by
Rosen et al.22-24
Adapted from Jaffe, N. Chemotherapy for malignant bone tumor. Bone tumors evaluation and treatment. Orthop C/in
North Am. 1989; 20:487-503.

Earlier controversies surrounding an survival after the appearance of even, an initial period with
the purported salutary effects of ad- the untreated patient is approxi- chemotherapy may be considered if
juvant chemotherapy appear to mately 3 months. Only 2% to 5% of the patient has not been exposed
have been resolved.1#{176}
This occurred patients are alive 3 years after the previously to aggressive treatment.
following publication of the results of development of metastases. Pa- This is determined by evaluating the
concurrent randomized trials in tients who develop metastases with- treatment previously administered.
which patients were denied the po- in the first 9 months are treated ag- Metastases developing during or af-
tential beneficial effects of adjuvant gressively with chemotherapy. Such ten partially effective adjuvant che-
treatment.1112 To date, most negi- treatment frequently includes MTX- motherapy are generally few in num-
mens administered to patients after CF, ADR, CDP, CTX, and IFX. Sun- ben and delayed in appearance;
extirpation of the primary tumor gery may be considered, however, if they usually can be resected.
yield survival rates varying from the tumor is extremely large or is Patients treated with a multi-
50% to 75%13-26 (Table 3). growing rapidly and appears unlike- disciplinary surgical-chemotherapy
ly to respond to the treatment being strategy may achieve a 30% to 40%
administered. survival after metastasectomy. Sun-
TREATMENT OF METASTATIC
Pulmonary metastases appearing gical resection of pulmonary metas-
DISEASE
after treatment with adjuvant che- tases is contingent upon complete
The lungs are the initial site for motherapy usually are treated by im- local control of the primary tumor,
the spread of metastases. The medi- mediate surgical resection. How- resectability of the lesions, and con-

