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Current Management and Future Directions of
Osteosarcoma Therapy
by
Lisa L. Wang, M.D.
Osteosarcoma (OS) is the most common primary malignant bone
tumor in children and adolescents. It accounts for approximately
5 percent of childhood cancers. OS has a peak incidence in the
second decade of life and tends to occur more frequently in boys
than in girls.
Survival of patients with localized OS has
improved significantly after the introduction of adjuvant
chemotherapy in the 1970s, but has plateaued at approximately
65 percent. Patients with metastatic or recurrent disease continue to
have a very poor prognosis. There are few predictive indicators,
with the exception of the absence of overt metastatic disease at
the time of diagnosis, to help determine which patients will
have a better clinical outcome in response to therapy. Given the
lack of improvement in patient survival and the paucity of
active agents against OS, the major challenges that lie ahead in
the field of OS research include defining patient-based
predictors or signatures of disease behavior in order to tailor
therapy, and understanding the biologic aspects of OS
particularly with regard to factors that influence genomic
stability.
The majority of OS cases are sporadic; however, certain
conditions are known to predispose to the development of OS,
such as previous exposure to ionizing radiation and to
alkylating agents. Cases of OS in patients older than 40 years
are almost always attributable to Paget’s disease. Genetic
conditions with a known predisposition to OS include hereditary
retinoblastoma, Li-Fraumeni syndrome and Rothmund-Thomson
syndrome. Because these genetic conditions have a known
predisposition to OS, careful detailing of family history in a
patient newly diagnosed with OS is important to identify
underlying genetic risk and for genetic counseling of family
members.
Most patients with OS present with pain in the involved area,
usually of several months’ duration. Soft tissue swelling may be
present, and patients may have pathologic fractures of the
affected bones. Systemic symptoms such as fever, weight loss and malaise
generally are absent. Laboratory evaluation is
usually normal except perhaps for elevated alkaline phosphatase
(in approximately 40 percent), elevated lactate dehydrogenase
(in approximately 30 percent) and elevated erythrocyte
sedimentation rate. These laboratory values do not, however,
correlate with extent of disease.
OS usually involves the metaphyseal region of the long bones.
The most common sites of involvement in descending order are:
distal femur, proximal tibia, proximal humerus, middle and
proximal femur.
Approximately 20 percent of patients present
with visible macrometastatic disease, most commonly to the
lungs, but also to the bone. Although 80 percent do not have
detectable metastatic disease, it is clear from historical
studies that if these patients are treated with surgery alone,
approximately 80 percent of these patients will have recurrent
or metastatic disease. Thus, micrometastastic disease is present
at the time of diagnosis even though disease may not be detected
by radiographic methods, and systemic chemotherapy is necessary
for virtually all patients in order to achieve a cure.
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History and physical examination
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Plain X-rays in two planes. If the tumor involves an
extremity, the X-rays should encompass both proximal and distal
joint regions. Generally abnormalities will be apparent on plain
films. Characteristic findings include a mixed lytic and
sclerotic appearance, periosteal new bone formation with lifting
of the cortex and formation of Codman’s triangle, and
ossification of the soft tissue in a radial or “sunburst”
pattern.
-
Magnetic resonance imaging (MRI) for evaluation of extent of
the tumor for planning of definitive surgery
-
Technetium-99 bone scan to evaluate involvement of other bones
and skip lesions within the same bone
-
Chest computed tomography (CT) to look for pulmonary
metastases. Visible metastases will be present in 15 percent to 20 percent
of patients at initial diagnosis.
-
Definitive diagnosis of osteosarcoma is made by biopsy,
preferably an open incisional biopsy, to ensure that a generous
sample of adequate and representative tissue is obtained. Proper
planning of the biopsy with careful consideration of the future
definitive surgery is important so as not to jeopardize the
subsequent treatment, particularly a limb salvage procedure.
