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© 2001 The Journal of Bone and Joint Surgery, Inc.
What’s New in Musculoskeletal Tumor Surgery
Mark C. Gebhardt, MD
Department of Orthopaedic Surgery, Children’s Hospital,
Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115. E-mail
address: mark.gebhardt{at}tch.harvard.edu 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. Identification of Prognostic Groups 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 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
Soft-Tissue Sarcoma 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. Novel Treatment Strategies In addition to their usefulness in determining risk groups, these genetic findings may have important ramifications for treatment strategies. At the Connective Tissue Oncology Society (CTOS) meeting held in Washington, D.C., in October 1999, a group from the National Institutes of Health reported on tumors that have known cytogenetic translocations (synovial sarcoma [SS], clear-cell sarcoma [CCS] and desmoplastic round-cell tumors [DSRCT])9. These translocations result in the formation of fusion proteins that are unique to tumor cells and provide targets for immunotherapy. It was hypothesized that these fusion breakpoint products could serve as tumor-specific neoantigens. The authors designed peptides representative of each type of fusion breakpoint and tested their ability to bind to various HLA class-I molecules9. Two peptides from the SS breakpoint specifically bind to HLA-B7, an SS and a CCS peptide bind to HLA-B27, and a peptide designed from the DSRCT breakpoint specifically binds to HLA-A3. The authors also observed specific T-cell responses. Their findings suggest that sequences resulting from these translocations can bind HLA class-I antigens and potentially serve as neoantigens. The clinical importance of this is that novel immunotherapies could be developed for HLA-matched sarcoma patients bearing these translocations. This same group of investigators recently reviewed this topic as it pertains to rhabdomyosarcoma and Ewing sarcoma10. Local Control in Soft-Tissue Sarcoma The local control of soft-tissue sarcomas of the extremity required amputation in the past because of high local recurrence rates with local resection. In the past thirty years, limb-sparing procedures combined with radiotherapy have allowed local control without amputation. Whether to administer radiation preoperatively or postoperatively has been an area of controversy. One of the advantages of preoperative radiation is the smaller volume of radiation delivered directly to the tumor target, whereas postoperatively the entire operative field must be irradiated. Preoperative radiation comes with a cost, however, because the risk of wound complications is higher when resection of large sarcomas is attempted after radiation. As reported at the Annual Meeting of the Musculoskeletal Tumor Society in Gainesville, Florida, in May 2000, a multidisciplinary group in Toronto carried out a prospective study of 185 patients with soft-tissue sarcoma in an extremity and randomized them to receive either preoperative or postoperative radiation11. The primary end point was wound complications, but functional measures such as the Musculoskeletal Tumor Society Rating Scale, the Toronto Extremity Salvage Score, and the Short Form-36 were used as well. The groups were balanced for age, gender, tumor size, tumor depth, and comorbidity. At six weeks postoperatively, significant differences in function were measured with use of all three instruments, but no difference was observed between the groups at later dates up to one year. The wound complication rate was higher in the group with preoperative radiation, but overall, the timing of radiation had a minimal impact on the function of patients in the first year after therapy. Pelvic Osteosarcoma Patients with pelvic osteosarcoma have historically had a poorer disease outcome than those with osteosarcoma in an extremity. A study by Yasko et al. at the M.D. Anderson Cancer Center retrospectively reviewed the cases of forty-three patients with primary osteosarcoma, seven patients with radiation-induced osteosarcoma, and three patients with Paget sarcoma of the pelvis12. Eighteen of all patients presented with metastatic disease. Patient age ranged from ten to seventy-seven years (median, thirty-seven years). Fifty patients received adjuvant chemotherapy, which included Adriamycin (doxorubicin), intra-arterial cisplatin, and, in some cases, ifosfamide and methotrexate. Thirty-three received surgical therapy (ten had microscopically positive margins). A good histologic response was reported in only four patients. In patients without metastatic disease at the time of diagnosis, the five and ten-year disease-free survival rate was 42% and the overall survival rate was 41% at five and at ten years. Six patients had a local recurrence, for a local relapse-free survival rate of 82%. All patients who had metastatic disease or a local recurrence died. Pelvic osteosarcoma remains a disease with an extremely poor prognosis despite aggressive therapy. Within this group of high-risk patients is a small subset that has a good histologic response and tumors that can be resected with wide margins. These patients have a reasonable chance of eradication of the tumor. The remainder of patients are in need of innovative, aggressive treatment strategies if survival rates are to be improved. Chondrosarcoma Chondrosarcomas of bone are generally treated by surgery alone. Chemotherapy has not been shown to be of value even in high-grade chondrosarcomas. One interesting report at the Musculoskeletal Tumor Society meeting showed that the proliferation of chondrocytes from chondrosarcoma explants was inhibited and apoptosis was induced following treatment with ciprofloxacin, a fluoroquinolone analog known to be toxic to chondrocytes13. Specimens of osteosarcomas and liposarcomas cultured similarly were not affected. When proposing possible mechanisms for this observed effect, Multhaupt et al. postulated that ciprofloxacin may cause a magnesium deficiency, inhibit proteoglycan synthesis, or enhance production of the apoptogenic interleukin-113. Ciprofloxacin is also known to inhibit DNA synthesis through interference with the enzyme topoisomerase II. Immature, poorly differentiated chondrocytes appear to be most susceptible to the effects of ciprofloxacin. Although more work is needed to assess the clinical relevance of this observation, it is intriguing to consider that an antibiotic might affect a "chemoresistant" sarcoma like chondrosarcoma. Angiogenesis is another topic of interest in the tumor field. Tumor-induced angiogenesis is necessary for the growth and metastasis