Current Combined Treatment of High-Grade Osteosarcomas
Current Combined Treatment of High-Grade Osteosarcomas
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.
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.
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 . In addition, among patients who experience a relapse, disease-free survival is significantly shorter in those with increased initial serum alkaline phosphatase concentration . 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 . 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. Bone scintigraphy defines the systemic extent of osseous disease, not only in terms of metastases but also in terms of multifocality .
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  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  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 .
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 :
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 . A major problem with currently available retrospective data is the gross difference in percentages of patients undergoing amputation between the adjuvant and neoadjuvant groups .
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% .
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 . 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  has reproduced the earlier success reported by Rosen . 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 . However, the addition of postoperative ifosfamide and etoposide (VePesid) may play a role in improving the prognosis of poor responders .
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  showed 52% 4-year actuarial survival among less than good responders without a change to salvage chemotherapy . 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 . 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) . Similarly, the German studies  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 .
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 . 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 . 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) . 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 . 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 . 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].