-
The diagnosis of OS depends on histopathologic criteria with
confirmatory radiologic appearance. The histologic diagnosis is
based on the presence of a malignant sarcomatous stroma
associated with the production of tumor osteoid and bone.
The mainstays of therapy for OS are surgery and chemotherapy. OS
is relatively resistant to radiation; therefore, radiation
therapy is not used as a primary treatment modality. Drugs shown
to be effective and most commonly used in the treatment of OS
include cisplatin, doxorubicin and high-dose methotrexate. The
main features of these drugs are as follows:
-
Cisplatin is a nonclassical alkylating agent whose main
toxicities include potentially irreversible renal damage,
irreversible high frequency hearing loss, and reversible sensory
peripheral neuropathy.
-
Doxorubicin is an anthracycline that causes myelosuppression,
mucositis, nausea and vomiting. It can cause both
acute and chronic cardiac toxicity that can lead to congestive
heart failure. Serial monitoring of cardiac function is
necessary many years after completion of therapy. Doxorubicin is
a potent vessicant so care must be taken to avoid extravasation
during infusion. It is also a radiation sensitizer and is
usually not given during radiation therapy.
-
Dexrazoxane is a cardioprotectant agent that chelates iron, a
cofactor in anthracycline free-radical reactions. It may be
administered concomitantly with doxorubicin to help prevent
cardiac toxicity.
-
Methotrexate is a folic acid analog that interferes with the
synthesis of purines and thymidine. Its major toxicities include
myelosuppression, mucositis, nephrotoxicity, and hepatic
toxicity.
-
Leucovorin, a tetrahydrofolic acid derivative, is given
intravenously or orally after high-dose methotrexate as a rescue
agent to counteract the renal toxicity from methotrexate.
-
Cyclophosphamide and ifosfamide are alkylating agents that
have also been shown to have efficacy in osteosarcoma in
combination with other drugs. The major toxicities include
myelosuppression, nephrotoxicity and hemorrhagic cystitis. Ifosfamide has also been associated with reversible
neurotoxicity. Rarely they can cause interstitial pneumonitis.
These agents are often used in conjunction with etoposide
(VP-16).
-
Mesna (2-mercaptoethane sulfonate) is an agent that helps to
eliminate the by-products toxic to the bladder and is given
before and after infusion of chemotherapy to prevent hemorrhagic
cystitis.
Definitive surgery generally occurs after several weeks of
chemotherapy. The goal of definitive surgery is complete
resection of the primary tumor and resection of any metastatic
sites. For most extremity tumors, this is feasible and either
amputation or limb salvage surgery is performed. For
axial tumors (e.g., of the pelvis), complete resection may not
be possible. Limb salvage involves removal of the involved tumor
and bone and placement of a spacer device (either allograft,
metallic implant or autograft) and prosthesis. In general,
recovery from surgery takes several weeks, and chemotherapy
should resume as soon as possible.
Histologic response of non-metastatic primary tumors to
pre-surgical chemotherapy (determined at the time of definitive
surgery) has been shown to be a predictor of disease-free
survival. Patients with less than 10 percent residual viable
tumor in the resection specimen have a better prognosis than
those with more residual viable cells.
The outcome of patients with non-metastatic OS has improved
dramatically over the past three to four decades from an
event-free survival rate of 10 percent to 20 percent to a
survival rate of 65 percent to 70 percent, mostly due to the use
of adjuvant chemotherapy and improvements in surgical and
diagnostic imaging techniques.
Advances in surgical
techniques have also allowed improvement in the quality of life
of patients with primary limb tumors through the use of
limb-sparing surgical procedures to control the primary tumor.
Non-metastatic OS
–
With current combinations of surgery and
chemotherapy, long-term disease-free survival and overall
survival rates are greater than 60 percent.
Metastatic OS
–
The ability to control all foci of macroscopic
disease is essential in managing metastatic OS. Patients with
only pulmonary disease have a survival rate on the order of 30
percent
to 50 percent, whereas patients with bone metastases have a
dismal prognosis. Similarly, patients with mutifocal OS have a
generally worse prognosis. The overall event free survival
among patients with metastatic OS remains less than 30 percent.
