Osteosarcoma: Clinical Features and Evolving Surgical and Chemotherapeutic Strategies

Solid Tumors in Children

0031-3955/91 $0.00

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Osteosarcoma Clinical Features and Evolving Surgical and Chemotherapeutic Strategies

William H. Meyer, MD, * and Martin M. Malawer, MDt

Osteosarcoma (osteogenic sarcoma), the most common primary bone malignancy in children and adolescents, is composed of highly malignant spindle-shaped tumor cells that form an extracellular matrix of osteoid. Low-grade osteosarcomas are rarely encountered in the pediatric and adolescent age group1l3. 13\ therefore, this review focuses on the more typical high-grade malignant tumors. Because osteosarcoma occurs in both adolescents and adults, its therapy has captured the attention of orthopedic (and oncologic) surgeons as well as medical and pediatric oncologists. Osteosarcomas are locally aggressive with characteristic patterns of growth. This behavior must be considered during planning for surgical ablation of the tumor. Most of these tumors are bicompartmental; they destroy the overlying cortical bone and directly invade the adjacent soft tissues (Fig. 1). The periphery of the tumor is least mature and generally enclosed by a pseudocapsule. The tumor frequently breaks through the pseudocapsule to form noncontiguous satellite lesions. These satellite lesions are called "skip metastases" (Fig. 2). A skip lesion may develop by embolization of tumor cells within the marrow sinusoids. Tumor also may involve the adjacent joint. Simon 122 noted articular extension in 17 of 45 carefully studied tumors. Such extension may occur either directly along intra-articular structures, through the articular cartilage, through a pericapsular route, or following a pathologic fracture that opens a direct communication from tumor bone to joint cartilage (Fig. 3). Finally, extension may occur across the joint via the periarticular venous anastomosis and, when present, is associated with a poor prognosis. 33. 80. 130 The determination of *Associate Member, Department of Hematology-Oncology, St. Jude Children's Research Hospital; and Associate Professor, the Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee tAssociate Professor, Department of Orthopedic Surgery, Children's National Medical Center; and Associate Professor, Department of Orthopedics, George Washington University School of Medicine, Washington, DC

Pediatric Clinics of North America-Vol. 38, No.2, April 1991

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Figure 1. Gross specimen of an osteosarcoma of the proximal humerus. Note the large extraosseous component (arrow). Approximately 95% of all osteosarcomas demonstrate extraosseous extension. The surgical classification is stage IIB, high grade with bicompartmental extension.

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Figure 2. Skip metastasis. Gross specimen of a femur after hip disarticulation for a stage lIB osteosarcoma of the distal femur. Note the large "skip" metastasis in the mid-shaft (solid arrows). The incidence of skip metastasis is about 1% to 2%.

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5. Fracture hematoma Via intra-articular structures (cruciate ligaments)

Figure 3. Mechanism of articular involvement. Five mechanisms of tumor are spread to the adjacent jOint. The most common is through a pathologic fracture or direct extension along the capsule or intra-articular structures.

local extent of tumor and of the anatomical compartments involved has become even more important with the advent of limb-preservation surgery. Thus, careful preoperative staging is essential for determination of the anatomic extent of tumor and the appropriate surgical procedure. Osteosarcomas demonstrate a high propensity for distant hematogenous spread. Over 80% of patients have micrometastatic disease at diagnosis. 64 Because this tumor disseminates almost exclusively through the vascular system, clinically recognizable metastases usually appear first in the lungs. 3 Because bones lack a lymphatic system, early spread of osteosarcoma to regional nodes is rare. 129 Physicians involved in planning therapy for the patient with osteosarcoma must work together closely to ensure that treatment is optimal. The complex multimodal care necessary for appropriate clinical management can be facilitated through participation in research protocols. The following sections (1) provide a brief overview of the development of effective therapy for osteosarcoma through rigorously performed clinical trials; (2) discuss the difficulties in assessing extent of tumor and initial response to chemotherapy; (3) review innovative approaches to local tumor control including limbsparing procedures; (4) summarize the alternate approaches to chemotherapy including the use of "neoadjuvant" therapy (upfront window) prior to surgical resection; and (5) indicate future directions aimed at improving the outcome for patients with this tumor.

DEVELOPMENT OF EFFECTIVE SYSTEMIC THERAPY Prior to 1970, there was no known effective therapy for patients with osteosarcoma, except amputation of the affected extremity. Over 80% of patients developed widespread metastatic disease, usually within 6 to 9

