Antonio Briccoli

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.

Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol

From January 1993 to March 1995, 162 patients with osteosarcoma of extremities were treated according to the IOR/OS-4 protocol. 133 patients had localised disease, while 29 had metastases at diagnosis. These last patients were simultaneously operated upon for their primary and metastatic lesions. Chemotherapy consisted preoperatively of two cycles of high dose methotrexate (HDMTX) and one cycle each of cisplatin (CDP)-doxorubicin (ADM), CDP/ifosfamide (IFO) and IFO/ADM. After surgery, patients were treated with the aforementioned drugs used as single agents. The mean follow-up of all patients was 6.5 years (5.5-8 years). Surgery was a limb salvage in 94% of cases, and the 5-year event-free survival (EFS) and overall survival (OS) rates were 56 and 71% for patients with localised disease, and 17 and 24% for patients with metastases at diagnosis. These results did not differ from those achieved in our previous study (IOR/OS-3) in which IFO was used only postoperatively in poor responders.

High grade osteosarcoma of the extremities with lung metastases at presentation: Treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions

Between 1986 and 2001, 162 patients with extremity osteosarcoma and lung metastases at presentation, were treated by neoadjuvant chemotherapy, simultaneous resection of primary and, when feasible, secondary lesions followed by chemotherapy.

Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy.

The pattern of relapse, treatment and final outcome of 235 patients with osteosarcoma of the extremity who relapsed after neoadjuvant treatments performed between 1986 and 1998 at a single institution is reported. The 235 relapses were treated by surgery, surgery plus second line chemotherapy, and only second line chemotherapy or radiotherapy. The 5-year post-relapse-event-free-survival (PREFS) was 27.6% and the post-relapse-overall-survival (PROS) 28.7%. All 69 patients who are presently alive and free of disease were treated by surgery, alone or combined with chemotherapy. None of patients treated only by chemotherapy or radiotherapy survived. We conclude that it is possible to obtain prolonged survival and cure in about 1/4 of relapsing osteosarcoma patients with aggressive treatments. The complete removal of the recurrence is essential for outcome, while the role of the association of second-line chemotherapy remains to be defined.

High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005.

BACKGROUND Approximately one-third of patients with localized osteosarcoma at presentation relapse as well as about three-fourths of the patients with metastases at diagnosis, about 90% of relapses are lung metastases. The role of lung metastasectomy remains to be determined. PATIENTS and methods: Three hundred and twenty three patients, 88 with resectable lung metastases at diagnosis and 235 with localized disease at presentation who relapsed with lung metastases were treated. RESULTS A total of 498 lung surgeries and 607 thoracotomies were performed. The 5 year overall survival was 37%. Final outcome was significantly related to presence or absence of metastasis, time of first relapse and presence of local recurrences. According to stage of the disease, the rate of a 5 year event-free survival (EFS) was 36% for patients with localized disease who later relapsed and 9% for patients with resectable lung metastases at presentation (p<0.0001). However, there were no differences in EFS between patients who underwent two or three thoracotomies and patients who had four or five thoracotomies (7.5 vs 18.7%, p=0.29). CONCLUSIONS In patients with recurrent resectable pulmonary metastases from high grade osteosarcoma treated with adjuvant or neoadjuvant chemotherapy, thoracotomy should always be considered regardless the number of previous lung relapses and the number of secondary pulmonary lesions.

Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy

BACKGROUND Most of the studies of the treatment of non-metastatic osteosarcoma of the extremity have reported results in terms of probability of survival up to five years with a minimum follow-up of less than two to three years. Definition of reliable indicators of prognosis and predictive factors for survival require mature data derived from a long-term survival analysis. PATIENTS AND METHODS A review of 127 patients with non-metastatic osteosarcoma of the extremity, treated between March 1983 and June 1986, was performed. The treatment protocol consisted of primary chemotherapy with MTX (randomization to high vs. moderate dosages) and CDP followed by surgery. Postoperatively, patients with < 60% tumor necrosis received ADM and BCD; those with tumor necrosis > or = 60% < 90% (Fair Responders FR) were given MTX, CDP and ADM. Up to January 1984, patients with tumor necrosis > 90% received MTX and CDP only, and after then they were given the same treatment as for FR. A multivariate analysis to test predictive factors for survival was performed. RESULTS With a median follow-up of 134 months (range 114-153), the 12-year DFS was 46%. A good histologic response, an LDH baseline value within the normal range, and the use of high-dose MTX were positive predictive factors for DFS. With a median time of observation for survivors of 130 months, the 12-year overall survival was 53%. None of the patients who relapsed with local or distant recurrences other than lung metastasis are now alive. Patients with a relapse-free interval longer than 24 months had a significantly better post-relapse survival than those with a shorter relapse-free interval (40% vs. 7%; P = 0.0159). All of the patients who were not surgically treated had disease progression and died within 40 months after the first recurrence. The surgically-treated patients had a 30% post-relapse survival probability. CONCLUSIONS In non-metastatic osteosarcoma of the extremity, chemotherapy-induced tumor necrosis, the baseline LDH serum value and the use of HDMTX are significant predictive factors for DFS. The relapse-free interval and the possibility of metastasectomy are significant factors conditioning the post-relapse survival.

