Extract
Advances in the diagnosis, treatment, and prevention of cancer have been
rapid on both the basic and the clinical research front. This review will
highlight recent discoveries and innovations and also will discuss refinements
in established techniques in the field of musculoskeletal oncology. The dates
and locations of future tumor-related meetings are included, and relevant web
sites are listed.
Advances in the diagnosis, treatment, and prevention of cancer have been
rapid on both the basic and the clinical research front. This review will
highlight recent discoveries and innovations and also will discuss refinements
in established techniques in the field of musculoskeletal oncology. The dates
and locations of future tumor-related meetings are included, and relevant web
sites are listed.
The diagnosis and treatment of musculoskeletal tumors have been
increasingly aided by techniques used by interventional radiologists. The
ability to perform less invasive procedures often allows more efficient, less
painful, and more cost-effective patient care. The trend toward the diagnosis
of tumors on the basis of small tissue samples will be discussed. The role of
arterial embolization of highly vascular tumors such as giant-cell tumor,
multiple myeloma, and metastatic renal-cell carcinoma will be reviewed.
Radiofrequency ablation has become the standard treatment for patients with
osteoid osteoma, but this technique is being expanded to assist in the
palliative treatment of patients with painful bone metastasis. Finally,
minimally invasive techniques such as kyphoplasty, vertebroplasty, and
acetabuloplasty may provide an alternative to major reconstructive surgery for
patients with metastatic disease.
Needle Biopsy
The original method of obtaining a histologic diagnosis of a bone or
soft-tissue tumor was open incisional biopsy. For most pathologists, this
method remains the so-called gold standard for making a diagnosis because it
provides the best chance of obtaining representative tissue. However, the
trend at many major musculoskeletal tumor centers over the past ten to fifteen
years has been to use smaller amounts of tissue for diagnosis. The benefits of
needle biopsy include cost efficiency, patient convenience, and avoidance of
the problems associated with poor open biopsy techniques. Smaller, more
specialized biopsy tools have been developed, leading to an 85% to 90% rate of
accuracy1. Conscious
sedation of the patient allows for outpatient protocols. Image guidance is
used to identify a "high-yield" area of the tumor. Computerized
tomography, ultrasound, and fluoroscopy can be used, depending on the location
and type of tumor. The advances in the field of radiology include faster
computerized tomographic scanners with better resolution. Three-dimensional
reconstruction can be used to better define the exact location of the tumor.
In the future, magnetic resonance imaging-guided biopsies will be performed,
which should enhance the diagnostic accuracy of the procedure by focusing on
the most viable sections of tumor.
Both fine-needle aspiration and core-needle biopsy can be performed on most
bone and soft-tissue lesions. A fine-needle aspiration initially can be
performed to confirm the presence of viable tumor, and then a larger
core-needle biopsy can be performed and processed for permanent review the
next day. The confirmatory diagnoses of metastatic carcinoma and recurrent
sarcoma are particularly amenable to needle biopsy. In order for these methods
to be effective as part of the multidisciplinary approach to the treatment of
patients with musculoskeletal tumors, the cytopathologist and surgical
pathologist must be well-trained to interpret small tissue samples. In
addition, the surgeon, radiologist, and pathologist must be in constant
communication. It is essential for the radiologist and pathologist to have
knowledge of the possible diagnostic and therapeutic algorithms in order to
provide the information that is needed by the clinician. Ideally, the biopsy
and treatment of bone and soft-tissue lesions that are suspicious for
malignancy should be performed by physicians who are experienced in the
treatment of musculoskeletal
tumors2,3.
Advances in the development of new tumor markers, techniques of antigen
retrieval, and methods of quality control have enhanced the sensitivity and
reliability of diagnosis. New markers such as CK7, CK20, CA125, and thyroid
transcription factor-1 (TTF-1) can help to determine the origin of an
adenocarcinoma or aid in the recognition of other tumors. In patients who do
not have an obvious primary site of disease on screening radiographs, these
new markers can help to focus the search for, and guide the treatment of, the
underlying lesion. CA125 is positive in patients with ovarian cancer, CK7 is
positive in patients with breast and lung carcinoma, and CK20 is indicative of
colon carcinoma if the CK7 marker is negative. Gastrointestinal stromal tumor
(GIST) is positive for CD117 (c-kit) and CD34, while 75% of bronchogenic
carcinomas are positive for TTF-1. With regard to melanoma, the standard S-100
protein has been augmented by HMB-45, MART-1 and Melan-A. Molecular techniques
such as flow cytometry, fluorescence in situ hybridization (FISH) and
polymerase chain reaction (PCR) are now being used to expand our knowledge of
genetic alterations within tumors while also ensuring a more accurate
diagnosis.