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months of diagnosis, and almost all subsequently died. 38 Doxorubicin 20. III and high-dose methotrexate with leucovorin rescue 47, 51 were shown to be active in patients with metastatic disease in the 1970s. Several institutions subsequently used these drugs in the adjuvant setting (i. e., after primary surgery and before the development of metastatic disease)21. 47. 52,105.110 and reported marked improvement in disease-free survival for patients with extremity lesions without radiographically apparent metastases at diagnosis. 21.47,52.105,110,115 These advances suggested the possibility of administration of chemotherapy prior to surgery (i.e., neoadjuvant therapy). Investigators at the Memorial Sloan-Kettering Institute reported tumor regressions with the use of neoadjuvant high-dose methotrexate that provided a window of time for fabrication of endoprosthetic devices and allowed limb-preservation.1I4, 115 In addition, methods were devised to deliver chemotherapy directly to the site of the tumor (i. e" intra-arterial therapy) and a new agent (e, g., cisplatin) was added to the therapeutic repertoire. 53, 55, 98 Despite these apparent advances, virtually none of these observations were based on well-controlled clinical trials. Patients with osteosarcoma treated with surgery only at the Mayo Clinic in the early 1970s had survival rates in excess of 50% at 2 years from diagnosis with disease-free survival of 43%. Because this improvement in survival could not be attributed to the use of chemotherapy, these investigators suggested that the natural history of osteosarcoma may have changed, making surgical resection alone adequate treatment for most patients. 128 Accordingly, other investigators questioned whether the claims regarding chemotherapy based on nonrandomized studies and the use of historical controls were true or whether improved diagnostic staging (e.g., chest tomograms and computed tomography [CT] scans) had selected a lower risk population of patients. In addition, concerns were raised regarding the short- and long-term toxicity and costs associated with chemotherapy. 15. 61, 65 Therefore, investigators at UCLA and members of a cooperative study group independently began randomized studies to resolve these issues. Eilber et al (reporting for the UCLA study)27 and Link et al (reporting for the Multi-institutional Osteosarcoma Study [MIOS])64 both demonstrated conclusively that the natural history of osteosarcoma had not changed and that administration of multiagent chemotherapy after ablation of the primary tumor results in disease-free survival in about 60% of patients. Although sharply criticized by some, because of inclusion of a nonchemotherapy treatment arm,56 these trials have now provided definitive evidence for continued use of adjuvant chemotherapy in this disease. INITIAL ASSESSMENT OF TUMOR EXTENT If plain radiographs suggest the presence of osteosarcoma (Fig. 4), imaging studies should be performed prior to biopsy. Optimal evaluation includes plain radiographs, bone scintigraphy, and CT scanning. Most centers now consider magnetic resonance (MR) imaging also to be essential. Patients who are considered for possible limb-sparing procedures need angiography.

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Plain Radiographs. Plain radiographs often suggest the correct diagnosis, demonstrate the presence of a pathologic fracture, and suggest the extraosseous extent of tumor. They often are helpful in defining a reliable area for biopsy. Bone Scanning. Imaging with Wfc methylene diphosphonate (MDP) bone scintigraphy helps define intraosseous extension of tumor. Radionuclide bone scanning often detects the skeletal metastases in the unusual situation where they are present. 71 CT Scanning. CT allows accurate determination of the intra- and extraosseous extension of tumor.24, 25, 68, 116 CT scanning should include the entire bone and the adjacent joint. To obtain the maximum benefit from CT, the treating physicians should discuss the required information with the radiologist. CT scanning is the most sensitive technique to detect pulmonary metastases. Magnetic Resonance Imaging. MR imaging has several advantages in the diagnosis and evaluation of bone sarcomas (Fig. 5).11, 19, 104, 127 It has better contrast discrimination than any other imaging modality; furthermore, imaging can be performed in any plane. MR imaging is ideal for defining the medullary and extraosseous extent of tumor as well as for

See legend on opposite page

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Figure 4. Typical radiographs of an osteosarcoma. There are three general radiographic appearances: sclerotic (A), osteolytic (8), and mixed (C), osteosclerotic and osteoblastic. Mixed is the most common type. There is no prognostic significance to the various radiographic types.

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Figure 5. Osteosarcoma of the proximal tibia. Gross specimen demonstrating a small intraosseous tumor (stage IIA) (A) and the corresponding MR imaging scan (8). The white area (solid arrow) indicates the tumor. Note the almost identical relationship to the gross specimen. MR images are extremely accurate in determining the intraosseous extent of tumor.

detection of skip lesions. This imaging technique is also invaluable in planning limb-sparing procedures. 26, 127, 130, 136 Angiography. Angiography is used routinely at institutions utilizing intra-arterial chemotherapy. Two views (biplane imaging) are necessary to determine the relation of the major vessels to the tumor (Fig. 6).49 Since experience with limb-sparing procedures has increased, it has become essential to determine individual vascular patterns prior to resection. This complete battery of imaging tests provides delineation of the extent of tumor, including vascular displacement and compartmental localization,42, 49, 63, 88, 116 and should demonstrate any macrometastatic disease. These evaluations are critical for tumor staging and definition of anatomic details. They allow the surgeon to develop a three-dimensional construct of the local tumor area prior to surgery and thereby to formulate a detailed surgical plan (Fig. 7).74 It is best to refer patients to the treatment center prior to extensive imaging evaluations and before biopsy of the suspected neoplasm (see Biopsy Technique). ASSESSMENT OF RESPONSE The histopathologic hallmark of osteosarcoma is the production of extracellular matrix. Unfortunately, when tumor cells die after exposure to