of a variety of cancers. A group of investigators at Brown University studied the microvascularity of cartilage tumors of various grades, using a murine anti-CD34 antibody that stains endothelial cells and erythroblast precursors14. Microvessel density was determined in three areas of each tumor. There were seven grade-3, seventeen grade-2, eight grade-1, and twenty-two benign cartilage tumors. The microvessel density of the grade-2 and 3 chondrosarcomas was greater than that of the grade-1 and benign groups (p < 0.00003). The investigators postulated that the greater microvessel density of the higher-grade tumors may be related to the known increase in the incidence of metastasis of these tumors compared with their low-grade and benign counterparts. Although not proven by this report, the hypothesis is of interest and merits further investigation, especially as more anti-angiogenesis drugs are being developed. This approach may be of particular importance for patients with chondrosarcoma since they do not seem to respond to standard chemotherapeutic regimens. Neoadjuvant Chemotherapy in Osteosarcoma A few years ago, a controversy regarding the treatment of osteosarcoma was whether "neoadjuvant" chemotherapy—that is, chemotherapy delivered prior to removal of the primary tumor—improves disease outcome in patients with nonmetastatic osteosarcoma. It is generally believed by most orthopaedic oncologists that limb salvage is easier and perhaps safer following such preoperative treatment. Between 1986 and 1993, the Pediatric Oncology Group carried out a study (trial 8651) of 106 patients who were randomized to receive presurgical chemotherapy (PRE) or immediate surgery and postoperative chemotherapy (SURG)15. Except for the timing of the therapy, patients were treated with identical chemotherapeutic regimens consisting of methotrexate with leukovorin rescue, doxorubicin, cisplatin, cyclophosphamide, bleomycin, and dactinomycin. The groups were balanced for age, gender, and tumor location. Limb salvage was performed in 50% of the patients in the PRE group and 55% of those in the SURG group. Limb salvage was associated with more postoperative complications than was amputation; however, quality-of-life measurements did not differ between the two types of local control at six or at twenty-four months. At five years, the projected event-free survival rate was 65% 6% overall. For the PRE group it was 61% 8%, and for the SURG group it was 69% 8% (p = 0.8). The overall survival rate was projected as 78%, again with no significant difference between the groups. Excellent local control was achieved in both groups (there was one local recurrence in the PRE group), and treatment with preoperative chemotherapy did not result in improved event-free or overall survival rates. No difference in the ability to perform limb salvage operations was associated with use of preoperative chemotherapy, and functional results were similar in the two groups. This study is of interest because it refutes the bias of many surgeons that preoperative chemotherapy improves disease outcome and local control, and it gives some assurance that we are not doing harm by delaying surgery. Preoperative chemotherapy has become the norm for osteosarcoma and has several advantages. It makes limb salvage easier and probably safer by reducing the peritumoral edema, it gives the surgeon time to prepare the patient for an extensive operation, and it allows the assessment of tumor necrosis following chemotherapy, which has been shown to be of prognostic importance. It is hoped that soon we will have novel treatment strategies for patients who do not respond well to standard treatment. Tissue Engineering Finally, numerous reports on reconstruction methods following limb salvage surgery in patients with sarcoma have been published in the literature and presented at meetings of the Musculoskeletal Tumor Society, the International Symposium on Limb Salvage, and the Connective Tissue Oncology Society. There are too many articles to single out one or two, and most deal with advances made in prosthetic design or allograft transplantation. Perhaps of more interest is where efforts in this field will lead, and that is probably to the field of tissue engineering. Although we will continue to improve the designs of prostheses and the results of allograft reconstruction, ultimately the optimal method of limb reconstruction will be to "engineer" an implant from the patient’s own cells. An article on a recent symposium summarizes some of the concepts of this extremely exciting field as it pertains to bone16. This field is important not only to oncologists but to all orthopaedists. Tissue engineering, which combines the concepts of tissue repair and regeneration with engineering principles of biocompatible materials used as scaffolds, is an interdisciplinary field requiring the input of physicians, biologists, and engineers. The primary objective is to isolate specific cells, expand them in culture, and then deliver them in a carrier material that will mimic the cellular environment and physical demands of the tissue that is being replaced. There are many biocompatible scaffolding materials that can be used, with the choice depending on the desired result. For bone and cartilage reconstruction, these materials are generally ceramics or synthetic polymers. Vacanti and Bonassar chose periosteum as the source of cells used to generate engineered bone, and they used chondrocytes to generate cartilage16. Weight-bearing and non-weight-bearing bone defects were created in male nude rats and filled with polymer-seeded chondrocytes, periosteal cells, and control constructs. Implants seeded with periosteal cells resulted first in the generation of cartilage that gradually underwent a morphogenesis to bone, whereas polymers seeded with articular chondrocytes generated hyaline-like cartilage. These are obviously preliminary data, but the results are exciting with regard to their potential application for the reconstruction of tumor defects. The reader interested in this field is referred to reports from the Association of Bone and Joint Surgeons workshop entitled "Orthopaedic Tissue Engineering" (published in 1999 as Supplement 367S to Clinical Orthopaedics and Related Research) and also to another recent review17 and is encouraged to attend the above-mentioned meetings in the next few years. It is likely that the field of orthopaedic oncology will undergo dramatic changes in the next several years, not only with regard to our understanding of the basic biology of the sarcomas we treat but also with regard to the methods that we use for surgical reconstruction of tumor defects.
References
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