Arterial Embolization
Arterial embolization of hypervascular tumors has been used as an adjunct
to surgical resection and, in some cases, has been used as the sole treatment
for a tumor that is located in the spine or pelvis. When used in a
preoperative setting, the embolization of feeder vessels to tumors such as
metastatic renal-cell or thyroid carcinoma, giant-cell tumor, multiple
myeloma, or aneurysmal bone cyst can result in a lower operative blood loss
and a decreased need for intraoperative transfusions. This is particularly
important in cases of large tumors that are located in sites where tourniquet
control is not possible. Sun and
Lang4, in a study of
sixteen patients who had preoperative embolization for metastatic renal-cell
carcinoma, found that the mean blood loss was significantly less for patients
with >70% reduction in tumor vascularity than for those who had <70%
reduction in tumor vascularity (460 compared with 750 mL; p < 0.01).
For large primary benign bone tumors (such as giant-cell tumor or
aneurysmal bone cyst) that are located in the pelvis, spine, or shoulder
girdle, embolization alone has been successfully used to halt growth of the
tumor or, in some cases, to promote healing and mineralization of the mass.
This may preclude the need for functionally debilitating surgery. Lin et
al.5 reported the
long-term results for eighteen patients in whom a sacral giant-cell tumor was
treated with arterial embolization with use of Gelfoam and coils. Repeat
embolizations were performed on the basis of clinical symptoms and the
vascularity of the tumor. Fourteen of eighteen patients had a favorable
response, with reduction of pain and neurological improvement, after a median
duration of follow-up of 105 months.
Advances in interventional radiology techniques also have been used for
neoadjuvant chemotherapy administration in patients with osteosarcoma
involving an extremity. Several major centers in the United States utilize
this approach for the administration of intra-arterial cis-platinum. The
rationale is that this approach has a regional pharmacokinetic advantage over
intravenous treatment. Maximizing local delivery of the drug theoretically
enhances the local response rate while still allowing a high-enough
concentration of the drug in the draining vein to provide a systemic effect on
micrometastasis. There have been conflicting reports in the recent literature
regarding the effect on local recurrence and overall survival. Researchers at
the MD Anderson Cancer Center reviewed 155 intra-arterial infusions of
cis-platinum in forty-two patients from 1999 to 2002 (unpublished data). The
procedure was found to be safe, with no reported instances of skin necrosis,
thrombosis, infection, neuropathy, or compartment syndrome. There were seven
painful burns (in six patients) consisting of skin erythema and induration.
The long-term results related to local recurrence and survival in this group
of patients are pending.
Radiofrequency Ablation
The use of radiofrequency ablation to treat osteoid osteoma began ten years
ago, and there is now an accumulated experience with patients who have had
long-term
follow-up6. These
small, painful, benign bone tumors traditionally have been treated with either
prolonged use of nonsteroidal anti-inflammatory medications or surgical
resection. The surgical procedures often were extensive as the nidus was
difficult to identify. Because the lesions frequently are located in
weight-bearing bones, patient activities were restricted postoperatively and
fractures were a known complication of the procedure. In addition, incomplete
removal led to local recurrence of the painful lesion. Radiofrequency ablation
provides a percutaneous, computerized tomography-guided alternative for
removal of lesions and has been associated with a low complication rate. It is
performed as an outpatient procedure, and the patient can bear weight as
tolerated immediately after the ablation. Rosenthal et
al.6 reported on 263
patients who had had 271 radiofrequency ablation procedures for the removal of
an osteoid osteoma over a period of eleven years. The rate of complications
was <1%, and successful ablation was achieved in 91% of the patients who
had a primary lesion. Of those who had a recurrent osteoid osteoma, 60% were
successfully treated with a second radiofrequency ablation procedure.
More recently, radiofrequency ablation has been used for the palliative
treatment of painful bone metastasis. This procedure provides an alternative
or adjunct to radiation or surgery and can be performed in conjunction with
fine-needle aspiration to confirm the diagnosis. Callstrom et
al.7 recently
described the mechanism of pain relief after radiofrequency ablation.
Specifically, the procedure results in physical destruction of sensory nerve
fibers involving the periosteum and cortex in addition to mechanical
decompression of the tumor volume, which, in turn, decreases the stimulation
of nerve fibers. In addition, radiofrequency ablation destroys tumor cells
that produce nerve-stimulating cytokines such as TNF-a and various
interleukins while also inhibiting osteoclast activity.