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Figure 6. Lateral angiogram of an osteosarcoma of the distal femur. Note that popliteal vessels are free of tumor. This patient was a good candidate for a limb-sparing resection.

chemotherapy, an extracellular "shell" is left behind, and it frequently calcifies. Consequently, there is often little change in the size of the tumor, even after an apparent response to therapy. Thus, investigators have relied on clinical assessment, radiographic changes, and histologic evaluation to define response to therapy. Clinical Evaluation. The clinical assessment of therapeutic response is difficult, even for experienced clinicians. Tumors that are responding to therapy may be associated with the resolution of pain and a decrease in local warmth and tenderness or a decrease in size. Decreases in serum alkaline phosphatase levels are frequently observed; however some patients do not have elevated levels at diagnosis. 4. 62 Some of these findings may be present in patients who, by histopathologic criteria, are not responding to therapy. Conversely, increase in pain, increasing levels of alkaline phosphatase, or increasing tumor size are generally signs of tumor progression. Plain Radiographs. There is a good correlation between plain radiographic response and the amount of tumor necrosis. 18. 70. 125 Increased ossification of tumor osteoid, marked thickening, and new bone formation of the periosteum are seen, producing a solid rim of new bone at the tumor

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Figure 7. Staging studies. Schematic drawing of the relationship of the various preoperative imaging studies to the' gross tumor and normal structures. Bone scan, MR imaging, CT, and biplane angiography are all required for complete evaluation of a patient with an osteosarcoma.

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border. A decrease in the soft-tissue mass also suggests a good response (Fig. 8 A, B). Computed Tomography. CT scans are more sensitive than plain radiographs in detecting small changes in mineralization, and they more clearly delineate decreases in the size of the soft-tissue component of tumor. 120 CT scanning often will demonstrate rim-like calcification, similar to that seen on plain radiographs (Fig. 8 C, D). 71, 74, 99 Magnetic Resonance Imaging. MR imaging provides the best delineation of the extent of tumor, particularly within the medullary cavity. 16, 41 It most accurately demonstrates decreases in tumor size following therapy. However, MR imaging is less sensitive than CT scanning in detecting increases in mineralization. Bone Scanning. Routine bone scanning is the best method for detection of metastases in bone; however, it is relatively insensitive in defining changes in the primary tumor following therapy. Specialized Techniques. Several imaging techniques that are sensitive to changes in regional blood flow and perfusion to tumor have been reported to correlate well with histologic response to therapy. Angiography, the most invasive of all imaging techniques, is highly sensitive in detecting decreases in neovascularity,14 and is considered by some to be one of the most reliable radiographic criteria of a good clinical response. 7-9 Chuang et aP8 demonstrated good correlation of complete angiographic response with high levels of histologic necrosis and concluded that angiography was as reliable as pathologic evaluation. Serial angiographic studies are typically performed only in centers where intra-arterial chemotherapy is used. Detection of changes in tumor perfusion by functional bone scintigraphy (using OOmTc MOP) has also been reported. 10, 126 Malawer et aFI reported a significant correlation between percent good and poor responders (as judged by tumor necrosis) with decrease of tumor flow as determined by quantitative bone imaging (also M. Malawer, D. Priebat, R. Schulof, unpublished data). This technique compares favorably to the use of angiography. More recently, osteosarcoma has been found to take up thallium avidly, with decreases in uptake following therapy.ll2 If these early reports are confirmed by other investigators, the use of radionuclide-based imaging techniques will prove to be quite valuable in assessing response of osteosarcoma. Recent studies at St. Jude Children's Research Hospital have evaluated changes in early uptake of gadolinium by MR scanning, an approach first reported from Germany.35 Two-dimensional mapping of a single tumor plane allows identification of local areas of early enhancement (which have correlated with viable tumor by histologic assessment) and local areas with no early uptake of gadolinium (which have correlated with tumor necrosis). These imaging techniques remain investigational and typically are available only at specialized imaging centers. There have been no reports describing the value of this approach with direct comparison to more established methods. Such studies are essential prior to adoption of new imaging techniques for routine assessment of response to therapy. Histopathology Evaluation of Necrosis. The "gold standard" for defining the response of osteosarcoma to therapy is histologic assessment of tumor necrosis. This technique, first described by investigators at the

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Figure 8. Osteosarcomas of the distal femur treated by intra-arterial chemotherapy. Plain radiograph prior to treatment (A) and after two courses of intra-arterial cisplatin (8). Note the marked reossification of the extraosseous component as well as some satellite nodules (arrow). CT prior to treatment (C) and after treatment (D). Note the marked "rimming reossification" of the soft-tissue component (arrowheads). These radiographic findings are indicative of tumor necrosis. This patient was initially deemed unresectable because of the size of the tumor and the proximity to the popliteal vessels. She underwent a successful limb-sparing procedure. Pathologic examination showed 95% tumor necrosis. (From Malawer M, Priebat D, Buch R, et al: The impact of preoperative intraarterial chemotherapy on the choice of surgical procedure (limb-sparing vs. amputation) for high grade bone sarcomas. Clin Ortbop, in press; with permission. )

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Memorial Sloan-Kettering Institute, established a four-grade system for describing the amount of viable and necrotic tumor 115 that has been correlated with disease-free survival in several studies. 114, 135 Although histologic evaluation of an entire tumor plane can provide the best estimate of tumor cell kill, it requires significant commitment from the pathologist and inadequate sampling may miss areas of viable tumor. Several variations and modifications of this system have been described and are now in use,93, 100, ll7 making it difficult to compare treatment results from different institutions.