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 ONCOLOGY

firmation of the absence of extra- their situations and lead full and ac- An additional alternative to ampu-
pulmonary disease. Patients who tive lives. It is important, under tation is a turnabout procedure. This
fail to respond to conventional forms these circumstances, to assist in ne- may be considered for patients with
of chemotherapy usually are treated socialization and to guide them in medial or distal femoral lesions. The
with investigational regimens. learning to deal with the reactions of operation involves excision of the fe-
others to their amputations. Every mur at the lesser trochanten and tib-
SOCIAL AND PSYCHOLOGIC effort should be made to keep pa- ia distal to the proximal physis. The
ADJUSTMENT TO AMPUTATION tients current in school and to main- intervening skin and soft tissue are
tam peer relationships. This helps then excised while concomitantly
Rehabilitation of a patient who promote a sense of accomplishment preserving the neunovascular bun-
has undergone amputation requires and self-esteem. Several hospitals, dIe. The tibia is then rotated through
the skills of many professions, in- including the M. D. Anderson Can- 180#{176}
and attached to the stump of
cluding pediatric oncologists, pros- cer Center, have also organized ski the proximal femur. As a conse-
thetists, physical therapists, nurses, programs which help the adolescent quence, the heel is converted to a
social workers, and psychologists. and child amputee to recognize that “knee”. Effectively, it converts an
The process of rehabilitation also they are able to accomplish and “above the knee amputation” to a
must recognize that adolescence, possibly even surpass sporting ac- “below the knee amputation” with
the time when the majority of osteo- tivities originally considered ne- an excellent functional result (Fig 6,
sarcomas occur, is a phase of transi- stnicted to individuals without loss of parts A through C).
tion in which individuals experience a limb.
profound physical, intellectual, and Occasionally, amputees may also PROGNOSTIC FACTORS
social changes. These are corn- experience phantom pain. This phe-
pounded by challenges that herald nomenon is treated best by neas- Through the course of several
the passage to adulthood. Self im- surance that this is a normal phe- years, a number of prognostic fac-
age and a mutual and reciprocal nomenon. The incidence of tons that possibly affected survival in
commitment to others are of major phantom pain will be reduced great- the presence of osteosarcoma were
importance. Adolescents at this pe- ly and possibly eliminated by coordi- investigated. These comprised age
nod also face the task of formulating nated communication between the and sex of the patient; location, size,
plans and goals for the future. services and the family. Occa- and histology of the primary tumor;
The adjustment process to limb sionally, however, analgesia and re- extent of bone and soft tissue in-
amputation has been described by fennal to a neurologist may be re- volvement; coexisting pathologic
Walters as having four phases: im- quired. fracture or metastases, or both, at
pact, retreat, acknowledgment, and The process of psychologic adap- diagnosis; and duration of symp-
reconstruction.28 During the impact tation to amputation may take sever- toms. In the past, children less than
phase, the patient initially learns al months or occasionally years to 10 years of age and patients with tel-
that the disease requires an ampu- be successful. However, most pa- angiectatic osteosarcoma were
tation. Despair, discouragement, tients adapt reasonably well.28 This thought to have a poor prognosis.
passive acceptance, or violent deni- can be facilitated also by permitting Some studies suggested that an im-
al may result. Once the reality of am- a potential amputee to discuss his or proved prognosis was present in
putation becomes apparent, a re- hen fears and anticipated problems girls. Also, tumors of the extremities
treat phase emerges. Here the with a patient who has undergone were considered to have an im-
patient experiences acute grief. This an amputation previously. Support proved prognosis as compared with
is characterized by somatic and from such an individual may also be those of the trunk. Several recent
emotional reactions and changes in invaluable for other family mem- studies suggest that the only prog-
behavior that include anxiety, ten- bers. nostic factors of significance are ex-
sion, depression, anorexia, weight tent of tumor destruction induced by
loss, fear, guilt, and anger. An un- ALTERNATE ORTHOPEDIC preoperative treatment and tumor
derstanding of this phase is of major PROCEDURES TO AMPUTATION size.13-15 23
importance.
When the loss becomes real, the Limb salvage is utilized as an al-
SUMMARY
patient acknowledges the stump ternate to amputation whenever
and incorporates the changed phys- possible. However, not all patients Osteosarcoma is principally a dis-
ical appearance into his on her body may be suitable for the procedure. ease of the pre-teenagen and teen-
image and is able to reconstruct his In these circumstances, an arthno- age individual. Pain and swelling of
or her life. Prosthesis training be- desis may be a viable alternative. an extremity are the usual initial
gins, activities of daily living are ar- This involves resection of the tumor symptoms. A number of neoplastic
ranged, and careen possibilities are and joint (generally the knee) and re- and nonneoplastic conditions must
evaluated. placing the deficit with allograft or be considered in the differential di-
The vast majority of adolescents, autognaft bone. The procedure will agnosis. Good quality radiographs
with help and support from family produce a stable limb without a complement pathologic material in
and professionals, make the best of functioning joint. establishing the diagnosis. Major

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Osteosarcoma

Fig 6. Turnabout procedure in a patient with a distal osteosarcoma. Figures demonstrate

creation of a “knee” from the heel and functional use of “knee. “Although cosmetically unattrac-
tive,external prosthesis camouflages disfigurement.