Goetz et al.8, in
a recent multicenter study, reported on forty-three patients with bone
metastases who were managed with radiofrequency ablation. The mean tumor size
was 6.3 cm, and the majority of lesions were located in the pelvis or sacrum.
Seventy-four percent of the patients had had prior radiation treatment, and
all patients either had failed to respond to such treatment or were considered
to be poor candidates for radiation or narcotic medication. Radiofrequency
ablation was associated with a clinically important benefit (a 2-point drop in
the "worst pain" parameter) in 95% of the patients.
Related percutaneous techniques of kyphoplasty and vertebroplasty have been
successfully used to relieve pain in patients with spinal compression
fractures resulting from osteoporosis, multiple myeloma, and metastatic
disease. Multiple studies in the recent literature have reflected the
popularity of these
techniques9.
Locked Plating Systems
The development of the locked plating system for internal fixation has
important applications in the treatment of bone tumors. This system merges
locking screw technology with standard plate-fixation techniques. The locking
screws provide the ability to make a fixed-angle construct, which is important
when treating bone of poor quality. The screws function as multiple small
blade-plates, rather than relying on compression of the plate to the
underlying bone, to achieve secure fixation. Koval et
al.10 reported that
a locking condylar plate on the distal part of the femur provided
significantly greater fixation stability during axial loading than did a
standard condylar plate or blade-plate.
There are several potentially useful applications of the locking plate
technology in musculoskeletal tumor surgery, although no large series has been
published to date. Documented complications such as nonunion and hardware
failure are not uncommon when an intercalary allograft is used for
reconstruction after resection of a primary malignant diaphyseal tumor, and a
stable construct is necessary to facilitate host-allograft healing. The
locking plate system can provide stable fixation when used alone or when
combined with a vascularized fibular graft. More importantly, unicortical
screw fixation is available with the locking plate systems and allows fewer
holes to be placed in the allograft. This may decrease the chance of allograft
resorption or fracture in these areas. In addition, the locking plate can be
used for prophylactic fixation of an impending fracture secondary to bone
metastasis in the distal part of the femur or proximal part of the tibia.
Uncemented Stem Fixation
Uncemented fixation of tumor prostheses has been employed commonly in
Europe but has not been the procedure of choice in the United States. The
technique has been popularized for total hip arthroplasty in patients with
degenerative joint disease, especially in the younger population. In recent
years, there have been several intermediate-term and long-term reports on
uncemented fixation of tumor megaprostheses. Donati et
al.11 reported on
twenty-five patients who had received an uncemented proximal femoral modular
prostheses after tumor resection. After more than ten years of follow-up, only
four patients had required revision but more than two-thirds of the patients
had evidence of stress-shielding. Mittermayer et
al.12, in a study
of 251 patients who had received an uncemented Kotz tumor prosthesis for
reconstruction of the femur or tibia, reported that twenty-one patients
required revision because of aseptic loosening. The chance of avoiding aseptic
loosening at ten years was 96% for patients who had received a proximal
femoral implant, 76% for those who had received a distal femoral implant, and
85% for those who had received a proximal tibial implant. The first signs of
loosening were noted radiographically at a mean of twelve months. These
results are comparable with or better than those in reports of aseptic
loosening of cemented
megaprostheses13,
although no direct comparison studies have been completed to date.
A novel spring-loaded, titanium-alloy uncemented implant was recently
developed to address the problem of loosening secondary to stress-shielding in
patients managed with tumor
prostheses14. The
Compliant Prestress segmental replacement and fixation system initially was
tested in a sheep model and now is being used in a multicenter clinical trial.
The Compliant Prestress device has a porous-coated surface that is compressed
against the cortical osteotomy site at the host-bone surface with Belleville
washers that are tightened over an 8-cm intramedullary traction bar. An
internal spring can create predetermined forces of 1800, 2700, or 3600 N at
the bone-implant interface. In the sheep model, a circumferential buttress of
new bone was noted at the prosthesis-bone interface and bone ingrowth was
identified on retrieval studies, implying stress transference through the
cortex. At the meeting of the Connective Tissue Oncology Society that was held
in Barcelona, Spain, in November 2003, twenty-six patients who had been
treated in the United States with a Compliant Prestress device following a
primary or revision oncologic distal femoral resection were compared with a
matched group of twenty-six patients who had been treated in the United
Kingdom with a traditional cemented intramedullary stem. After a mean duration
of follow-up of 2.2 years for the group treated in the United States and of
1.8 years for the group treated in the United Kingdom, there had been only one
device-related prosthetic failure in each group. Additional follow-up is
necessary, but this unique, uncemented compression system may improve implant
survival in young patients with bone sarcomas who require resection and
reconstruction of weight-bearing joints.