SURGICAL MANAGEMENT OF EXTREMITY OSTEOSARCOMA Biopsy Technique The biopsy of a suspected bone tumor must be performed with care. 29, 82, 94 One of the most common causes for amputation is a poorly placed biopsy with significant local tumor contamination. It is strongly recommended that the biopsy be performed by the surgeon who will make the ultimate decision regarding the ablative procedure. Trephine or core biopsy (Fig. 9) often obtains adequate tissue for diagnosis and is preferred if a limb-sparing option exists, as it entails less local contamination than does open biopsy. 82, 94, 118 If core biopsy proves to be inadequate, a small incisional biopsy should be performed. Every precaution should be taken to avoid contamination when performing an open biopsy. If a soft-tissue component is present, there is no need to perform a biopsy on the underlying bone. Open biopsy is preferred in some centers so that sufficient material may be obtained for biologic studies, such as flow cytometry.66 Ablative Surgery. Amputation has been the standard method of ablation of the primary tumor. 72, 85 The past decade has witnessed the development of limb-sparing surgery as an alternate technique for many patients. 13, 34, 37, 83-86 Advances in orthopedics, bioengineering, radiographic imaging, and chemotherapy have contributed to safer and more reliable surgical procedures. The development of improved imaging techniques, as noted elsewhere in this article, permits accurate evaluation of the local anatomy and enhances the possibility of safe resection. At centers with appropriate surgical expertise, limb-sparing procedures may be offered as an appropriate surgical option for 50% to 80% of patients with osteosarcoma. Successful limb-sparing procedures consist of three surgical phases: 74, 75 1. Resection of Tumor. This follows strictly the principles of oncological surgery. Avoiding local recurrence is the criterion of success and the main determinant of the amount of bone and soft tissue to be removed. Most studies report less than 5% local recurrence. 103, 123 2. Skeletal Reconstruction. The average skeletal defect following adequate bone tumor resection measures 15 to 20 cm. Techniques of reconstruction vary and are independent of the resection, although the size of the resected area may make one technique preferable to another (Fig. lO). Common techniques utilize custom prostheses or allograft replacements.69. 81, 84, 92, 121

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Figure 9. Needle biopsy of the extraosseous component of a distal femoral osteosarcoma. There is no need to perform a biopsy of the underlying bone if a soft-tissue component is present (arrows).

3. Soft-tissue and Muscle Transfers. Muscle transfers are performed to cover and close the resection site and to restore motor power. Adequate skin and muscle coverage is mandatory. Soft-tissue reconstruction has dramatically decreased the local wound complication and infection rate. 78 Guidelines for Limb-sparing Resection Based on the above, the criteria and technique for limb-sparing surgery utilized by the author (MM) are summarized: 74• 80 1. No major neurovascular involvement by tumor. 2. Wide resection of the affected bone, with a normal muscle cuff in all directions. 3. En bloc removal of all previous biopsy sites and all potentially contaminated tissue. 4. Resection of bone 6 to 7 cm beyond abnormal uptake, as determined by CT/MRlbone scan. 5. Resection of the adjacent joint and capsule. 6. Adequate motor reconstruction, accomplished by regional muscle transfers. 7. Adequate soft-tissue coverage.

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Figure 10. Limb-sparing for distal the distal femur. A, intraAn intraFigure 10. Limbparing surgsurgery ry for th t mur. A, An operative photograph showing a 6-in modulargmsegmental replacement op rativ photograph howing a 6-in modular ntal r placement (Howmedica Rutherford, NJ)thof di thetaldistal femur (Howm dica Inc, Inc, Rutherford, J) of femur and and kne knee joint.jOint. The The arrow indicates a bone olidsolid arrow indicat s a bon graftgraft that that will will growgrow into into the the und underlying rlying extracortical porous surface porou surface of thof the pro prosthesis. th si . Thi This ha · has b nbeen t rmtermed d xtracortical modular prosthesis assembled the rating operating fixation. fixation. Th The modular prosth i is assis mbled in thin op roomroom and and require to 8-week in obtaining custom quir the utheualusual 4- to4-8-w k d laydelay in obtaining a trua true cu tom do does not rnot B, Postoperative radiograph the modular segmental the i . B, Postop rati e radiograph of thof modular segmental pros-prospro prosthesis. th sithesis. .

