Current Combined Treatment of High-Grade Osteosarcomas

April 1, 1995

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

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.

Introduction

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 maturity.

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 management.

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 chemotherapy.

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 [22].

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].

Surgical Management

The transition from amputation to limb-sparing surgical treatment of osteosarcoma has not come without controversy. The functional benefits have been fairly obvious, but demonstrating the absence of oncologic disadvantages has required ongoing evaluation.

Functional Assessment After Limb Salvage--Assessment of function after oncologic limb-salvage procedures has thus far focused primarily on the lower extremities [34,35]. The newly developed functional assessment system of the Musculoskeletal Tumor Society is now being used to grade patients after operations on the upper and lower extremities for malignancy, and the early results are encouraging [36]. Based on a series of 144 patients, most (70%) of 116 patients undergoing limb-sparing operation had 50% to 75% normal function at follow-up. A small fraction (6%) had better function, while 24% had less than 50% normal function. This is in contrast to the results after amputation in the same series, in which most patients (64%) had less than 50% normal function. After amputation, no patient had better than 75% function.

Functional analysis using physiologic variables has shown that patients treated for a malignant skeletal tumor adjacent to the knee by way of above-the-knee amputation, resection arthrodesis, or replacement arthroplasty all walk at a similar speed and with comparable efficiency at three velocities [34]. The rates of oxygen consumption for each of the groups were not different from those of a normal control group.

Subjective analysis in the same study confirmed that each group had the expected advantages and disadvantages [34]. The amputees were active and the least concerned about damaging their affected extremity, but they encountered difficulty walking on steep, rough, or slippery surfaces. Patients with arthrodeses had the expected difficulty with sitting, but had a more stable limb than the amputees and were able to do the most demanding physical work and recreational activities (Figure 2a and 2b). Those with prosthetic reconstruction were the least self-conscious about their limb, but also generally led sedentary lives and were the most protective of the extremity. Documentation of the functional benefits of limb-sparing operation for sarcomas about the shoulder and pelvic girdle awaits further study.

Oncologic Soundness of Limb Salvage--The advent of limb-sparing surgical treatment predated widespread use of neoadjuvant chemotherapy, bringing about some interesting early observations with respect to the oncologic soundness of nonablative surgery. When chemotherapy is not initiated until after operation, relapse-free survival is slightly worse for patients undergoing limb-sparing operation than for those undergoing amputation [37]. There is also a higher metastatic rate when adjuvant chemotherapy is delayed instead of beginning essentially immediately after operation [38]. These findings would certainly discourage limb salvage if neoadjuvant chemotherapy were not available, but in the current combined treatment setting, they do not argue against limb-sparing operation.

In fact, only two studies have cast reasonable doubt on the oncologic safety of such procedures. The results of the Combined Osteosarcoma Study-80 reported in 1984 by Winkler et al [17] suggested that overall disease-free survival and pulmonary metastatic rates were worsened by neoadjuvant chemotherapy and limb salvage, compared with immediate amputation followed by chemotherapy, although the two groups were not randomized and nearly two thirds had amputation. Numerous other reports [14,15,19,39,40] have failed to demonstrate the higher incidence of metastases reported by Winkler et al. The second study casting doubt on limb salvage was that of Rosen [23], in which a 15.5% local recurrence rate was found in 122 patients with lower extremity osteosarcoma treated first by neoadjuvant chemotherapy; 67% had a limb-salvage procedure.

However, another study [21] contemporary to Rosen and a more recently reported study [14] have shown acceptable local recurrence rates of 5.4% and 5.5%, respectively, following limb-sparing surgery in a combined total of 183 patients. Local recurrence after amputation in the more recent study was 3.1% [14]. Other studies have shown more intermediate local recurrence rates of about 10%, and it is generally accepted that limb-sparing surgery has a slightly greater risk of local recurrence than does amputation.