advances as a consequence of che- ment of osteogenic sarcoma. Cancer. Martinus Nijhoff Publishers; 1985:223-
motherapy have been achieved dur- 1976;7:1-1 1 233
ing the past decade. Disease-free 5. Shirkoda A, Jaffe N, Wallace S, et al. 1 1 . Eilber FP, Giuliano A, Eckardt K. Adju-
Computed tomography of osteosarcoma
survival following surgical ablation vant chemotherapy for osteosarcoma: a
following intra-arterial chemotherapy. randomized prospective trial. J Clin On-
of the primary tumor and postopera- AJR. 1985;1 44:95-99
col. 1987;5:21-26
tive adjuvant chemotherapy is ap- 6. Chuang VP, Benjamin RS, Jaffe N, et al. 12. Link MP, Goorin AM, Miser AW, et al. The
proximately 60%. The majority of Radiographic and angiographic changes effect of adjuvant chemotherapy on re-
patients undergoing modern forms of osteosarcoma following intra-arterial lapse free survival in patients iwth osteo-
chemotherapy. AJR. 1 982;1 39:1065- sarcoma of the extremity. N Eng! J Med.
of treatment are also candidates for 1069 1986;314:1600-1 606
limb salvage. 7. Ochs JJ, Freeman Al, Douglas HO Jr, et 13. Jaffe N, Raymond AKR, Ayala A. Intra-
al. Cis-diamminedichloroplatinum (II) in arterial cis-diamminedichloroplatinum-Il
advanced osteogenic sarcoma. Cancer in pediatric osteosarcoma. Relationship
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 ONCOLOGY

tive trial (COSS-82) with salvage chemo- coma. A five year follow-up on T10 neo- B. 90% of the tumors occur in the meta-
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Neoadjuvant high dose methotrexate,
chemotherapy.
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Self-Evaluation Quiz D. Postoperative chemotherapy.
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duce T10 protocol in a single institution ment regarding etiologic factors associ- 10. The initial site of spread of metastases
(Abstract C-91 9) Proc Am Soc Clin Oncol.
ated with osteosarcoma, except: with osteosarcoma is:
1985;4:236
21. Winkler K, Beron G, Kotz A, et al. Neoad- A. Peak incidence occurs between the A. Liver.
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Austrian study. J Clin Oncol. 1984;2:617- viduals and young adults. D. Lung.
624 C. Repeated trauma increases the risk for E. Spleen.
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Preoperative chemotherapy for osteo- D. Prior therapeutic radiation to bone and
genic sarcoma. Selection of psot-opera- 11. Recent evidence suggests which of
exposure to radioactive substances
tive adjuvant chemotherapy based on the the following prognostic factors to be ben-
have been associated with osteosar-
response of the primary tumor to pre- eficial?
coma.
operative chemotherapy. Cancer. 1983; A. Tumors of the extremities (compared to
49:1221-1230 E. It has been associated with reti-
those of the trunk).
23. Rosen G, Nirenberg A. Neoadjuvant che- noblastoma.
B. Telangiectic form of osteosarcoma (com-
motherapy for osteogenic sarcoma: A pared with chondroblastic forms).
7. Which of the following is a true state-
five year follow-up (T-10) and preliminary C. Sex of the patient.
reportof new studies (112). Prog Clin ment concerning the clinical manifesta-
tions of osteosarcoma? D. Coexisting pathologic fracture.
Biol Res. 1985;201 :39-51
24. Rosen G. Role of chemotherapy in the A. Few patients complain of pain and swell- E. Tumor size and amount of destruction
treatment of primary osteogenic sar- ing at the tumor site. induced by preoperative treatment.

DEPARTMENT OF CORRECTIONS
In the supplement to the March 1991 issue of Pediatrics in Review, “Guide for
Record Review: Neonatal Hyperbilirubinemia,” a line of type was omitted on page 5.
The second and third sentences in the first complete paragraph on page 5 should
read, “All infants with clinically significant hemolytic disease of the newborn should
be treated with phototherapy in an effort to avoid the need for exchange transfusion.
Likewise, all infants who have had exchange transfusions should be treated with
phototherapy to prevent, if possible, the need for a second exchange transfusion.”

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 Osteosarcoma
Norman Jaffe
Pediatrics in Review 1991;12;333
DOI: 10.1542/pir.12-11-333

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 Osteosarcoma
Norman Jaffe
Pediatrics in Review 1991;12;333
DOI: 10.1542/pir.12-11-333

The online version of this article, along with updated information and services, is located on
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