The field of musculoskeletal oncology is broad
and includes the study and treatment of a rare group of connective-tissue
tumors. Although these tumors are uncommon, they can have devastating
consequences for the life and the limb of the patient. In this field,
which involves not only orthopaedics but other subspecialties as
well, there is a rapid explosion of new information each year from a
variety of fronts. I will try to summarize the important findings
as reported both in the literature and at tumor meetings in 1999
and 2000. I will focus primarily on malignant neoplasms of bone and
soft tissue.
One area of interest to orthopaedic oncologists is the stratification
of patients into specific prognostic groups, not only to predict
outcome but also to identify the patients with poor prognoses who might
benefit from innovative treatment strategies. For most tumors there
are known clinical factors that indicate a good or poor prognostic
category.
Ewing Sarcoma/ Primitive Neuroectodermal
Tumor
Ewing sarcoma/primitive neuroectodermal tumor is a family
of primitive round-cell tumors with a common karyotypic translocation
between chromosomes 11 and 22. In the past they were nearly uniformly
fatal neoplasms, but major advances in treatment have been made,
primarily as a result of the use of adjuvant chemotherapy and proper
local control. Prognostic factors in 975 patients with Ewing sarcoma
were reported in a paper from the European Intergroup Cooperative
Ewing’s Sarcoma Study Group (EICESS), which is a cooperative effort
of the Medical Research Council/United Kingdom Children’s
Cancer Study Group and the Cooperative Ewing Sarcoma Study1. The study included patients treated
between 1977 and 1993 with similar chemotherapy protocols. The strengths
of this retrospective analysis are the large number of patients
and the substantial follow-up period (a median of 6.6 years). The
most important adverse prognostic factor was metastatic disease detectable
at the time of diagnosis. An interesting observation was that even
at six years the survival curves had not reached a plateau. The
five-year relapse-free survival rate was 22% of patients
with metastatic disease at the time of diagnosis compared with 55% of
patients without metastasis at the time of diagnosis (p < 0.0001).
Patients with metastasis in the lung fared better than those with bone
metastasis or a combination of bone and lung metastases. Multivariate
analysis revealed that, in patients without metastasis, tumor site,
patient age, and year of diagnosis affected outcome (all p < 0.005).
Tumors located at axial sites had a worse outcome than those at
other sites, as did patients fifteen years old or more compared
with those who were younger. For patients with and without metastasis,
those diagnosed after 1986 had a better outcome than those diagnosed
earlier, attesting to the improvement in chemotherapy regimens.
The authors confirmed the findings of others that tumor size and
lactic dehydrogenase (LDH) levels are of prognostic importance (tumor
volume > 100 mL and elevated lactic dehydrogenase were
adverse factors).
Another large study, which involved 359 patients without metastasis
who were treated at a single institution, the Istituto Ortopedico
Rizzoli, was reported by Bacci et al.2.
Data from patients treated during a similar time period (1979 through
1995) were retrospectively analyzed for prognostic factors. Like
the authors of the previous study, Bacci et al. found that metastasis
at the time of diagnosis was the most important prognostic factor,
but within their population without metastasis they refined other
prognostic variables. Multivariate analysis showed that male gender,
an age of more than twelve years, fever, anemia, high lactic dehydrogenase
serum levels, and an axial site had an adverse effect on outcome. The
type of chemotherapy regimen also affected outcome. Tumor volume
did not seem to be a significant prognostic factor in this study.
The authors also studied the impact of tumor necrosis following chemotherapy
in surgically treated patients and found it to be an independent
prognostic factor (p < 0.001).
One aspect that both of these papers discussed is the effect
of local control of the tumor on outcome. In these and other reports,
patients who had had the primary tumor treated by surgical resection
had a better prognosis than those who had not. In the Italian study,
this was an important factor according to univariate analysis, but
its significance disappeared with use of multivariate analysis.
In the EICESS study, factors such as tumor site and size and the year
of diagnosis were considered confounding factors. At most centers,
surgical resection is now considered to be the optimal method of
obtaining local control if a complete resection with negative margins
and reasonable functional outcome can be achieved. However, since
a controlled study of the effect of surgery on outcome has never
been carried out, we cannot be certain that surgical resection favorably
affects disease outcome. One advantage of resection is the elimination
of treatment-associated malignant tumors, which occurred in five
of the 975 patients in the EICESS study. Resection also allows the
assessment of tumor necrosis, which has been found to be of prognostic
importance in osteosarcoma.