Two orthopedic studies, markedly different in their approach to the same questions, established the current support for limb-sparing operation as an oncologically sound alternative to amputation. The first was a multi-institutional Musculoskeletal Tumor Society study with a large number (n = 227) of patients having osteosarcoma restricted to the distal femur [41]. The results were compared among those patients receiving limb-sparing operation, above-the-knee amputation, and hip disarticulation (Table 2). Although local recurrence was greater in the group receiving nonablative procedures, there was no significant difference among the groups in metastatic rate or survival at median 5.5-year follow-up. Despite its strength in terms of having adequate numbers for statistical analysis, this study was criticized for being multi-institutional and without standardized review of the histopathology. The limb-salvage group, generally having been more recently treated, may also have had the advantages of newer chemotherapy protocols and more routine use of chest CT for initial screening to exclude those with disseminated disease.

Addressing most of the weaknesses of the Musculoskeletal Tumor Society study was a 1988 report of a single-institution experience with 53 osteosarcoma patients at the University of Florida [42]. All patients were treated with the same adjuvant chemotherapy regimen and whole-lung radiation. All pathologic specimens were reviewed by one pathologist. Although the smaller numbers did not allow statistical analysis of local recurrence between groups, there was no significant difference in metastatic rate or survival between the limb-salvage group and the amputation group. In addition, there was no significant difference in metastatic rate or survival between wide and radical margins. The Florida study was not limited to the distal femur and, like the Musculoskeletal Tumor Society study, predated routine use of MR imaging and neoadjuvant chemotherapy. Although neither study was randomized, emotional and ethical issues pragmatically preclude such ideal science in this setting.

Candidates for Limb Salvage--Not all patients with osteosarcoma are candidates for limb-sparing operation. Absolute requirements for consideration of limb salvage include absence of neurovascular compromise due to tumor invasion, attainment of an adequate margin around the tumor, and a plan for reconstruction that will likely provide better function than amputation. Relative contraindications include extreme skeletal immaturity, pathologic fracture, and poor response to chemotherapy.

Skeletal immaturity primarily comes into consideration when excision of the tumor sacrifices the adjacent growth plate. When the extent of expected limb-length discrepancy will be significant, consideration must be given not only to an ablative procedure but also to rotationplasty in the lower extremity. Expandable prostheses are still considered developmental and are not widely used. Pathologic fractures are not a routine contraindication to limb-sparing operation, as long as imaging studies show that the neurovascular bundle may still be preserved with an adequate margin at excision. Poor response to chemotherapy is only considered an absolute contraindication to limb-salvage when the tumor progresses to involve the neurovascular structures despite neoadjuvant chemotherapy.

Adequate Margins--The adequacy of margin continues to evolve. For osteosarcoma, a radical margin implies resection of the entire bone of origin as well as any involved soft-tissue compartments. A hip disarticulation accomplishes a radical margin for a tumor of the distal femur. The belief that only a radical margin could achieve oncologic goals has been disproved [42]. A wide margin, defined as excision of the tumor with a cuff of normal surrounding tissue, has the same oncologic efficacy as a radical margin and is now the standard acceptable margin [42].

Whether a marginal margin, defined as excision of the tumor and its surrounding reactive pseudocapsule but with no intervening normal tissue, is oncologically safe appears to depend on the chemotherapeutic response. Local control is directly influenced by both the surgical margin and the chemotherapeutic response, and these two factors appear to be additive. The incidence of local recurrence in the recent Italian series was 1.5% among good responders, but 8.3% among fair and poor responders, regardless of the margin [14]. In fact, the only local recurrence in a good responder in that series occurred in a patient in whom a skip lesion was erroneously not excised. The additivity of these two factors is demonstrated by the 50% local recurrence among patients with less than a good response and less than a wide excision, compared with 3.7% local recurrence among patients with the same response but wide or radical margins [14]. The additive effect on local recurrence of poor response and less than wide excision has been calculated to be 46 times that of good response and wide excision [43].

The nearly negligible local recurrence rate with a good chemotherapeutic response after wide excision, less than 1% in another recent series [43], makes marginal excision all the more enticing, especially when the difference between wide and marginal excision may mean sacrifice or preservation of the distal femoral articular surface. However, in order to know preoperatively whether a marginal excision will be safe oncologically, one must know what the tumor responsiveness has been. As of yet, there is no single radiologic test that can reliably provide this information [44-46].

