This update will focus on the material in the field of musculoskeletal
oncology that was published or presented over the past year. However, it
should be noted that because musculoskeletal tumors are rare, the majority of
the new articles and published research tends to be composed of retrospective
or nonrandomized studies.
Giant-cell tumor of bone accounts for 5% of all primary tumors of bone. The
current standard treatment for giant-cell tumor of bone is curettage and
cementation or bone-grafting. Adjuvant therapies have been shown to decrease
the rate of recurrence of giant-cell tumors. In a recently published study
evaluating the efficacy of argon beam coagulation as an adjuvant for the
treatment of giant-cell tumors, the authors found that the patients had a good
to excellent functional outcome after a mean duration of follow-up of
seventy-three
months37. The
five-year recurrence-free survival rate was 87.2%. Several authors have
suggested that, in terms of recurrence, it does not matter which adjuvant is
employed38,39.
That study showed that argon beam coagulation can be another adjuvant
option.
Giant-cell tumor of bone is a locally aggressive lesion that has the
propensity to metastasize. At the present time, there are no reliable
predictors of recurrent or metastatic disease in cases of giant-cell tumor. In
an attempt to identify a clinically relevant molecular marker, investigators
performed array comparative genomic hybridization on twenty frozen tumors and
showed that 20q11.1 is frequently amplified in giant-cell tumor. They also
correlated the presence of 20q11.1 with the development of metastatic disease.
Thus, 20q11.1 may serve as a prognostic marker of adverse events associated
with giant-cell tumors.
The clinical presentation of polyostotic fibrous dysplasia is extremely
varied. There is substantial variation between patients in terms of
orthopaedic manifestations, including the number of fractures, the degree of
deformity of the limbs, and the presence of scoliosis. There are no clear
treatment guidelines, and thus the orthopaedic surgeon has to make treatment
decisions on a case-by-case basis. Leet et al. evaluated a group of young
patients with polyostotic fibrous dysplasia to see if there was any
correlation between function, disease burden, and
deformity40. With
use of the Pediatric Outcomes Data Collection Instrument, the authors found
that the loss of the normal femoral neck-shaft angle and the disease burden in
the lower extremities had the greatest effect on functional activity.
Preserving the neck-shaft angle may improve the functional outcome for these
patients.
Osteogenesis imperfecta is caused by a defect in collagen-I synthesis.
Otherwise known as brittle bone disease, osteoporosis is a common sequela. In
an attempt to combat the osteoporosis and decrease the risk of fracture, many
children have been managed with bisphosphonate therapy. The effect of an oral
bisphosphonate in children was evaluated in a randomized, double-blind,
placebo-controlled
trial41.
Thirty-four children with osteogenesis imperfecta were randomized to receive
olpadronate or placebo and were followed for two years. Children were assessed
with regard to the number of fractures, bone mineral content, bone density,
and function. Compared with the placebo group, children in the olpadronate
group had a reduction in the risk of fracture of the long bones as well as a
greater increase in bone mineral content and bone density. However, there were
no detectable effects on functional outcome or vertebral height. Although that
study showed that the use of bisphosphonates will decrease the risk of
fracture, how its use will affect osteogenesis imperfecta in the long term
remains to be investigated.
Investigators also evaluated the use of bisphosphonates to prevent early
collapse in patients with osteonecrosis of the femoral head. Many young adult
and pediatric survivors of solid tumors and hematopoietic malignancy have
development of osteonecrosis as a sequela of the disease and its treatment.
Lai et al. identified forty patients with Steinberg stage-II or III
nontraumatic osteonecrosis of the femoral
head42. Patients
were randomly divided into a bisphosphonate treatment group (alendronate) and
a control group (no treatment). Patients were evaluated radiographically every
ten weeks. In the control group, twenty patients had progression of disease,
with nineteen hips having collapse of the femoral head; however, in the
bisphosphonate group, only four hips had progression, with two of the four
having collapse of the femoral head. That was not the first study to conclude
that use of a bisphosphonate will retard osteonecrosis, but as a prospective,
randomized study it served to confirm the results of an earlier prospective
open-label trial43.
However, long-term follow-up is needed to ascertain whether bisphosphonate
therapy prevents or simply retards the progression of osteonecrosis.
The five most common carcinomas that metastasize to the bone are breast,
kidney, lung, thyroid, and prostate. A considerable amount of work is being
done to combat skeletal metastases. In order to decrease skeletal events and
improve patient outcomes, investigators are exploring both clinical and
preclinical strategies to inhibit the growth of bone metastases.