Recurrent OS – More than 85 percent of recurrences are in the
lung, and most occur within three years of initial presentation.
The therapeutic approach to recurrent disease depends on the
location and timing of relapse. Patients with isolated pulmonary
relapse may be long-term survivors with just surgical removal of
nodules, particularly if the relapse is late (greater than one
year after diagnosis) and there are a small number of nodules
that do not invade the pleura and can be completely resected. In
some patients multiple procedures may be necessary, although
long-term survival decreases with each subsequent relapse.
Patients with early relapse fare less well even with complete
resection of pulmonary tumor nodules. Unresectable pulmonary or bone
disease is incurable with surgery alone, and may require a
combination of surgery, chemotherapy and possibly radiation
therapy.
While patients with OS have experienced improved outcomes
compared to several decades ago, there have been no major
improvements in therapy over the past years despite attempts to
escalate pre- and post-surgical chemotherapy. Therefore, new
approaches toward treatment of this unique childhood tumor need
to be explored. Current research efforts at Texas Children’s
Cancer Center (TCCC) are focused on defining patient-based
predictors or signatures of disease behavior in order to tailor
therapy, and on understanding the biologic aspects of OS
particularly with regard to factors that influence genomic
stability in order to identify potential therapeutic targets. By
utilizing a variety of approaches, including genomic and
proteomic profiling, as well as genetic models of cancer
predisposition, researchers at TCCC are seeking to understand
the molecular mechanisms underlying the pathogenesis of OS and
the crucial factors determining metastatic potential that will
provide better clinical predictors of outcome and more rational
and targeted therapies.
In parallel to the laboratory efforts investigating the
molecular pathogenesis of OS, investigators at TCCC have also
conducted a multi-institutional collaborative treatment protocol
for newly diagnosed patients with OS. This study, which includes
the Pediatric Branch of the National Cancer Institute, Cook
Children’s Hospital, Ft. Worth and the University of Oklahoma
Health Science Center, has two main objectives. They are: 1) to improve
survival by using high doses of alkylating agents with stem-cell
rescue; and 2) to perform molecular profiling on tissues
obtained at the times of initial diagnosis, of definitive
surgery, and of recurrence. The aim is to develop molecular
signatures that can accurately predict the outcome of patients
at the time of initial diagnosis.
This study has already led to
the identification of a chemoresistance signature and
construction of a multivariate classifier that can predict the
response to neoadjuvant chemotherapy at the time of diagnosis
prior to the initiation of any therapy. More recently another
multi-gene signature has been identified that can predict the
metastatic potential of OS in patients who initially present
with non-metastatic disease. These signatures will be validated
in a prospective manner through the upcoming joint
European-North American Osteosarcoma Study (EURAMOS), which is
expected to accrue a combined total of 1,400 patients in 3.5
years.
The Pediatric Program Cancer Genomics laboratory at TCCC
will serve as the reference laboratory for expression profiling
of all the EURAMOS samples collected in North America. These
signatures will hopefully improve the risk-based stratification
of OS patients so that they can receive more individualized and
effective treatment at the time of initial diagnosis.
Lisa L. Wang, M.D., is
a pediatric oncologist/hematologist and member of the
Solid
Tumor Team at Texas Children’s Cancer Center and assistant professor of
pediatrics at Baylor College of Medicine. Dr.
Wang's clinical interest is in osteogenic sarcoma. Her research focuses on cancer predisposition syndromes,
specifically Rothmund-Thomson syndrome, a rare inherited
disorder in children that predisposes affected individuals to
osteosarcoma and other cancers.
Acknowledgments
Drs. Chris Man, Ching Lau, Pulivarthi Rao, Murali
Chintagumpala and other researchers at Texas Children’s Cancer
Center, Baylor College of Medicine, who are conducting the
studies described in this review.
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