Current Combined Treatment of High-Grade Osteosarcomas

Current Combined Treatment of High-Grade Osteosarcomas

ABSTRACT: The evaluation and treatment of osteosarcoma have evolved considerably over the past 2 decades, with corresponding dramatic improvements in prognosis. In large part, the improved outlook is attributable to intensive multiagent adjuvant chemotherapy, with better imaging modalities and reconstructive techniques also playing an important role. The current standard treatment for nonmetastatic osteosarcoma includes neoadjuvant chemotherapy, limb-sparing "wide" surgical resection, and reconstruction of the defect. Approximately 80% of patients are spared amputation. Limb salvage should be considered when an adequate surgical margin is attainable without significant neurovascular compromise and the surgical reconstruction is likely to provide better function than amputation. Because a good chemotherapeutic response is an important favorable prognosticator, much recent attention has been focused on predicting response preoperatively to allow closer surgical margins. Aggressive surgical treatment of pulmonary metastases has also been of measurable benefit. [ONCOLOGY 9(4):327-350, 1995]


The last 20 years have seen dramatic changes in the treatment
of osteosarcoma and corresponding improvements in prognosis. Until
the early 1970s, standard treatment for patients with osteosarcoma
was operation alone, namely, amputation. Despite operation, approximately
80% of patients died within 5 years from disseminated disease.
Current 5-year projections from recent trials show nearly 80%
actuarial survival, with most patients retaining the involved
limb. The key factors in this dramatic turnaround have been intensive
multiagent adjuvant chemotherapy, improved diagnostic imaging,
and more refined surgical reconstructive techniques.

Osteosarcoma is the most common primary pediatric bone tumor,
but it may afflict patients of all ages. It most frequently involves
the distal femur, proximal tibia, or proximal humerus. Patients
present with pain, a mass, or both. Radiographically, osteosarcoma
most often appears as a destructive osteoblastic lesion in the
metaphyseal region with an associated soft-tissue mass due to
extension of the tumor beyond the cortex. Most are histologically
high-grade malignancies, although multiple pathologic subtypes
of both high and low grades have been described. Despite the diverse
histologic appearances, the only prognostically important histologic
variable is the tumor grade. Patients with low-grade tumors have
generally done well without adjuvant treatment, whereas patients
with high-grade tumors have not.

From the initial presentation and evaluation of the patient, management
of high-grade osteosarcoma requires a team effort, including the
musculoskeletal radiologist, pediatric or medical oncologist,
orthopedic oncologist, and, in some cases, thoracic surgeon.

Preoperative Evaluation

Evaluation of patients presenting with probable osteosarcoma includes
laboratory studies and radiologic assessment of local and systemic
disease stage.

Laboratory Evaluation is generally unrewarding for diagnostic
purposes, but an increased serum alkaline phosphatase concentration
has been associated statistically with poorer prognosis [1,2].
Among patients without metastatic disease, a preoperatively increased
serum alkaline phosphatase concentration is associated with a
40% long-term disease-free survival, compared with 70% in patients
with normal levels. Among those with increased serum alkaline
phosphatase concentration, higher levels are prognostically worse
than lower levels [1]. In addition, among patients who experience
a relapse, disease-free survival is significantly shorter in those
with increased initial serum alkaline phosphatase concentration
[1]. Postoperative values usually return to normal and are not
associated with prognosis. The value of this information in any
given pediatric patient with osteosarcoma is limited, however,
because increases in serum alkaline phosphatase concentration
are frequently the result of normal growth preceding skeletal

Radiologic Analysis--The most well-accepted staging system
for osteosarcoma is that developed by Enneking and adopted by
the Musculoskeletal Tumor Society (Table 1). Based on the two
most important prognostic factors, the presence or absence of
metastases and the histologic tumor grade, this system allows
differentiation of patients into three major stages. Within each
of these stages, patients are subclassified according to whether
the tumor is limited to or extends beyond the confines of the
anatomic compartment of origin (eg, the bone). The subclassification
is most important for surgical planning.

Appropriate staging requires both local and systemic radiologic
analysis (Figure 1a-c, 1d-i). Local radiographs are now routinely supplemented
by magnetic resonance (MR) imaging. Intramedullary extent is best
seen on coronal T1 images, which also allow examination for discrete
"skip" lesions elsewhere within the same bone [3]. Intramedullary
disease nearly always produces a low signal intensity on T1 images.
Extraosseous extent is best evaluated on T2 sagittal and axial
images, with high signal intensity indicating tumor. The most
common site of metastatic disease is the lungs, followed by the
skeleton. Hence, systemic staging now most commonly uses lung
computed tomography (CT) and bone scintigraphy. Computed tomography
has clearly surpassed the ability of conventional tomography in
imaging pulmonary metastatic nodules[4]. Bone scintigraphy defines
the systemic extent of osseous disease, not only in terms of metastases
but also in terms of multifocality [5].

