Marco Manfrini

Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli.

PURPOSE The identification of prognostic factors in patients with nonmetastatic Ewings sarcoma could allow the use of risk-adapted therapeutic strategies of treatment. PATIENTS AND METHODS Data on 359 patients with nonmetastatic Ewings sarcoma of bone treated at a single institution between January 1979 and April 1995 were retrospectively considered. The influence of clinical, hematologic, therapeutic, and histologic parameters on event-free survival was assessed. RESULTS By univariate analysis, the following features were found to be associated with a poor prognosis: male sex (P <.02), age older than 12 years (P <.006), fever (P <.0001), anemia (P <.0025), high serum lactate dehydrogenase (LDH) level (P <.0001), axial location (P <.04), radiation therapy only for local control (P <.009), type of chemotherapy regimen (P <.0001), and poor chemotherapy-induced necrosis (P <.001). After multivariate analysis, the adverse independent prognostic factors were male sex (P <.04), age older than 12 years (P <.001), fever (P <.0002), anemia (P <.02), high serum LDH level (P <.0003), axial location (P <.02), and type of chemotherapy regimen (P <.0003). When the multivariate analysis was restricted to surgically treated patients, the adverse independent prognostic factors were poor chemotherapy-induced necrosis (P <.0001), fever (P <.015), anemia (P <.02), and high serum LDH level (P <.025). CONCLUSION The prognosis in cases of nonmetastatic Ewings sarcoma is influenced by many different clinical and hematologic variables, all of which are to be considered when patients are being stratified according to the risk of relapse. In surgically treated patients, the most important prognostic factor is chemotherapy-induced necrosis.

Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin

Between March 1983 and June 1986 127 patients with localized osteosarcoma of the extremity were treated with neoadjuvant chemotherapy. Preoperative chemotherapy consisted of two cycles of methotrexate (MTX) (high or moderate doses) followed by 6 days by cisplatin (CDP). Surgery was an amputation or a rotation plasty, or a limb salvage. Necrosis was good in 52% of cases, fair in 36%, and poor in 12%. Postoperative chemotherapy consisted of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor responders; and ADM, MTX, and CDP for fair responders. Good responders were treated as fair responders or with only MTX and CDP. At a 47‐month follow‐up, 66 patients remained continuously disease free and 61 patients developed metastases. Six of these patients had also a local recurrence. According to the grade of necrosis, the cumulative disease‐free probability at 5 years was 67% for good responders, 42% for fair responders, and for poor responders 10% at 45 months. According to the doses of MTX, survival at 5 years was 58% for patients who received high doses and 42% for patients treated with moderate doses. No differences in the rate of survivors were observed between amputated patients and patients treated with limb salvage. The authors conclude that (1) a limb salvage procedure is possible in about 70% of cases and as safe as demolitive surgery, if adequate surgical margins are achieved; (2) good responders have a better prognosis than fair and poor responders if postoperative chemotherapy is sufficiently prolonged and also includes ADM; (3) a different postoperative chemotherapy for poor responders did not improve their prognosis; and (4) a multidrug regimen using high doses of MTX is probably more effective than moderate doses.

Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.

PURPOSE This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewings sarcoma. PATIENTS AND METHODS The response to chemotherapy was evaluated from the specimens of 118 Ewings sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.

Long‐term results in 144 localized Ewing's sarcoma patients treated with combined therapy

The results of 144 previously untreated cases of primary Ewings sarcoma of bone are reported with a minimum follow‐up of 5 years. This series was treated between 1972 and 1982 at Istituto Ortopedico Rizzoli with a combined therapy. The local control of the disease consisted of amputation (ten cases), resection followed by radiation therapy (35‐45 Gy) (48 cases) and radiation therapy alone (40‐60 Gy) (86 cases). Adjuvant chemotherapy, rigorously standardized, was performed according two different protocols: the first (85 cases treated in the period 1972–1978) consisted of vincristine (VCR) Adriamycin (doxorubicin) (ADM), and cyclophosphamide (EDX); the second (59 cases treated in the period 1979‐1982) of VCR, ADM, EDX and dactinomycin (DACT). At a follow‐up of 5 to 16 years (median, 9), 59 patients (41%) are continuously disease‐free (CDF), 81 (56%) developed metastatic disease and/or local recurrence, and four (3%) had a second malignancy. Three factors seem to be correlated to prognosis: the site of the initial lesion (only 23% of the pelvic lesions are represented in the CDF group versus 46% of the other locations); the chemotherapy protocol (32% of the cases in the first protocol are CDF versus 54% in the second); the type of local treatment (60% of the patients treated with amputation or resection plus radiotherapy versus 28% of those treated with radiation therapy alone are CDF). A local recurrence was observed in 24% of the patients (8% in the group locally treated with surgery or surgery plus radiation therapy versus 36% in the group treated with radiation therapy alone). These data suggest that even though adjuvant chemotherapy can improve the long‐term results in localized Ewings sarcoma patients, this disease still represents, in a high percentage of cases, a lethal process whose final prognosis widely depends on the local control of the lesion. Due to the questionable effect of the radiation therapy alone in controlling the primary lesion and its important side effects, the role of surgery in treating Ewings sarcoma of bone should be extended.

Massive bone allograft reconstruction in high-grade osteosarcoma.