Bone metastases in non-small-cell lung cancer are associated with a worse
prognosis. Unfortunately, there are no predictive or diagnostic markers to
identify the patients who are at high risk for metastatic bone disease. In an
attempt to identify prognostic markers, Papotti et al. compared the
clinicopathologic parameters for thirty patients with resected non-small-cell
lung cancer who had subsequent development of bone metastases with those for
thirty control patients with resected non-small-cell lung cancer who did not
have any metastases and twenty-six patients with resected non-small-cell lung
cancer and non-bone metastatic
lesions44. Primary
tumors were investigated with immunohistochemistry studies for ten markers
involved in bone resorption or the development of metastases. The presence of
bone sialoprotein was strongly associated with the development of bone
metastases and, independently, with worse survival outcome. To allow for the
evaluation of bone sialoprotein expression in non-small-cell lung cancer as a
whole, a series of 120 consecutive resected lung carcinomas was added to the
study, and the bone sialoprotein prevalence reached 40%. The authors concluded
that bone sialoprotein expression in non-small-cell lung cancer could be
useful for identifying high-risk patients and thus alerting the clinician to
the need for careful surveillance and preventive treatment.
Similarly, Brown et al. investigated whether alkaline phosphatase and
N-telopeptide (markers of bone formation and the bone resorption,
respectively) had prognostic significance for bone metastases secondary to
prostate cancer and non-small-cell lung
cancer45,46.
With use of patients from the placebo arm of two phase-III trials on
zoledronic acid, the levels of urine N-telopeptide and serum alkaline
phosphatase were assessed every three months. Patients were monitored for
skeletal events, bone disease progression, and death. In each disease group
and in the overall group, high levels of each marker at the beginning of the
study were significantly associated with an increased risk of negative
outcomes. After long-term follow-up, high N-telopeptide levels were associated
with an increased risk of skeletal events and were a better predictor of
negative outcomes than alkaline phosphatase levels were. This
study45 suggests
that N-telopeptide can be used as a prognostic indicator. The monitoring of
N-telopeptide urine levels may provide a method for alerting the physician to
which patients are at risk for the development and progression of osseous
metastases.
The early diagnosis and treatment of bone loss and bone metastases with
bisphosphonates has become common in patients with metastatic carcinoma.
Clemons et al. prospectively evaluated the efficacy of zoledronic acid as a
second-line agent in patients who had already received first-line therapy for
metastatic breast cancer with another bisphosphonate (pamidronate or
clodronate)47. By
the eighth week of treatment, patients experienced a significant decrease in
pain. That study was the first to demonstrate that patients with either
progressive bone metastases or skeletal events while receiving clodronate or
pamidronate can obtain palliative benefits with a switch to the more potent
bisphosphonate, zoledronic acid. Although the question would benefit from
examination in a prospective, randomized trial, these findings have
significant implications related to the use of bisphosphonates in the cancer
population.
Radiation therapy is an effective way to palliate symptoms resulting from
osseous metastatic disease. A wide variety of dose schedules have been used,
varying from one fraction of 6 to10 Gy to multiple fractions, most often 30 Gy
delivered in ten fractions. Several groups have performed prospective,
randomized, controlled studies to investigate whether single-fraction
radiation therapy is equal to multiple fractions for the treatment of painful
metastases. In a study by Kaasa et al., 376 patients were prospectively
randomized to single or multiple-fraction radiation
therapy48. The
treatment groups had similar outcomes. Both groups experienced similar pain
relief within the first four months, and this was maintained throughout the
follow-up period. No differences were found in terms of fatigue or global
quality of life, and the rate of survival was similar in both groups. The
conclusion of that study was confirmed by the findings of the Dutch Bone
Metastasis Study, in which 320 prospectively enrolled patients were randomized
to receive a single fraction of 8 Gy or a total of 24 Gy in six fractions for
painful bone
metastases49. The
investigators concluded that single-fraction radiation therapy should be the
standard dose schedule for all patients with painful bone metastases,
including patients with an expected favorable
survival49. They
based their conclusion on the fact that among the 320 patients surviving more
than fifty-two weeks, the duration of the response and the rate of progression
were similar between the two groups. Sze et al. performed a systemic review
and meta-analysis of the randomized trials comparing single fraction and
multiple-fraction radiation therapy for the palliation of metastatic bone
pain50. They
identified eleven trials involving 3435 patients; the two trials discussed
above were not included in their analysis. The study revealed that there was
no significant difference between single-fraction radiation therapy and
multiple-fraction radiation therapy in reducing the overall pain response;
however, there were higher percentages of pathological fracture and the need
for retreatment in the group of patients who received single-fraction dosing.
Thus, although single-fraction therapy may be as effective for relieving pain
as multiple-fraction therapy, the increased incidence of pathological fracture
and need for retreatment may render it less economically feasible in term of
health-care dollars and patient outcome.