Type of Skeletal Reconstruction Large skeletal defects are reconstructed following tumor resection by several different modalities. Osteoarticular defects are most often reconstructed by segmental, custom prostheses that are fixed to the remaining intramedullary bone by polymethylmethacrylate (PMMA).6, 17,28,30,69.84 The newer knee prostheses allow some rotation as well as flexion and extension; this mobility decreases the forces on the bone-cement interface and thus lessens the risk of loosening, Within the past few years, there has been interest in combining porous coating with the prosthesis in order to obtain biological in-growth, in the hope of obtaining long-term, perhaps even permanent, fixation (see Fig, 10).48.69 Most of these devices can be custom made within several weeks, In the hope of eliminating even this delay, modular systems that can be assembled in the operating room now are being evaluated,69 Alternative methods of segmental replacement include large auto- or allografts, used to obtain an arthrodesis, or osteoarticular allografts that may replace the affected joint. 30, 81 In addition, a composite allograft (Le., allograft placed over a prosthesis) has been utilized. In general, allografts tend to have a higher infection rate (20% or higher) versus less than 5% to 7% for prosthetic replacements. 46, 71, 81. 101, 102 Relative Contraindications to Limb-sparing Surgery In general, if more than one of these following problems exist, the tumor is likely to be unresectable 74 :

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1. Major Neurovascular Involvement. 2. Pathologic Features: A fracture through a bone affected by a tumor spreads tumor cells to the hematoma and beyond accurately determined limits. The risk of local recurrence increases under such circumstances (Fig. 11). Occasionally, pathologic fractures will heal with neoadjuvant chemotherapy. 3. Inappropriate Biopsy Sites. An inappropriate or poorly planned biopsy jeopardizes local tumor control by contaminating normal tissue planes and compartments and is one of the most common indications for amputation. 4. Infection. The risk of infection following implantation of a metallic device or allograft in an infected area is prohibitive. If a biopsy site becomes infected, amputation is usually indicated.

Figure 11. Gross specimen of a femur after a pathologic fracture through a diaphyseal osteosarcoma. This patient underwent a high above-knee amputation. In general, a pathologic fracture is best treated by an amputation.

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5. Immature Skeletal Age. The predicted leg length discrepancy should not be greater than 6 to 8 cm. Upper extremity reconstruction is independent of skeletal maturity. Recent experience with expandable prostheses has made this a less serious consideration. 6. Extensive Muscle Involvement. There must be enough muscle remaining for reconstruction of a functional extremity.

LIMB-SPARING SURGERY: SPECIFIC ANATOMIC SITES AND THEIR UNIQUE CONSIDERATIONS Distal Femur

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The distal femur is the most common site for osteosarcoma. Traditional treatment has been above-knee amputation or hip disarticulation. Approximately 70% to 80% can be safely treated by a limb-sparing resection (see Fig. 10). Adequate en bloc resection requires adequate bone and soft tissue margins. 78 Biplane angiography is crucial to determine popliteal vessel involvement. Large tumors requiring removal of the entire quadriceps or hamstrings can be adequately reconstructed by an arthrodesis, although knee function is sacrificed. 33 Postoperatively, knee range of motion exercises are begun early if a prosthetic replacement was used. If an arthrodesis is performed, a long-leg cast is required until incorporation of the grafts occurs. In general, hip and ankle motion is normal. A cane and brace are routinely recommended for 3 to 6 months. Proximal Tibia The proximal tibia is the second most common anatomic site for osteosarcoma. 50 Above-knee amputation has been considered the traditional procedure of choice. Today, about two thirds of these patients can be treated successfully by resection (Fig. 12). Resection and reconstruction in this area is difficult and demands absolute attention to anatomic and surgical details. 75 It is more difficult to obtain an adequate margin of resection and a good functional result with lesions of the proximal tibia, which tend to have a higher incidence of local complications than do resections of distal femoral tumors. These problems are directly related to anatomic constraints: minimal adjacent soft tissue and the normal subcutaneous location of the medial tibial border. It is extremely important that the biopsy be small and that it avoid the knee joint. A large posterior tumor component makes resection unadvisable. Reconstruction is either by prosthetic replacement or arthrodesis. The medial gastrocnemius is routinely transferred to provide soft-tissue coverage of the reconstructed area. Proximal Humerus The shoulder is the third most common site for osteosarcoma. 50 Angiography is the most useful preoperative imaging modality. Adequate resection of the proximal humerus requires removal of the proximal humerus and shoulder joint with the deltoid, rotator cuff, and portions of the biceps and triceps muscles (Fig. 13) with provision for adequate soft-

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Figure 12. Osteosarcoma of the proximal tibia. A, Gross specimen after resection. Note the biopsy (BX) site has been removed en bloc with the tumor. The tibia-fibular joint (solid arrow) is routinely removed with the tumor. B, Intraoperative photograph showing the prosthesis. Illustration continued on opposite page

