Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group.

BACKGROUND: The outcome for patients with Ewing sarcoma family of tumors (ESFTs) of bone with metastases at diagnosis remains poor despite new approaches to treatment. We evaluated whether a dose-intensity chemotherapy regimen improved survival for patients with ESFTs of bone with metastases at diagnosis. METHODS: We entered 60 patients with metastatic ESFTs of bone onto a single arm trial of a new intensive therapy. Treatment consisted of 51-weeks of chemotherapy and local control of the primary with radiation, surgery, or both. The chemotherapeutic protocol included two alternating blocks: one with vincristine (2 mg/m(2)), doxorubicin (90 mg/m(2)), and cyclophosphamide (2,200 mg/m(2)); and the second with ifosfamide (2,800 mg/m(2)/day x 5 days) and etoposide (100 mg/m(2)/day x 5 days). RESULTS: Of the 60 patients with metastatic ESFTs of bone enrolled onto this single arm trial, 12 had metastasis to lung only, 7 to bone marrow or bone only, 38 to multiple sites, 2 in other sites and 3 not specified. There were three toxic deaths. Six patients (6-year cumulative incidence: 9%) developed second malignant neoplasms and died. The 6-year overall event-free survival (EFS) was 28% (standard error (SE) 6%) and survival (S) was 29% (SE 6%). CONCLUSION: An intensified treatment regimen using higher doses of cyclophosphamide, ifosfamide, and doxorubicin increased toxicity and risk of second malignancy without improving EFS and S.

Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study.

PURPOSE: One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes. METHODS: Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days. RESULTS: Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms. CONCLUSION: Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.

Long-term results of segmental prosthesis fixation by extracortical bone-bridging and ingrowth.

BACKGROUND: The technique of extracortical bone-bridging and ingrowth fixation with a porous coating over the shoulder region of the implant and augmentation by autogenous bone-grafting was introduced to improve the longevity of implant fixation. The potential advantages of this technique are that new-bone formation across the bone-prosthesis junction may share stress and may prevent osteolysis by sealing off this critical region against the infiltration of wear particles. The objectives of this study were to examine the prevalence of stem-loosening with use of the extracortical bone-bridging and ingrowth technique, the amount of bone formation over the porous-coated region of this prosthesis, and the characteristics of bone formation over the porous-coated region and adjacent bone. METHODS: Forty-three patients who had prosthetic reconstruction with the extracortical bone-bridging and ingrowth technique from 1976 to 1990 were included in this retrospective study. The mean length of follow-up was 9.7 years (range, two to twenty-one years). All but one patient were managed with autogenous bone graft; five, with allograft and autograft; and one, with allograft only. Extracortical bone formation was measured over a 2-cm length of the porous-coated region of the prosthesis in four zones (the medial and lateral aspects on anteroposterior radiographs and the anterior and posterior aspects on lateral radiographs) and was reported as the percentage of the total length (8 cm) covered by extracortical bone with a thickness of >1 mm. The Spearman rank coefficient was used to assess the correlation between pairs of continuous variables. RESULTS: The final average percentage of the porous-coated region that was covered by extracortical bone formation was 76% +/- 34% for all patients and anatomical sites of reconstruction. Use of bone cement was associated with less bone formation (p = 0.04), and this value remained lower at the final measurement (p = 0.06). One stem had aseptic loosening, but no sign of osteolysis was found. The radiographic appearance of the bone formation had stabilized at two years of follow-up. All patients with allograft augmentation had greater bone formation. The amount of extracortical bone formation did not differ in relation to the type of porous coating, anatomical sites, pathological disorder, sex or age of the patient, or length of reconstruction. CONCLUSIONS: As shown by the low prevalence of stem-loosening (two of fifty-six stems or one of forty-three patients), the use of the extracortical bone-bridging and ingrowth fixation technique is associated with improved stem fixation in segmental bone-replacement prostheses applied for limb salvage. In the demanding biomechanical environment and with the risk of stress and particle-related bone resorption, the extracortical bone-bridging and ingrowth fixation is an attractive method to provide long-lasting implant fixation.

Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone.

BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease. METHODS: Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. RESULTS: A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01). CONCLUSIONS: The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.

Vertebra plana caused by primary Ewing sarcoma: case report and review of the literature.