Medical Treatment

Among the three factors--diagnostic, medical, and surgical--that
have played important roles not only in improving survival from
osteosarcoma but also in enhancing the limb-salvage capability,
no doubt the most influential has been the advance in medical

Adjuvant Chemotherapy--The efficacy of doxorubicin and
high-dose methotrexate as single chemotherapeutic agents for adjuvant
treatment of osteosarcoma developed from their success in patients
with pulmonary disease. Additional drugs that have since been
found to have efficacy in an adjuvant role include cisplatin (Platinol);
cyclophosphamide (Cytoxan, Neosar), alone or combined with bleomycin
(Blenoxane) and dactinomycin (Cosmegen) in BCD therapy; and ifosfamide
(Ifex). Uncontrolled trials with single and multiple agents during
the 1970s suggested improvements in the projected 5-year survival
rates from the dismal 17% to 20% level with operation alone, to
39% to 61% with adjuvant chemotherapy [6-8].

The apparent improvement attributed to chemotherapy was called
into question when a retrospective review at the Mayo Clinic of
patients treated there after 1969 without chemotherapy showed
an apparent improvement in prognosis. Although some of those patients
had been treated with prophylactic pulmonary irradiation, a potential
improvement in the natural history of the disease was suggested.
In a subsequent study, Edmonson et al [9] cast further doubt on
the effects of chemo- therapy. In this prospective trial of Mayo
Clinic patients randomized to adjuvant chemotherapy with high-dose
methotrexate or operation alone, disease-free survival was 44%
in the group of patients treated by operation alone.

The role of chemotherapy in adjuvant treatment of osteosarcoma
was not firmly proved until the reports of the Multi-Institutional
Osteosarcoma Study group [10] Among a group of 36 patients younger
than age 30 years who accepted randomization, 2-year actuarial
relapse-free survival for the adjuvant group was 66%, compared
with 17% for the control group. Similar results were seen in 59
patients who declined randomization. Other reports have further
solidified the role of adjuvant chemotherapy [11,12]. The updated
results of the Multi-Institutional Osteosarcoma Study show 6-year
actuarial relapse-free survival rates among the randomized patients
of 61% for the adjuvant group and 11% for the control group, with
similar results in those who declined randomization [2].

Neoadjuvant Chemotherapy, although not as firmly supported
by scientific data, has become nearly universally accepted. The
initial development of preoperative chemotherapy was at Memorial
Sloan-Kettering Cancer Center in the mid-1970s, with the primary
purpose being to gain time in order to obtain custom prostheses
for patients undergoing limb-salvage operations. Additional arguments
used to support administration of preoperative chemotherapy in
the 1970s included [13]:

1. Early attack on microscopic disease foci to avoid disease progression
during the delay before resection of the primary site.

2. Reduction in potential spreading of tumor cells intraoperatively.

3. Evaluation of the effectiveness of chemotherapeutic agents
on the basis of tumor necrosis, and the potential to make changes
in the chemotherapeutic regimen on the basis of chemosensitivity.

4. The possibility that less aggressive surgical resection might
become a viable option in the event of tumor regression during

Experience with neoadjuvant chemotherapy during the last 20 years
has generally supported its continued use. From a purely oncologic
standpoint, there at least does not appear to be any disadvantage
in terms of overall disease-free survival[6,8,14]. On the other
hand, there also does not appear to be any demonstrable oncologic
benefit to neoadjuvant initiation of medical treatment. In a prospective
but nonrandomized trial in which 16 patients opted for immediate
operation and then were treated with the same chemotherapeutic
regimen as 61 patients treated under a neoadjuvant protocol, survival
was 73% in the adjuvant group and 70% in the neoadjuvant group
at comparable follow-up duration [6]. A major problem with currently
available retrospective data is the gross difference in percentages
of patients undergoing amputation between the adjuvant and neoadjuvant
groups [14].

One of the greatest benefits of neoadjuvant chemotherapy thus
far has been the recognition of the close correlation between
chemosensitivity and survival [7,15,16]. Complete or near-complete
tumor necrosis, generally referred to as a good chemotherapeutic
response and defined as 90% or greater primary tumor killed based
on histomorphometric analysis of the resected tumor specimen,
has been associated with actuarial long-term survival of 80% and
better [7,17,18]. The latest published Istituto Rizzoli 5-year
disease-free survival after a good chemotherapeutic response to
a regimen including postoperative doxorubicin was 78.4% [14].

Salvage Chemotherapy--With the recognition of the poor
prognosis for patients with relatively chemoresistant primary
tumors has come interest in salvage chemotherapy, based on extent
of necrosis of the resected specimen alone. Historically, the
best results of such postoperative changes in the chemotherapy
regimen were reported by Rosen and Nirenberg at Memorial Sloan-Kettering,
using the T10 protocol and Nirenberg [8]. Primary chemotherapy
consisting of high-dose methotrex- ate, bleomycin, and doxorubicin
was changed postoperatively in poor responders to bleomycin, cisplatin,
and doxorubicin. According to their reports, continuous disease-free
survival in the salvage group approximated that of the good responders.
However, neither the same T10 protocol [19,20] nor a modified
T10 protocol that included all patients with less than 90% necrosis
[21] has reproduced the earlier success reported by Rosen [8].
The initial experience with salvage therapy at the Istituto Rizzoli
was similarly unsuccessful when methotrexate and cisplatin were
discarded postoperatively in favor of bleomycin for poor responders
[14]. However, the addition of postoperative ifosfamide and etoposide
(VePesid) may play a role in improving the prognosis of poor responders