From 1986 to 1994, 112 bone allograft reconstructions were performed in patients with high-grade osteosarcoma in whom neoadjuvant chemotherapy was administered. The allograft reconstruction was used in arthrodesis in 44 cases (41 knees, three ankles), as an intercalary graft in 39 (28 femurs, 11 tibias), as an osteoarticular graft in 22 (three proximal and/or distal humeri, six distal femurs, 13 proximal tibias), and as an allograft and prosthesis composite in seven (two proximal humeri, one proximal femurs, four proximal tibias). In 20 patients an autologous vascularized fibula was used to augment the allograft. Functional results were excellent or good in 74% of the patients after the primary surgery, and in 83% of the patients after secondary surgery. Complications include delayed union (49%) and fracture (27%), although there were no cases of deep infection. The incidence of delayed union, but not infection or fracture, was increased by the use of chemotherapy.

Neoadjuvant Chemotherapy for High-Grade Central Osteosarcoma of the Extremity Histologic Response to Preoperative Chemotherapy Correlates with Histologic Subtype of the Tumor

In primary central high‐grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy.

Giant-cell tumor of bone in skeletally immature patients.

Giant-cell tumor of bone is predominantly an affliction of adults and is rarely found in skeletally immature patients. We are reporting six new cases of histologically confirmed giant-cell tumor of bone in patients with radiographically open epiphyseal plates. These patients account for 1.8 per cent of the 326 giant-cell tumor of bone observed at the Bone Tumor Center of the Istituto Ortopedico Rizzoli in Bologna, Italy.

High Dose Ifosfamide in Combination with High Dose Methotrexate, Adriamycin and Cisplatin in the Neoadjuvant Treatment of Extremity Osteosarcoma: Preliminary Results of an Italian Sarcoma Group/Scandinavian Sarcoma Group Pilot Study

Abstract With the intention of starting an international protocol between Italy and Scandinavia on neoadjuvant treatment of extremity osteosarcoma using the four active drugs at maximum doses (doxorubicin 75 mg/m2 pre-operatively, and 90 mg/m2 post-operatively, cisplatin 120 mg/m2, methotrexate 12 g/m2, and ifosfamide 15 g/m2), a single center (the Rizzoli institute) performed a pilot study to closely monitor toxicity, safety, and tumor necrosis. Only 7 patients (10%) had a reduced number of the scheduled cycles. A total of 1050 of the expected 1076 cycles (98%) were administered. Delays and dose reduction were minimal, leading to a mean received dose intensity of 89%. Limb salvage surgery was performed in 59 cases (87%), with 6 amputations and 3 rotation plasties. Chemotherapy-induced necrosis higher than 95% was observed in 38 patients (56%). Eleven patients had total necrosis (16%). At a median follow-up of 60 months (range 50-65 months), 53 patients (73%) were continuously disease-free. Six of the relapsed patients were rescued with further treatments leading to an overall survival of 87%. Hematological toxicity was remarkable despite the use of G-CSF and hospitalization due to febrile neutropenia occurred in 25 patients (37%). Platelet transfusions were required in 77 of the 194 episodes of grade 4 thrombocytopenia, but no case of major bleeding was observed. Red blood cell transfusions were necessary in all patients (in 15 cases perioperatively only). Non-hematological toxicity comprised grade 1-2 nephrotoxicity in 3 cases, CNS toxicity in 2 cases, and dilatative cardiopathy leading to heart transplantation in 1 case. In conclusion, the pilot study was feasible in the vast majority of cases with toxicity not superior to that of the previous protocols where chemotherapy was given in lower doses. The rate of limb salvage procedures, event-free survival and overall survival seemed to be higher than in previous protocols. On the basis of this study, in March 1997 the Italian and Scandinavian Sarcoma Groups started a new protocol for osteosarcoma of the extremities.

Osteogenic sarcoma of the extremity with detectable lung metastases at presentation

In the past 20 years, it has been demonstrated that the combination of surgery and chemotherapy improves the prognosis for patients with osteosarcoma of the extremity without detectable metastases at presentation. By contrast, the efficacy of chemotherapy coupled with aggressive surgery has not yet been well established for patients with metastatic disease at diagnosis. The current study evaluates the efficacy of chemotherapy associated with simultaneous surgery of primary and metastatic lesions in patients presenting with osteosarcoma of the extremity with lung metastases.

Vascularized Proximal Fibular Epiphyseal Transfer for Distal Radial Reconstruction

BACKGROUND Treatment of the loss of the distal part of the radius, including the physis and epiphysis, in a skeletally immature patient requires both replacement of the osseous defect and restoration of longitudinal growth. Autologous vascularized epiphyseal transfer is the only possible procedure that can meet both requirements. METHODS Between 1993 and 2002, six patients with a mean age of 8.4 years (range, six to eleven years) who had a malignant bone tumor in the distal part of the radius underwent microsurgical reconstruction of the distal part of the radius with a vascularized proximal fibular transfer, including the physis and a variable length of the diaphysis. All of the grafts were supplied by the anterior tibial vascular network. The rate of survival and bone union of the graft, the growth rate per year, the ratio between the lengths of the ulna and the reconstructed radius, and the range of motion of the wrist were evaluated for five of the six patients who had been followed for three years or more. RESULTS The mean duration of follow-up of the six patients was 4.4 years (range, eight months to nine years). All six transfers survived and united with the host bone within two months postoperatively. The five patients who were followed for three years or more had consistent and predictable longitudinal growth. Serial radiographs revealed remodeling of the articular surface. The functional result was rated as excellent for all but one patient, in whom the distal part of the ulna had also been resected because of neoplastic involvement. No major complication occurred at the recipient site, whereas a peroneal nerve palsy occurred at the donor site in three patients. The palsy was transient in two patients, but it persisted in one. No instability of the knee joint was observed. CONCLUSIONS After radical resection of the distal part of the radius because of a neoplasm in children, vascularized proximal fibular transfer, based on the anterior tibial artery, permits a one-stage skeletal and joint reconstruction, provides excellent function, and minimizes the discrepancy between the distal radial and ulnar lengths.