A 7-year-old boy presented with vertebra plana of T11. The presumptive diagnosis suggested by clinical presentation, conventional radiographs, and computed tomographic scans was eosinophilic granuloma. Progressive neurologic symptoms required surgical excision of the lesion and decompression. Histopathologic examination of the surgical specimen confirmed the diagnosis of Ewing sarcoma.

Etiology of osteosarcoma.

Although the prognosis and quality of life of patients with osteosarcoma were improved significantly during the past decades, the pathogenesis and etiology of this disease remain obscure. Significant interest and effort in this cancer led to the identification of numerous etiologic agents. Several chemical agents such as beryllium, viruses such as FBJ, subsequently found to contain the src-oncogene, and radiation were shown to be potent inducers of osteosarcoma. Paget's disease, electrical burn, or trauma all are thought to be other factors that may contribute to the pathogenesis. More recently, patients with hereditary diseases such as Rothmund-Thomson syndrome, Bloom syndrome, and Li-Fraumeni syndrome were found to have an increased risk of having osteosarcoma develop. During the past few years, the molecular analysis brought a wealth of new information with numerous genes that were associated with osteosarcoma and its clinical disease progression. They can be categorized into self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue evasion and metastasis. Although the understanding of these processes in osteosarcoma still is incomplete, it may have the potential to significantly affect the patient care in the future.

Chemotherapy, irradiation, and surgery for function-preserving therapy of primary extremity soft tissue sarcomas: initial treatment with ifosfamide, mitomycin, doxorubicin, and cisplatin plus granulocyte macrophage-colony-stimulating factor.

BACKGROUND: Most institutional teams utilize multimodality therapy in their efforts to cure patients with primary high-grade extremity soft tissue sarcomas, although the value of adjuvant systemic chemotherapy is still disputed by some oncologists. This single-institution Phase II study describes an effort to control metastasis by the use of two cycles of chemotherapy as the initial preoperative treatment. METHODS: Between March 1994 and October 1997, 20 women and 19 men with primary extremity or limb girdle high-grade soft tissue sarcomas were registered to a study of preoperative ifosfamide, mitomycin, doxorubicin, cisplatin (IMAP) plus granulocyte macrophage-colony-stimulating factor (GM-CSF) followed by preoperative irradiation and subsequent limb-sparing surgery. The two sequential monthly cycles of IMAP involved intravenous ifosfamide, 2500 mg/m(2), and mesna, 2500 mg/m(2), on Day 0, followed by identical doses of these agents plus intravenous mitomycin, 4 mg/m(2), doxorubicin, 40 mg/m(2), and cisplatin, 60 mg/m(2), on Day 1. Sargramostim (GM-CSF) 250 microg/m(2) was given subcutaneously every 12 hours for 4 days beginning 6 days before the chemotherapy, and then for 14 more days beginning the day after chemotherapy was completed. At the beginning of the third month, external beam irradiation was administered daily, 5 days each week for 5 consecutive weeks to total preoperative doses of 4500 centigrays (cGy). This was accompanied by reduced doses of MAP chemotherapy (mitomycin, 6 mg/m(2), doxorubicin, 30 mg/m(2), and cisplatin, 45 mg/m(2)) intravenously on Days 0, 21, and 42 of the radiation therapy segment. Approximately 1 month after preoperative irradiation ended, each patient had complete surgical excision with curative intent, using limb-sparing techniques when possible. Radiation to total doses of 5500-6500 cGy was accomplished by delivery of an additional 1000-2000 cGy to the tumor bed via intraoperative electron beam, brachytherapy, or external beam irradiation at the completion of surgery. RESULTS: All except 5 patients had tumors at least 5 cm in diameter. Chemotherapy toxicity grade three or higher consisted primarily of vomiting (23%), leukopenia (54%), and thrombocytopenia (77%). Six patients have died of metastatic sarcoma, and one other died in a motorcycle accident. Kaplan-Meier curves indicate estimated 5-year survival of approximately 80% and freedom from metastasis at 2 years of approximately 85%. CONCLUSIONS: IMAP plus GM-CSF is satisfactory as initial treatment for primary extremity soft tissue sarcomas in two monthly cycles preceding irradiation. The prescribed irradiation was generally tolerable and effective in permitting limb-sparing surgery. Although the outcome of patients treated on this regimen has been favorable, the metastasis problem has not been eliminated.