Expandable Prostheses for Pediatric Patients
Another challenge for the orthopaedic oncologist is the treatment of
skeletally immature patients in whom the tumor location necessitates resection
of the physis. Continued growth of the contralateral limb often results in a
substantial limb-length discrepancy, depending on the years of remaining
growth. Therefore, many patients whose anticipated limb-length discrepancy is
>4 cm may undergo amputation or rotationplasty. If prosthetic
reconstruction is performed, an expandable device is necessary to allow for
gradual equalization of limb lengths by the completion of growth. The early
expandable devices had a high rate of failure at the expansion mechanism,
necessitating additional operations and resulting in an increased chance of
prosthetic infection. There has been a trend toward minimally invasive
expandable devices over the past ten years. Most recently, a novel,
noninvasive, expandable device has become available with energy stored in a
compressed spring that is released in a controlled fashion during application
of an electromagnetic field. The lengthening is performed in an outpatient
setting. The Phenix prosthesis (now manufactured as the Repiphysis by Wright
Medical Technology, Arlington, Tennessee) is a fixed-hinge, titanium implant
with the capability to expand that depends upon the length of bone resection
as well as the anticipated limb-length discrepancy at skeletal maturity.
During application of an electromagnetic field that heats to 130°C, the
polyethylene around a titanium tube melts. This allows a controlled slide and
elongation of 6 to 20 mm with no undue heating of the surrounding tissues.
The early multicenter experience with the Phenix implant has been
promising. Neel et
al.15 reported on
eighteen prostheses that were implanted in fifteen children with osteosarcoma
of the distal part of the femur or proximal part of the tibia. Sixty
expansions were performed, with 97% occurring in an outpatient setting. After
a mean duration of follow-up of 21.5 months, Musculoskeletal Tumor Society
functional scores were a mean of 90% (27 of 30 points). Eight revisions for
stem fracture or loosening were required. There have been subsequent
modifications of the prosthesis, and more recent data were presented at the
Twelfth International Symposium on Limb Salvage (ISOLS), held in Rio de
Janeiro, Brazil, in September 2003. From 1999 through 2003, twelve patients
had placement of the Repiphysis device and were followed for a mean of
twenty-eight months. Fifty-one expansions in eleven patients were performed,
with an average lengthening of 8.3 mm per expansion. One prosthesis was
revised after a fall, but no aseptic loosening was noted in any patient. The
mean ISOLS functional score was 96%. This novel technique may have more
widespread application in the treatment of limb-length inequality or spinal
deformity.
The recent literature was reviewed along with the tumor-related national
and international meeting abstracts from 2003. Several interesting studies
that were presented or published had diagnostic or treatment implications for
patients with bone or soft-tissue sarcomas. Recent basic-science studies have
focused on the association of different growth factors, cytokines, or enzymes
with specific tumors. Data also are being generated from microarray analyses,
and the daunting task in the next ten to twenty years will be to synthesize
this information into something that is clinically meaningful. Despite the
association of certain factors with specific tumors, extensive multicenter
cooperation will be necessary in order to collect sufficient data to develop
real guidelines for molecular diagnosis and targeted treatment. A focus on
basic mechanisms of how sarcomas proliferate and metastasize may provide new
avenues for treatment.
It has been proposed that an imbalance in the proteolytic cascade involving
matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) may play a role
in the development or progression of malignancy. Benassi et
al.16 studied the
activity of MMP2 and MMP9 as well as their inhibitors, TIMP2 and TIMP1,
respectively, in patients with high-risk soft-tissue sarcomas. The TIMP
activity was weak or nonexistent and MMP activity was high in the majority of
sixty-nine biopsy tissue samples tested with zymography and
immunohistochemistry. The plasma concentration of TIMPs was significantly
lower in fifty-three patients with soft-tissue sarcoma than in the fifty-six
control patients (p = 0.0001). The authors suggested that identifying the
levels of the tissue inhibitors of MMPs might allow better selection of
patients with aggressive tumors who have a poor prognosis. These patients
would be candidates for clinical trials with experimental therapies.