Although large clinical studies like these are of importance,
they have certain limitations. As more is learned about the biology
of sarcomas, it is becoming apparent that even among tumors with the
same histologic characteristics there is biological diversity. Molecular
biological techniques now allow us to further define and classify
sarcomas, as seen by the numerous reports in the literature within
the last year. One of these, by de Alava et al., analyzed
the p53 status, along with Ki-67 (a marker of proliferation)
and p21WAF1 (a cyclin-dependent
kinase inhibitor transactivated by wild-type p53), in fifty-five
patients with Ewing sarcoma/primitive neuroectodermal tumor3. P53 is a tumor suppressor gene located
on chromosome 17q, and it has a variety of functions. It is a transcription
factor that is involved in cell-cycle regulation, and alterations
in p53 affect the regulation of cell-cycle progression and result
in cell proliferation. P53 has many other functions important to
the cell, such as repair of DNA damage and apoptosis. Missense mutations
of p53 have been associated with a poorer outcome in a variety of cancers,
and these mutations can be detected with use of various methods,
including immunohistochemical techniques. De Alava et al. found
that p53 mutations were infrequent (six patients [11%] had
expression in >20% of tumor cells). However, univariate
analysis of prognostic factors revealed that patients whose tumors
had p53 expression in >20% of cells exhibited
a significantly poorer overall survival rate than those who did
not, in both a subgroup of forty-three patients with nonmetastatic disease
(p = 0.001) and the entire study group (p = 0.01).
Multivariate analysis showed that p53 was the strongest negative
prognostic factor studied. Interestingly, it did not predict histologic
necrosis, an end point used to assess prognostic factors in other
studies, since necrosis is associated with outcome in osteosarcoma
and Ewing sarcoma/primitive neuroectodermal tumor. These
findings confirm prior observations that a small subset of patients
with Ewing sarcoma/primitive neuroectodermal tumor who
have a particularly poor prognosis can be identified4. If this is substantiated in larger
studies, it may be possible to develop innovative treatment strategies specifically
for these patients. As pointed out by de Alava et al.3, some research has shown that the
specific type of translocation may have prognostic importance. It
is likely that in the future molecular phenotyping will dictate
how patients are to be treated.
Osteosarcoma
As in the case of Ewing sarcoma/primitive neuroectodermal
tumor, major advances have been made in the ability to treat patients
with osteosarcoma successfully. Approximately 70% of patients
who present without detectable metastases at the time of diagnosis
can expect to remain free of disease if they receive adjuvant chemotherapy
and adequate local control. Unfortunately, that means that 30% will
have a relapse, and many of these patients will eventually succumb
to the disease. Our ability to identify patients at high risk may
allow novel treatment strategies for these high-risk patients, and, alternatively,
some patients with a more favorable prognosis may not need such
aggressive therapy. The need to stratify patients into high and
low-risk groups has been recognized at many centers. The current
studies by the Children’s Oncology Group mandate the collection
of tissue for study of biological factors that might be related
to prognosis. Potential factors identified to date include p-glycoprotein
(a membrane-bound glycoprotein encoded by the multidrug resistance
MDR-1 gene involved in resistance to a variety of chemotherapeutic
and other agents), p53, and others. In patients with osteosarcoma,
the expression of HER2/erbB-2 was found
to be of prognostic importance in a recent report5.
The c-erbB-2 proto-oncogene encodes the human epidermal growth
factor receptor 2 (HER2). The authors studied archival biopsy material
from a subset of fifty-three patients5.
Immunohistochemical analysis of tumor specimens was used to study
the expression of HER2/erbB-2, p-glycoprotein,
and p53. P-glycoprotein was expressed in 22.6% of
the specimens; p53, in 15%; and HER2/erbB-2,
in 45.3%. Neither P-glycoprotein nor p53 expression was
associated with histologic evidence of necrosis in this study, whereas
HER2/erbB-2 expression was significantly
associated with histologic evidence of more severe necrosis (p = 0.02),
and high levels of HER2/erbB-2 at the
time of diagnosis were associated with a significantly worse event-free
survival rate (78% compared with 40% [for
patients with low levels of expression] at five years;
p = 0.01). Similar associations between HER2/erbB-2
expression and outcome have been found in patients with breast cancer,
and HER2/erbB-2 expression has been observed
more frequently in patients with metastatic osteosarcoma, which suggests
that this may be a good marker of a particularly poor prognosis.