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.

Value of P-Glycoprotein and Clinicopathologic Factors as the Basis for New Treatment Strategies in High-Grade Osteosarcoma of the Extremities

PURPOSE To evaluate the prognostic value of P-glycoprotein and clinicopathologic parameters in a large series of high-grade osteosarcoma (OS) patients treated at the Rizzoli Institute. PATIENTS AND METHODS With the use of immunohistochemistry, P-glycoprotein was assessed in 149 patients with primary, nonmetastatic, high-grade OS who were homogeneously treated with chemotherapy protocols based on doxorubicin, high-dose methotrexate, and cisplatin and the addition of ifosfamide in the postoperative phase. RESULTS P-glycoprotein positivity was found in 47 of 149 cases (32%) and was significantly associated with a higher incidence of relapse and a worse outcome, as was age younger than 12 years and tumor volume greater then 150 mL at diagnosis. Multivariate analysis further confirmed the prognostic value of these parameters, which all were independent adverse prognostic factors. Event-free survival and proportional hazards regression analyses confirmed that overexpression of P-glycoprotein at clinical onset is the most important adverse prognostic factor for high-grade OS patients treated with these chemotherapy protocols. CONCLUSION Increased P-glycoprotein levels, together with tumor volume and age, should be taken into consideration to identify, at time of diagnosis, subgroups of OS patients with a higher risk of recurrence. This subgroup identification will constitute the basis for drawing individualized treatment protocols on the basis of risk evaluation, with the aim of using more aggressive chemotherapy, or combination chemotherapy with other adjuvants, only in those patients for which more aggressive regimens are strictly necessary and warranted.

Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: Local and systemic control by amputation or limb salvage after preoperative chemotherapy

To determine whether a pathologic fracture in osteosarcoma of long bones has prognostic importance, and limb salvage can be safely performed in such cases, we reviewed the surgical treatment and oncologic results in 46 patients with nonmetastatic osteosarcoma of the extremity and pathologic fracture at presentation who had been treated in our Institution with neoadjuvant chemotherapy, between 1983 and 1999. Neoadjuvant chemotherapy was given according to 6 consecutive protocols. Surgery consisted of limb salvage (34 patients), amputation (11 patients) and rotationplasty (1 patient). The average follow-up was 11 (320) years. 28 patients remained continuously disease-free, 17 patients relapsed and 1 died of chemotherapy-related toxicity. Despite the high rate of limb salvage, only 2 local failures occurred, 1 after amputation and 1 after limb salvage. The 5-year disease-free survival and overall survival rateswere 59% and 65%, respectively, with no differences between amputated and resected patients. These results are similar to those obtained in 689 contemporary patients having an osteosarcoma without a pathologic fracture treated in our Institution, and using the same protocols for chemotherapy. We conclude that with neoadjuvant chemotherapy, osteosarcoma patients presenting with a pathologic fracture can be surgically treated like those with no fracture, and that limb salvage procedures do not increase the risk of local recurrence or death of these patients.

Osteoid osteoma and osteoblastoma of the talus (a report of 40 cases)

Forty patients with osteoid osteoma or osteoblastoma of the talus are presented. Clinical and radiographic findings, histologic features, and therapy of these lesions are discussed. The body of the talus was involved in two patients, all other lesions being located in the neck of the bone. Subperiosteal lesions accounted for 75% of cases, and medullary lesions for 25%. Thirty of the 40 lesions were paraarticular. Five radiographic appearances in the talus are discussed: subperiosteal target lesions of the neck (54%); medullary lesions of the neck (20%); subperiosteal radiolucent lesions of the neck (13%); medullary lesions of the body (5%); and exostotic osteoid osteoma of the talar neck (3%).