At the Twelfth International Symposium on Limb Salvage in September 2003,
it was reported that expression of vascular endothelial growth factor in the
tumors of patients with both Ewing sarcoma and chondrosarcoma was a negative
prognostic indicator. The expression of this factor is associated with
angiogenesis and aggressive growth of many tumors, making it a potential
therapeutic target. At the same meeting, investigators from Australia used a
mouse tibial injection model to demonstrate that the hyaline cartilage of the
epiphyseal plate and joint surface was resistant to local invasion by
osteosarcoma cells, irrespective of tumor size. The tumors were positive for
vascular endothelial growth factor and negative for the anti-angiogenic
factor, pigment epithelium-derived factor. In contrast, there was high
expression of pigment epithelium-derived factor in the upper layers of the
growth plate. The investigators hypothesized that the balance between
pro-angiogenic and anti-angiogenic factors plays a role in the resistance of
hyaline cartilage to invading osteosarcoma cells. This may partially explain
the clinical observation that while tumors occasionally may cross the growth
plate, they do not cross the articular surface unless there has been a
fracture.
Holzer et al.17,
in a clinical study, determined the bone-mineral density of forty-eight
long-term survivors of high-grade osteosarcoma who had been managed with a
specific international protocol that included high-dose methotrexate. The mean
age of the patients was thirty-one years. Dual-energy x-ray absorptiometry of
the spine and the contralateral femur was performed after a mean duration of
follow-up of sixteen years. Ten patients were found to have osteoporosis,
twenty-one were found to have osteopenia, and seventeen had normal bone
density. Eighteen patients sustained a fracture after chemotherapy and had low
bone-mineral density levels at all measured locations. That study underscores
the importance of long-term evaluation of patients with osteosarcoma. Patients
should have follow-up bone-mineral density studies and should be counseled
regarding possible treatments or activity modifications.
Grier et al.18,
in an important study of 518 patients with Ewing sarcoma that was published in
the New England Journal of Medicine, noted that the addition of
ifosfamide and etoposide to the standard regimen of doxorubicin, vincristine,
cyclophosphamide, and dactinomycin was effective in patients with localized
disease. The five-year event-free survival rate and the overall survival rate
were significantly improved in the experimental therapy group (p = 0.005 and p
= 0.01, respectively). The results of that work are now reflected in the
design of current treatment regimens for patients with Ewing sarcoma.
Conversely, a clinical study performed at the Rizzoli Institute in Italy
evaluated a dose-intensive chemotherapy regimen in patients with osteosarcoma
and found no improvement in the histologic response to chemotherapy, the rate
of local recurrence, or the five-year event-free and overall survival rates
when increased doses were
used19. From 1993
to 1995, 175 patients with nonmetastatic osteosarcoma of an extremity were
treated with neoadjuvant methotrexate, cisplatin, doxorubicin, and ifosfamide.
From 1995 to 1999, 196 similar patients were treated with increased doses of
the same agents. The postoperative treatment was the same in both groups, with
a longer course for patients with poor necrosis rates. A lower pretreatment
serum alkaline phosphatase level and a better histologic response to
chemotherapy were each predictive of an improved five-year rate of event-free
survival. The results of these two studies might suggest that the histologic
response to chemotherapy is a result of the inherent chemosensitivity of the
particular tumor. Rather than increasing doses of currently used drugs,
innovative therapies are necessary to further increase the survival of
children with malignant bone tumors.
Upcoming meetings will provide the latest information related to the
treatment of patients with primary bone and soft-tissue tumors and those with
metastatic disease. The American Society of Clinical Oncology
()
is focused on clinical research and the latest clinical trials for all types
of cancer. The next meeting will be held on June 5 through 8, 2004, in New
Orleans, Louisiana. The annual meeting of the Musculoskeletal Tumor Society
()
will be held on July 22 through 24, 2004, in Long Beach, California. The
American Society for Bone and Mineral Research
()
is a smaller group of researchers and clinicians focused on disorders of bone,
including osteoporosis and cancer. The next meeting will be held on October 1
through 5, 2004, in Seattle, Washington. The International Skeletal Society
(ISS)
()
is an organization comprising pathologists, radiologists, and surgeons
interested in musculoskeletal tumors and related diseases. The next meeting
will be held on October 6 through 9, 2004, in St. Julian's, Malta. The
Connective Tissue Oncology Society
()
is a multidisciplinary group of orthopaedic surgeons, surgical oncologists,
medical/pediatric oncologists, pathologists, and radiation oncologists
interested in the treatment of patients with sarcoma. The next meeting will be
held on November 11 through 13, 2004, in Montreal, Quebec, Canada. In
addition, the Musculoskeletal Tumor Society participates in Specialty Day at
the annual AAOS meeting, which will be held on February 23 through 27, 2005,
in Washington, DC.
Patient Education
American Cancer Society
()National Cancer Institute
()
American Cancer Society
()
National Cancer Institute
()
Resident Education
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