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tissue coverage. 73, 74, 76, 79 The major contraindications to local resection are tumor involvement of the neurovascular bundle, lymph nodes, chest wall, massive soft-tissue contamination, or pathologic fracture. A custom prosthesis may be used for reconstruction. Soft-tissue reconstruction and suspension are essential to avoid postoperative pain, instability, and fatigability. Hand and wrist function is normal follOwing resection. Shoulder motion is minimal, but stable, and scapulothoracic motion provides some internal and external rotation. Cosmesis is acceptable and can be enhanced with use of a shoulder pad (Fig. 13C). Pelvis and Proximal Femur Osteosarcomas of the pelvis and proximal femur are less common than those occurring at other anatomic areas, accounting for 10% and 5%, respectively, of all tumors. 50 Tumors arising from these structures are often large, involve important structures, and are difficult to resect. Hemipelvectomy is often required for pelvic tumors, whereas modified hemipelvectomy is used for tumors of the proximal femur. 72 The limb-sparing options, when feasible, are all functionally superior to amputation. 31, 32, 92 A poorly planned biopsy often contaminates the extrapelvic structures, often making a hemipelvectomy the only safe option. In general, pelvic resections and reconstruction have a high rate of local recurrence (about 20%) and high local morbidity from infection and mechanical instability. Within the past two years, a new "saddle" endoprosthesis has made reconstruction following

Figure 12 (Continued). C, Postoperative radiograph of the proximal tibial replacement. (From Malawer MM, McHale KC: Limbsparing surgery for high grade tumors of the proximal tibia: Surgical technique and a new method of extensor mechanism reconstruction. Clin Orthop 237:68-85, 1988; with permission.)

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Figure 13. Proximal humeral Figure 13. Proximal humeral osteosarcoma. A, Gross specimen osteosarcoma. A, Gross specimen after resection. Approximately after resection. Approximately 6 6 inches of the proximal humerus inches of the proximal humerus was resected en bloc with the was resected en bloc with the glenohumeral joint. B, Plain radioglenohumeral joint. B, Plain radiograph demonstrating a modular graph demonstrating a modular segmental prosthesis. C, Clinical segmental prosthesis. C, Clinical photograph 2 months after surgery. photograph 2 months after surgery. There is a stable shoulder girdle There is a stable shoulder girdle with almost normal function of the with almost normal function of the elbow and hand. No external orelbow and hand. No external orthosis was required. (From Mathosis was required. (From Malawer MM, Meller I: A new surlawer MM, Meller I: A new surgical classification system for gical classification system for shoulder girdle resections: Analysis shoulder girdle resections: Analysis of 38 patients. Clin Orthop, in of 38 patients. Clin Orthop, in press; with permission.) press; with permission. )

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pelvic resection more feasible with a good functional result. This prosthesis permits simple and reliable reconstruction of the hips and pelvis. Approximately 15 such procedures have been performed in the United States.

GENERAL CONSIDERATIONS OF LIMB-SPARING SURGERY VERSUS AMPUTATION IN THE TREATMENT OF OSTEOSARCOMA Limb-sparing surgery is now considered by many the preferred treatment for a significant number of patients with osteosarcoma. 5, 6,13,34,37,57,77, 83-86 Amputations are reserved principally for patients in whom the primary tumor is deemed unresectable. Extensive experience and data have been obtained withih the past 5 years regarding the crucial factors in the decision to perform a limb-sparing procedure or an amputation. The major considerations and goals to be met in choosing a limb-salvage procedure can be summarized as follows. 74 1. Local Recurrence. The chance of local recurrence should not be higher than that associated with amputation. 2. Survival. Overall survival should not be jeopardized, either due to treatment delay or an ineffective (adjuvant) treatment program. 3. Functional Outcome. The means of reconstruction should be functional, with minimal long-term morbidity and need for additional surgery. The psychological impact and duration of rehabilitation must be considered.30, 32, 92 Several recent studies have shown that the risk (less than 5%) oflocal recurrence in patients who have undergone limb-sparing surgery is about the same as in those treated by amputation. 28, 95, 101, 124 These are carefully selected patients, however, and the procedures have been performed in institutions whose staff is familiar with the techniques. Similarly, the reported continuous disease-free survival rate appears to be similar to that of patients undergoing amputation. 28, 80, 95, 101 If the criteria for patient selection are met, despite the variations among institutions, limb-salvage appears to be a safe procedure. Eilber et al,28 from UCLA, reported 64 of 83 consecutive patients with malignant skeletal tumors who were treated by a limb-sparing resection, with no difference in overall survival compared to those treated by amputation. The overall local recurrence rate was 2.7%. The functional advantages of limb-sparing surgery merit careful consideration. Preservation of the upper humerus following resection of a proximal humeral sarcoma, for example, leaves a normal hand and elbow that are far superior to any prosthesis. Except for lack of shoulder motion, function is essentially normal. The advantage of such a procedure over forequarter amputation is obvious. Similarly, the functional advantages after successful preservation of the lower extremity following proximal femoral resection or pelvic resection are superior to a hemipelvectomy. The outcome of limbsparing procedures about the knee continues to generate controversy. EnnekingJ° has reported that resections followed by reconstruction by several different modalities at this site had a higher functional rating than

