High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study.

BACKGROUND: Patients with metastatic osteosarcoma at diagnosis or axial primary tumors have a poor prognosis. The aim of the study was to evaluate the feasibility and efficacy of intensified treatment with high-dose chemotherapy (HDCT) and stem cell rescue in this group. METHODS: From May 1996 to August 2004, 71 patients were included in a Scandinavian-Italian single arm phase II study. Preoperative chemotherapy included methotrexate, doxorubicin, cisplatin and ifosfamide, and postoperative treatment consisted of two cycles of doxorubicin, one cycle of cyclophosphamide and etoposide and two courses of high-dose etoposide and carboplatin with stem cell rescue. RESULTS: Twenty-nine patients (43%) received two courses and 10 patients (15%) received one course of HDCT. HDCT was associated with significant toxicity, but no treatment-related deaths were recorded. Fourteen patients (20%) had disease progression before completion of the study protocol, and only 29/71 patients (41%) received the full planned treatment. Median event-free survival (EFS) was 18 months, and estimated 5-year EFS was 27%. Median overall survival (OS) was 34 months, and estimated 5-year OS was 31%. When patients who did not receive HDCT due to disease progression were excluded, there was no difference in EFS (P = 0.72) or OS (P = 0.49) between patients who did or did not receive HDCT. CONCLUSIONS: The administration of high-dose chemotherapy with stem cell rescue was feasible, but associated with significant toxicity. Patient outcome seemed comparable to previous studies using conventional chemotherapy. We conclude that HDCT with carboplatin and etoposide should not be further explored as a treatment strategy in high-risk osteosarcoma.

Langerhans cell histiocytosis: 40 years' experience.

OBJECTIVES: Our study analyzes 40 years' experience with pediatric Langerhans cell histiocytosis patients. MATERIALS AND METHODS: Between June 1968 and December 2009, 121 patients (79 males, 42 females; median age 4.13 y) were diagnosed at our center (74% monosystemic disease; 26% multisystemic), treated according to current protocols. We evaluated the response, the survival, and the neuroendocrinological sequelae. RESULTS: Overall survival (OS) for all patients was 93% at 10 years from diagnosis, event-free survival (EFS) 77%. OS for patients younger than 2 years and older than or equal to 2 years was 82% and 97% (P = 0.003); EFS 48% and 87% (P = 0.001). OS for patients diagnosed before and after April 1, 1991 was 84% and 98% (P = 0.007), EFS 66% and 85% (P = 0.03). OS for monosystemic and multisystemic disease was 100% and 71% (P < 0.001); EFS 88% and 45% (P < 0.001). OS for "risk" patients (involvement of bone marrow, spleen, liver, lungs) and "low-risk" patients was 50% and 94% (P = 0.007), EFS 37% and 54% (P = 0.06). Fourteen patients developed diabetes insipidus, 7 patients growth hormone deficiency, 2 hypothyroidism, and 1 neurodegeneration. CONCLUSIONS: Our study confirms improvement of pathogenetic knowledge and treatment over the last 20 years. Age at diagnosis older than or equal to 2 years and standardized treatment are associated with improved prognoses. Multisystemic involvement, especially with "risk" organs seem to be correlated to a worse outcome.

Nonossifying fibroma: A possible pitfall in F18-FD-PET/CT imaging of Hodgkin's disease.

A 14-year-old girl was examined for a right lateral neck swelling and radiographic mediastinal widening. Biopsy of a right supraclavicular lymph node demonstrated the nodular sclerosing form of Hodgkin's lymphoma. An 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (F18-FDG-PET/CT) study showed several pathological areas of lymph-node uptake in the upper mediastum and right distal tibia. Radiography of the tibia revealed a nonossifying fibroma in the site corresponding to the distal tibial uptake. The PET appearance of benign fibro-osseous lesions may be similar to those of skeletal metastases. Information obtained by the CT component of the PET/CT study and by conventional radiography can be useful in preventing erroneous interpretations of F18-FDG-PET uptake.

Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis.

Cytokines and chemokines determine mobilisation of Langerhans cells and their dysregulation is implicated in the pathogenesis of Langerhans cell histiocytosis (LCH). Twenty point mutations of 12 different cytokine genes were studied in 41 Italian children, 15 with single-system (SS) and 26 with multi-system disease. The allele and genotype distributions of interleukin-4 (IL-4) and interferon-gamma (IFNgamma) were significantly different in patients vs. 140 controls (P = 0.007, and P = 0.018). Older children with single-system disease shared the 'anti-inflammatory profile' determined by the intermediate producer genotype IFNgamma +874A/T (P = 0.029) and the high-producer genotypes IL-4 -590C/T and T/T (P = 0.029). Our findings suggest that specific cytokine gene variants affect susceptibility to LCH and its clinical heterogeneity.

Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.

PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 40 years of age with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. RESULTS: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.

Long-term survival in high-grade axial osteosarcoma with bone and lung metastases treated with chemotherapy only.

A boy, age 2 years 10 months, with high-grade malignant osteosarcoma of the fifth lumbar vertebra with secondary bilateral pulmonary lesions and bone metastasis at the fifth thoracic vertebra is described. The primary site of disease was inoperable and the patient was treated with chemotherapy only. At present, 83 months from diagnosis and 64 from the end of therapy, he is in very good general condition. Although a surgical approach on the primary and secondary sites is fundamental, this case may be considered an indication of the efficacy of aggressive chemotherapy in treating osteosarcoma.

Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival.

PURPOSE: To identify factors that influence postrelapse survival (PRS) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: One hundred sixty-two patients with recurrent osteosarcoma of the extremity were retrospectively reviewed. The first-line treatment included surgery of the primary lesion and chemotherapy with methotrexate, doxorubicin, cisplatin, and ifosfamide. RESULTS: The projected 5-year PRS rate was 28%. Patients who had complete surgery of recurrence had a 5-year PRS of 39%, whereas for those who did not have complete surgery, PRS was 0% at 3 years (P <.0001). In the latter group, PRS was not influenced by site of recurrence and relapse-free interval (RFI), although it was influenced (P =.006) by the use of second-line chemotherapy (PRS, 53% at 12 months for patients who received chemotherapy v 12% for those who did not). In patients who had complete surgery, PRS was influenced by site of relapse (5-year PRS, lung 44%, other 19%; P <.06), RFI (5-year PRS at < or = 24 months, 20%; at > 24 months, 60%; P <.0001), and number of lung metastases (5-year PRS, two or fewer nodules, 59%; more than two nodules, 14%; P <.0001) but not by the use of a second-line chemotherapy treatment. CONCLUSION: RFI, site of metastases, and number of pulmonary nodules are the main prognostic factors for PRS in osteosarcoma. Complete surgery of recurrence is pivotal in the strategy of treatment. Patients with unresectable recurrence benefit from second-line chemotherapy, whereas our data do not support a generalized use of chemotherapy after complete surgery of first recurrence.