Ifosfamide in the Neoadjuvant Treatment of Osteogenic Sarcoma

Osteogenic sarcoma is the most common primary tumor of bone, with an approximate incidence of three per million. There are two peaks of incidence: one during adolescence, and a later peak in the eighth decade. Despite what can be considered adequate therapy, adults fare worse than children. Nonetheless, the treatment of osteosarcoma represents one of the genuine success stories in oncology. Limb-sparing surgery minimizes the need for physically and psychologically scarring amputations, and newer generations of implants account for bone growth, because these tumors are most common in adolescence. Chemotherapy, administered in both the neoadjuvant and adjuvant settings, has improved the cure rate for osteosarcoma from 5% to 20% in the prechemotherapy era to the 60% to 70% range. On the basis of single-arm phase II studies, single agents and combinations of systemic therapeutics have demonstrated the activity of methotrexate, doxorubicin, and cisplatin (MAP) in metastatic osteosarcoma, leading to two seminal randomized studies confirming the activity of adjuvant chemotherapy. This three-drug combination represents a standard of care for osteogenic sarcoma therapy in the United States. No randomized studies have examined the role of doxorubicin in adjuvant therapy, and randomized studies of cisplatin have been performed based only on patient response to other therapy. However, a methotrexate-free alkylating agent– intensive regimen yielded survival results similar to those of MAP in a single-arm phase II study, and two randomized multicenter clinical trials demonstrated that regimens without methotrexate resulted in overall survival (OS) rates no different than those of more complex combinations containing methotrexate. A separate study examining highversus intermediate-dose methotrexate in the adjuvant setting favored high-dose methotrexate. Criticisms of the negative randomized studies include low dose-intensity and lack of adjustment of methotrexate levels in the experimental arms. Early studies of primary and metastatic osteosarcoma gave rise to other key clinical observations: one, the degree of necrosis observed with neoadjuvantchemotherapypredicts foroverall survival,withaminimum of 90% to 95% tumor necrosis defining a good response; and two, resection of isolated lung metastatic disease may be curative, whereas multifocal disease to bone is generally not curable. Caveats to each observation exist. For example, chondroblastic osteogenic sarcoma may not respond as well to chemotherapy as osteoblastic osteosarcoma, but the poorer response does not portend poorer prognosis; isolated bone metastatic lesions may be resected with curative intent. Dose-intensification and the addition of newer agents have been examined in a variety of single-arm phase II studies, which are inherently difficult to compare. Nonetheless, well-conducted phase III studies performed in pediatric and expert adult sarcoma centers have provided oncologists with strong foundations on which to make clinical decisions. It is in this light that Ferrari et al applied the experience with ifosfamide in the recurrent setting to primary disease. Ifosfamide, in phase I to II combination studies with other agents, has significant activity in recurrent or metastatic osteosarcoma. Thus, it was anticipated that ifosfamide would be useful in primary disease. Supportive data for the adjuvant use of ifosfamide have come from the Istituto Ortopedici Rizzoli, where the authors conducted the present study, and elsewhere. In a study accruing patients with suboptimal necrosis of tumor after neoadjuvant therapy, ifosfamide and etoposide were added to MAP therapy, which had been administered preoperatively. This cohort of high-risk patients had a 56% event-free survival (EFS) rate, which was heartening enough to move ifosfamide into the neoadjuvant setting. In the article that accompanies this editorial, Ferrari et al describe the results of their randomized study of 246 patients with osteosarcoma, younger than age 40 years, who were treated between 2001 and 2006 with neoadjuvant MAP chemotherapy with or without ifosfamide. After surgery, treatment was stratified but not randomized. Patients receiving ifosfamide before surgery continued with it to complete adjuvant treatment, whereas those patients receiving MAP alone received ifosfamide only if they had suboptimal tumor necrosis ( 90%) at time of surgery. The experimental arm demonstrated more hematologic toxicity, as anticipated. However, with a 66-month medianfollow-up, therewasnostatisticallysignificantdifferencebetween the standard and experimental arms in the proportions of patients with at least 90% tumor necrosis (48% v 42%), in EFS (64% v 55%), or in 5-year OS (73% v 74%), the primary end point of the study. The principal conclusion was that ifosfamide did not improve the degree of tumor necrosis significantly and thus was not recommended as part of neoadjuvant chemotherapy. The present study highlights results of the adjuvant osteogenic sarcoma study from the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG), which was conducted between 1993 and 1997 with 777 eligible patients, 662 without metastases. The CCG/ POG study was hampered in data collection, because the primary end JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 17 JUNE 1