Of perhaps more interest is the therapeutic agent rhuMAb Her2, which
in breast cancer trials has been of clinical benefit to patients
with tumors that express HER2/erbB-2.
A multi-institutional phase-II trial of rhuMAb HER2 treatment of
patients with metastatic osteosarcoma at presentation and those
with refractory or relapsed osteosarcoma whose tumors express HER2/erbB-2
is being carried out.
Soft-Tissue Sarcoma
Identification of prognostic groups is also of importance when
treating patients with soft-tissue sarcoma. One recent study involved
121 patients with synovial sarcoma who were treated at two large European
tumor centers; all but eight of the tumors were in extremities6. Treatment was primarily surgical,
but some patients received preoperative or postoperative radiation
and/or chemotherapy. The estimated five, ten, and fifteen-year
survival rates were 60%, 50%, and 45%,
respectively. The local recurrence rate was 31%. Risk factors
for local tumor recurrence, as determined by multivariate analysis,
were large tumor size (5 cm) and primary resection at an outside
institution. Independent risk factors for metastasis were older
patient age, poor histologic differentiation, and tumor necrosis;
those factors, in addition to tumor size, were identified, with
use of multivariate analysis, as independent factors affecting survival.
Local recurrence was associated with a 3.66-fold increase in the
rate of tumor-related death. The investigators were able to identify
a low-risk group (patient age of younger than twenty-five years,
tumor size of <5 cm, and no histologic evidence of a poorly
differentiated tumor) that had an 88% overall disease-free
survival rate, and a high-risk group (patient age of twenty-five
years or older, tumor size of 5 cm, and poor histologic differentiation)
with an 18% overall disease-free survival rate (p < 0.001).
The authors suggested that treatment strategies should differ for
these groups.
Prognosis based on the type of cytogenetic translocation was
the focus of a study of thirty-three patients with synovial sarcoma7. It is well established that synovial
sarcoma tumors have a t(X:18)(p11.2;q11.2) translocation that results
in a fusion between the SYT gene on chromosome
18 and SSX1 or SSX2 on the X chromosome.
The authors examined the clinical relevance of SYT-SSX1 and SYT-SSX2 fusion
transcripts analyzed by reverse-transcription polymerase chain reaction
and sequence analysis. They also looked at proliferation rates with
use of anti-Ki-67 antibodies. Thirteen patients had the SYT-SSX1 transcript
whereas nineteen had the SYT-SSX2 (one patient
was excluded). The patients with SYT-SSX1 had a
significantly reduced metastasis-free survival rate (p = 0.005)
and overall survival rate (p = 0.02). There was also a
significant association (p = 0.02) between SYT-SSX1 and
a high tumor proliferation rate, suggesting that SYT-SSX1 determines
the proliferation rate and is an important predictor of clinical
outcome in patients with synovial sarcoma. This was a small study
in which univariate analysis and log-rank tests were used to assess
the differences, so a larger study is necessary to document these
differences, but they again demonstrate that molecular changes present
in sarcoma cells may play a key role in how we will treat patients
with synovial sarcoma in the future.
An association between the MDR phenotype and the outcome in patients
with high-grade soft-tissue sarcoma has recently been reported8. Tumor specimens with a variety of
histotypes were analyzed before and after neoadjuvant chemotherapy
in twenty-nine patients with use of two monoclonal antibodies that
recognize different epitopes of p-glycoprotein (C494 and JSB-1).
Ten (34%) were MDR-positive and nineteen were MDR-negative.
A poor outcome was observed in 90% (nine of ten) of the
MDR-positive group compared with 37% (seven of nineteen)
of the MDR-negative group (p = 0.0078). None of the patients with
MDR positivity had a good histologic response to preoperative chemotherapy
compared with six (32%) of the nineteen with an MDR-negative
tumor. Again, these findings need to be confirmed in a larger group
of patients, but they offer a possibility of stratifying patients
for therapeutic trials on the basis of prognostic information present
in tumor tissue at the time of diagnosis. The benefit of adjuvant
chemotherapy in adults with soft-tissue sarcoma has not been conclusively
demonstrated, and these results suggest one way to identify a subset
of patients who might benefit from such therapy.