Plain radiography, quantitative CT [46], and bone scintigraphy [44] are less reliable than the best current test, MR imaging [44,45]. Several static MR imaging parameters, often suggested as indicators of good tumor response, are not seen with significantly greater frequency in tumors that histologically have 90% or more necrosis than in tumors with less than 90% necrosis [44]. On the basis of static MR imaging, decrease in tumor volume always represents decrease in the extraosseous tumor extent, and is seen in 73% of good responders, but also in 50% of others. Reduction in peritumorous edema is observed in 82% of good responders, but also in 50% of nonresponders. Improved delineation of the tumor margins relative to adjacent tissues occurs in 64% of good responders and in 30% of nonresponders. The best static MR imaging indicator of good response is a decrease in the T2 signal intensity, but even this has only 71% accuracy and 46% sensitivity [44].

One promising radiologic technique for predicting response is dynamic MR imaging, a fast low-angle shot gradient echo sequence with gadolinium [44]. When a 60% reduction in slope values occurred after neoadjuvant chemotherapy, a good chemotherapeutic response could be predicted with 85.7% accuracy [44]. Further work using both radiologic and biologic markers of chemotherapeutic response will be important if routine acceptance of less than wide surgical margins is to be considered.

Reconstruction Techniques--Surgical techniques for reconstruction after limb-sparing procedures depend on numerous factors, including the tumor location, joint involvement, extent of bone and soft-tissue resection, age of the patient, and the patient's functional demands. In general, the options following intra-articular excision of high-grade osteosarcoma in patients close to or beyond skeletal maturity include custom segmental total joint replacement, whole segment osteoarticular allograft, allograft-prosthetic composite, arthrodesis with autogenous or allogeneic bone, and arthrodesis with custom segmental porous ingrowth prosthesis and bone graft. Our current preferences at the Mayo Clinic after this type of excision in the proximal humerus would be an allograft-vascularized fibular arthrodesis; in the proximal femur, an allograft-prosthetic composite; and in the distal femur, a custom segmental replacement total knee arthroplasty (Figure 3a and Figure 3b).

After extra-articular excision, options include arthrodesis with autogenous or allogeneic bone, arthrodesis with custom segmental porous ingrowth prosthesis and bone graft, and segmental prosthetic spacer. At the Mayo Clinic, we will most commonly perform segmental intercalary allograft arthrodesis at the knee and hip, and use a segmental prosthetic spacer at the shoulder in such instances. After intercalary excisions that preserve the proximal and distal joints, the defect may be filled with an intercalary allograft, a vascularized or nonvascularized fibular graft, a composite of the two, or a custom segmental metallic prosthesis with porous ingrowth capabilities combined with bone graft.

One expected result of these newer limb-sparing surgical techniques has been a higher surgical complication
rate, ranging between 28% and 75% [14,36] (Figure 4a,4b, and 4c). After excluding minor complications and those major complications consisting of wear of a polyethylene bushing in a knee prosthesis requiring simple operative exchange, the series with a 75% complication rate actually had only 34% truly significant complications [36].

Metastatectomy--Disseminated osteosarcoma was at one time a relative contraindication to surgical management. Today, metastatectomy plays an important role in the management of osteosarcoma. Even though the prognosis for the 15% to 20% of patients with high-grade osteosarcoma who present with metastatic disease at diagnosis remains poor, increasingly aggressive surgical management and chemotherapeutic advances have resulted in improvements [47]. During the earlier eras of single- or dual-agent chemotherapy (1962 to 1972) and standard multiagent chemotherapy (1972 to 1982), survivorship beyond 3 years was nil [47]. However, during the era of intensive multiagent chemotherapy combined with pulmonary wedge resections (1982 to 1990), there has been a 50% survival at 3 years and an apparent plateau of 30% survival at 4 years [47]. A definite lengthening of survival has been demonstrated in multiple series [48-53] in patients undergoing pulmonary wedge resection.

Important variables in the surgical treatment of pulmonary osteosarcoma metastases include aggressiveness of operation, sites of pulmonary metastases (unilateral versus bilateral), number of metastases (unifocality versus multifocality), time to development, vascular invasion, hilar node involvement, and availability of additional chemotherapy to treat any remaining microscopic deposits [47]. The role of bony metastatectomy has not yet been well defined, perhaps because the occurrence of bony metastases is so much less frequent than that of pulmonary metastases [54] (Figure 5a-c and 5d-h).

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