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an amputation in a multi-institutional study utilizing a standard evaluation scheme. No prospective comparative study has been completed, however, and at most centers, patients undergoing limb-sparing procedures are carefully selected. The psychologic adjustment appears to be similar in patients undergoing amputation or limb-sparing surgery. 132 Ultimately, the best procedure for each patient must be based on the individual clinical situation, the surgical expertise, the availability of good prosthetic care, and the motivation of the patient. CURRENT STATUS OF THERAPEUTIC TRIALS FOR OSTEOSARCOMA High-dose methotrexate, cisplatin, and doxorubicin are the most effective agents for the adjuvant and neoadjuvant therapy of osteosarcoma. Several protocols have used bleomycin, cyclophosphamide, and dactinomycin in combination with these agents. 96 Table 1 summarizes recent clinical trials for patients with osteosarcoma. Although randomized trials have failed to demonstrate improved treatment results using high-dose methotrexate with leucovorin rescue compared with use of lower doses,2, 60 and a solid rationale for such use continues to Table 1. Recent Adjuvant and Neoadjuvant Osteosarcoma Trials

AGENTS

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35.5 72 47

HDMTX, BCD ..... CDP, Dox versus CDP, Dox, HDMTX ..... CDP, Ifos, BCD

125

24

24

66

17 (no CMT) 77 (at 2 yr) 64 52 (58% HDMTX) (42% Mod MTX) 58

Goorin et al45 Eilber et al·7 Link et al64 Weiner et al '33 Ettinger et al36 Bacci et al5

Winkler et al'34

Abbreviations: BCD = bleomycin, cyclophosphamide, dactinomycin, CDP = cisplatin, chemo = chemotherapy, Cyclo = cyclophosphamide, Dox = doxorubicin, HDMTX = highdose methotexate, Ifos = ifosfamide, MDMTX = moderate dose MTX, RT = radiotherapy, VCR = vincristine.

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be questioned, 58 most centers include high doses of this agent in frontline therapy. Careful attention to hydration and alkalinization of urine are important for the safe administration of high-dose methotrexate; the monitoring of methotrexate plasma levels is essential. It is important to recognize that other antineoplastic drugs, such as cisplatin, can affect renal function and cause delays in methotrexate excretion. 22 Doxorubicin (Adriamycin) is used in virtually all protocols, even though cardiotoxicity continues to be a major concern. Despite limitations on cumulative dosage (450 mg/m 2 or less) and close monitoring of cardiac function during therapy, survivors of osteosarcoma treated with doxorubicin still have a risk of cardiac damage. 43 , 119 Cisplatin also has become a component of most frontline protocols. Its use carries a risk of renal toxicity and ototoxicity, which is dose related. Other agents used in the treatment of osteosarcoma, such as ifosfamide, may also increase the risk of ototoxicity. 91 Some investigators have advocated the intra-arterial administration of cisplatin, 54 because this approach appears to result in high rates of local tumor necrosis and affords an opportunity for limb-sparing procedures in many patients. However, this apparent increase in local tumor cell kill has not resulted in decreased rates of metastases or higher cure rates. 54, 55, 71 The combination of bleomycin, cyclophosphamide, and dactinomycin (BCD), as initially reported by Mosende et al,96 has been included in several protocols in attempts to duplicate promising results of clinical trials at the Memorial Sloan-Kettering Institute. 100, 135 However, no randomized trials support the inclusion of BCD in frontline therapy; other investigators have not seen responses to BCD,I08 and the inclusion of these three agents in combination with other antineoplastic drugs increases toxicity appreciably. The development of effective chemotherapy provided impetus to the development of limb-sparing surgery. Today, many surgeons intuitively feel that neoadjuvant chemotherapy permits limb-sparing surgery to be performed more safely, i.e., with a lower local recurrence rate. Eilber et al28 reported an encouraging low rate of local recurrence (5/183) and concluded that this was due to multidisciplinary therapy including preoperative chemotherapy that destroys microscopic disease at the periphery of the primary tumor. However, neoadjuvant therapy has no proven effect on the disease-free survival of patients with osteosarcoma. Because all preoperative chemotherapeutic agents entail the risk of increased local morbidity, skin breakdown, infection, and possible tumor progression with the possibility of losing a nonamputative surgical option, additional studies are needed to determine the value of preoperative chemotherapy in increasing the number of cases of osteosarcomas that can be effectively treated with limb-sparing procedures and chemotherapy. The value of neoadjuvant therapy is presently being tested in a randomized study by the Pediatric Oncology Group. With modern adjuvant or neoadjuvant therapy about two thirds of patients with resectable primary tumors without clinically evident metastatic disease at diagnosis will be cured. Those patients with metastatic disease at diagnosis fare poorly, although some of them may be salvaged with

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intensive chemotherapy and surgical resection of the primary tumor and metastatic deposits. The lungs continue to be the most common site of metastatic disease. Up to one third of these patients may ultimately be cured by resection of pulmonary metastases. 44, 90 The use of chemotherapy after removal of metastatic disease continues to be controversial. Survival after thoracotomy without institution of further chemotherapy appears to be equivalent to published survival rates in series treated with additional chemotherapy. 90