Despite ongoing trials to determine the efficacy of salvage chemotherapy,
the rationale for postoperative changes in the chemotherapy regimen
is not universally accepted. When such changes are based only
on the responsiveness of the primary tumor focus, there is no
corresponding consideration for the chemosensitivity of presumed
microscopic disease elsewhere. Although the chemosensitivity of
microscopic foci is assumed to be the same as that of the primary
focus, such a hypothesis is currently unproved. The results of
the Combined Osteosarcoma Study-80 [17] showed 52% 4-year actuarial
survival among less than good responders without a change to salvage
chemotherapy [21]. The prognosis in such patients with a change
in regimen appears still to be significantly better than the 11%
and 17% actuarial survival at 2 and 6 years, respectively, achieved
in controls without chemotherapy in the Multi-Institutional Osteosarcoma
study [10]. The definitive role of tailored chemotherapy programs
based on responsiveness has yet to be defined.

Doxorubicin--Among the chemotherapeutic agents used for
osteosarcoma, doxorubicin is, at this time, an essential drug.
Because of its cardiotoxicity and potential resultant congestive
heart failure and cardiomyopathy, attempts have been made to eliminate
doxorubicin from some osteosarcoma regimens. Although results
from Memorial Sloan-Kettering [7,23] suggested that this was a
viable option that did not decrease continuous disease-free survival,
other studies [14,21] have not shown this to be the case.

An attempt at the Istituto Rizzoli to eliminate doxorubicin from
the postoperative regimen only in good responders led to disastrous
results: Continuous disease-free 5-year survival was 26.6% in
patients treated with a 4-week postoperative regimen of only methotrexate
and cisplatin, compared with 78.4% in controls who received this
regimen plus a 24-week regimen of doxorubicin (P < .001)
[14]. Similarly, the German studies [21] found lower good response
rates (26% versus 60%) and overall 4-year actuarial survival rates
(49% versus 68%) when doxorubicin was reserved for patients with
less than good response. In fact, of the four most commonly used
osteosarcoma chemotherapeutic agents (doxorubicin, high-dose methotrexate,
cisplatin, and dactinomycin), only doxorubicin's dose-intensity
curve correlates directly with histopathologic tumor response,
based on a recent meta-analysis [24].

One focus of recent Mayo Clinic trials has been to provide doxorubicin
by continuous infusion while using a preoperative regimen that
also includes ifosfamide, mesna (Mesnex), and high-dose methotrexate,
with and without cisplatin [25-27]. Histopathologic response assessed
in 133 patients thus far has been excellent overall. Fully 32%
had 100% necrosis, an additional 33% had 95% to 99% necrosis,
and 7% had 90% to 94% necrosis [27]. For the total of 153 patients
enrolled in both pilot studies, median follow-up is 31 months.
Disease-free survival and survival at 3 years for patients without
metastasis to extremities using the regimen without cisplatin
were 75% and 94%, respectively. At 2 years for the regimen including
cisplatin, the corresponding figures were each 97%. Continuous
infusion of doxorubicin does not seem to decrease the histopathologic
response, disease-free survival, or overall survival rate, based
on early trials.

High-Dose Methotrexate--Early osteosarcoma chemotherapy
regimens typically included high-dose methotrexate, and its routine
use has generally continued, supported primarily by convention.
Changes in early protocols by increasing the dose intensity of
both methotrexate and doxorubicin simultaneously led to significant
improvement in long-term disease-free survival and have been cited
as support for continuing high-dose methotrexate use [12]. Comparison
of continuous disease-free survival between patients receiving
high-dose methotrexate (58%) and moderate-dose methotrexate (42%)
at one institution also suggested a benefit with use of the higher
dose (P = .07) [14]. However, the only published randomized
clinical trial addressing the need for high-dose methotrexate
failed to demonstrate significant benefits, compared with moderate-dose
methotrexate of approximately one tenth the higher dose intensity
[28]. This latter multi-institutional study of 166 patients revealed
a similar incidence of toxicities between the two regimens, but
hospitalization beyond that required for the protocol occurred
only in patients on the high-dose regimen [28]. The potential
gastrointestinal, renal, hepatic, bone marrow, and infectious
complications associated with high-dose methotrexate have led
to continued interest in either eliminating methotrexate altogether
or lowering its dose intensity.

Ifosfamide--The latest addition to the classic osteosarcoma
chemotherapy drug line-up is ifosfamide. Based on several phase
II trials showing between 15% and 35% complete and partial responses
in recurrent osteosarcoma, ifosfamide response rates appear to
be comparable to those achieved with doxorubicin and methotrexate
[29-33]. The addition of ifosfamide in the current Mayo Clinic
protocol described previously appears to have improved the overall
outcome in nonmetastatic extremity osteosarcoma, but a randomized
trial will be necessary to definitively establish the role of
this agent [26,27].


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