FUTURE DIRECTIONS Further improvement in the cure rate of osteosarcoma will likely depend on the introduction of new effective therapeutic agents. Ifosfamide, an analogue of cyclophosphamide first synthesized in the 1950s, is the only compound evaluated since the introduction of cisplatin to show significant activity against osteosarcoma. However, until MESNA was shown to prevent the urotoxicity of ifosfamide, there were no serious attempts to investigate the clinical activity of this agent. Initially, European investigators suggested that ifosfamide had activity against osteosarcoma in some patients who had relapsed after intensive multiagent therapy. 23. 39, 87 More recently, Pratt et al at St. Jude 107, 109 demonstrated that about a quarter of previously treated patients respond to ifosfamide. A major problem in assessing the clinical efficacy of new agents for osteosarcoma is finding patients whose prior treatment does not preclude an objective evaluation. An attractive option is to test the agents before ablative surgery (i. e., so-called "phase II window"). At The Children's National Medical Center (Washington, DC), this approach relies on intraarterial therapy to maximize the early response to therapy and thus improve the opportunity for limb-sparing. Presumably, this approach allows a higher cytotoxic concentration of chemotherapy to be directed to the primary tumor (Le., a higher local drug concentration) and potentially improves penetration of drug across the tumor cell membrane (Fig. 14). Doxorubicin and cisplatin are the two most common drugs evaluated using this technique. Malawer et aPO reported that 9 of 12 patients with unresectable extremity osteosarcomas were rendered resectable without amputation using this approach (see Fig. 8). In addition, no patient deemed initially resectable progressed during the preoperative (intra-arterial) phase of treatment. It is important to understand, however, that no study has attempted to directly compare the effectiveness of intravenous to intraarterial administration. Thus, it is uncertain whether or not intra-arterial chemotherapy results in a higher limb-sparing rate for extremity sarcomas. No difference in overall survival has been demonstrated using this approach.70, 71 At St. Jude Children's Research Hospital, the phase II window has been used since 1986 to explore the actual level of activity of ifosfamide given as a single agent in patients with previously untreated tumors. The risk is that tumors may be intrinsically resistant to this single-agent therapy and may progress during the initial treatment phase. Hence, the study was

f' 341

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w.---\-- Presumed microscopic pulmonary metastases

Intra-arterial catheter Femoral Vein & Artery -f----+~:1

Presumed microscopic skip tumor nodules (local metastases)

Figure 14. Postulated mechanisms of intra-arterial (regional) chemotherapy. (From Malawer M, Priebat D, Buch R, et al: The impact of preoperative intraarterial chemotherapy on the choice of surgical procedure (limb-sparing vs. amputation) for high grade bone sarcomas. Clin Orthop, in press; with permission.)

designed and monitored to ensure an acceptable rate of progressive disease that would not compromise disease-free survival (the ultimate endpoint for patients with cancer). Although the data are still preliminary, about one half of previously untreated tumors have responded to ifosfamide,89 a rate potentially superior to that reported for high-dose methotrexate and doxorubicin in early phase II trials, which were performed in patients who generally had not been exposed to a significant amount of therapy. All patients in the St. Jude trial continue to receive ifosfamide as part of a multiagent schedule unless the tumor progresses during the phase II window evaluation. The rate of disease progression in patients treated with ifosfamide alone is acceptable. More importantly, the probability of diseasefree survival for patients with progressive disease after ifosfamide treatment is identical to that of patients with stable disease or responses to ifosfamide; 81 % (SE 9%) at a median follow-up of 24 months. 89 More recently, Miser et al93 initiated a trial of ifosfamide in combination with doxorubicin and high-dose methotrexate as primary therapy. Of the first 19 patients enrolled in this study, 15 had greater than 90% necrosis by histopathologic examination of the resected tumor. Whether the addition of ifosfamide to other active agents will improve disease-free survival for patients with osteosarcoma is a question that is most appropriately answered in a randomized study by a multi-institutional cooperative group.

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No other new agents have shown substantial activity in clinical trials. The immunostimulatory compound, muramyl tripeptide phosphatidylethanolamine (MTP-PE), has shown promising activity in preclinical studies, 59 has prevented the development of pulmonary metastases in a canine osteosarcoma model,67 and has an acceptable toxicity profile in early human trials. 97 Classic phase II trials of MTP-PE would not be rational, because this type of therapy is most likely to be effective for micrometastatic disease.

SUMMARY Osteosarcoma is the most common neoplasm of bone in children and adolescents. The first effective therapy became available in the early 1970s, and although controversy existed for several years regarding the relative value of aggressive multiagent chemotherapy, presently about 60% of patients with resectable primary tumors and no metastases at diagnosis will be cured. New imaging methods, including computerized tomography, magnetic resonance imaging, and radionuclide techniques, that are sensitive to changes in local tumor perfusion have improved the ability to define the extent of tumor and the response to chemotherapy, and to plan surgery. Although amputation historically has been the primary method for local tumor control, newer surgical techniques and endoprosthetic devices, coupled with effective preoperative chemotherapy, have offered less radical surgery for 50% to 80% of patients with osteosarcoma. New therapeutic agents, including ifosfamide and the immunosuppressive drug, muramyl tripeptide phosphatidylethanolamine, hold promise for improvement in the cure rate of osteosarcoma.

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