Neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremities: the recent experience at the Rizzoli Institute.
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Actuarial Analysis↗
Biomedical subjects
P Picci
Publications and source records attributed to P Picci.
Influence of adriamycin dose in the outcome of patients with osteosarcoma treated with multidrug neoadjuvant chemotherapy: results of two sequential studies.
The results of two sequential studies of neoadjuvant chemotherapy for osteosarcoma of the extremities performed at Rizzoli Institute between 1986 and 1991 in 228 patients are presented. In both studies preoperative chemotherapy consisted of two cycles of high dose methotrexate (HDMTX), cisplatinum (CDP) and adriamycin (ADM). Postoperatively the good responder patients were treated with the same drugs used before surgery while in the poor responder patients ifosfamide was added to these three drugs. The preoperative treatment was the same in both studies while after surgery in the second protocol either the cumulative dose of ADM (270 mg/m2 instead of 360 mg/m2) or the single dose per cycle of this drug (60 mg/m2 instead of 90 mg/m2) was reduced. These changes in the last protocol were done to reduce the cardiotoxicity of ADM that was high in the first study (2 deaths and 1 heart transplantation). Since in the last protocol--in comparison with the first protocol--after surgery chemotherapy was restarted earlier and ADM was administered not as a single drug but in combination with the CDP the dose intensity of ADM was unchanged while the dose intensity of MTX, CDP and ifosfamide was higher than in the first study. The preliminary results of the 84 patients treated in the second study show a 2-year disease free survival significantly lower than that achieved in the 144 patients treated in the first study (37/51--73% vs 123/144--85%: P < 0.008). In addition, even if in the last study there were no cases of clinical cardiotoxicity due to ADM, there was a significantly higher percentage of severe myelodepression that led to two deaths for infectious complications. These results suggest that in neoadjuvant treatment of osteosarcoma the total dose of ADM and/or the single dose per cycle of the same drug are an important determinant of outcome and that increasing the dose-intensity of less toxic but less active agents, MTX, CDP and ifosfamide, at the expense of the more active and more toxic agent, ADM, can lead to a poorer outcome without reducing toxicity.
Adolescent↗
No advantages in the addition of ifosfamide and VP-16 to the standard four-drug regimen in the maintenance phase of neoadjuvant chemotherapy of Ewing's sarcoma of bone: results of two sequential studies.
Between January 1988 and December 1990, 74 patients with localized Ewing's sarcoma of bone were treated with a new protocol that consisted of an initial 6-week period of chemotherapy with vincristine (VCR), adriamycin (ADM) and cyclophosphamide (EDX) followed by local therapy and additional chemotherapy with the same drugs previously indicated plus ifosfamide and VP-16. The rationale for the addition of ifosfamide and VP-16 to the four drugs of the standard chemotherapy of this tumor was that this drug combination was previously very effective in the treatment of metastases from Ewing's sarcoma even in patients who did not respond to cyclophosphamide. As local treatment all patients were offered surgery, when feasible (70 cases). Forty-three patients accepted and 27 refused. These patients, as the 4 patients in whom surgery was not considered feasible, were treated with radiation therapy alone (50-60 Gy). In the remaining patients amputation was performed in 4 cases, rotationplasty in 3 and resection in 36. Where conservative surgery was marginal or intralesional (30 cases), radiotherapy at lower doses (40-45 Gy) was also delivered. At a mean follow-up of 3.5 years (2-7), 43 patients (58%) remained continuously disease-free and 31 relapsed (29 with metastases and 2 with both metastases and local recurrences). These results do not differ from those obtained at our Institution in 98 patients treated between 1983 and 1988 with a neoadjuvant protocol in which only VCR, ADM, EDX and dactinomycin (DAC) were used (3-year continuously disease-free survival (CDFS) respectively of 54% and 55%). Despite the fact that these results came from a nonrandomized study, the Authors conclude that the addition of ifosfamide and VP-16 to the four-drug standard regimen did not improve the outcome of the patients with Ewing's sarcoma of bone which remains a lethal disease in about 50% of the cases. These findings stress the need to find more effective chemotherapeutic regimens for the associated treatment of this tumor.
Adolescent↗
Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing's sarcoma of the extremities.
PURPOSE: To evaluate more accurately the effectiveness of preoperative chemotherapy in the treatment of patients with Ewing's sarcoma, we studied histopathologically the chemotherapeutic response and correlated it to oncologic outcome. PATIENTS AND METHODS: Between June 1983 and December 1989, 68 patients with nonmetastatic Ewing's sarcoma of the extremities were treated at our institute with preoperative chemotherapy (without radiation therapy) and surgery. The specimens were retrospectively evaluated for areas of viable tumor cells and graded from I to III (macroscopic, microscopic, or no residual disease, respectively) in a blinded fashion. Clinical follow-up data were available on all patients for a mean of 60 months (range, 32 to 111). RESULTS: This histopathologic analysis was strongly correlated with oncologic outcome (P = .004). Patients who demonstrated grade III response (no identifiable viable tumor nodules present) had improved 5-year disease-free survival rates as compared with patients with grade II (microscopic nodes present; P = .023; 90% v 53%) and grade I responses (macroscopic nodules present; P = .0003; 90% v 32%). Patients with grade II necrosis had statistically improved survival rates over those with grade I necrosis (53% v 32%; P = .074). CONCLUSION: This new histopathologic analysis technique for the evaluation of neoadjuvant chemotherapy effectiveness (which does not rely on tumor volume for its assessment) is a valuable prognostic indicator for patients with Ewing's sarcoma treated with surgery. Based on this preliminary report, cases of grade I or II chemotherapeutic tumor response should be considered clinical failures and a different, more aggressive postoperative chemotherapy regimen should be considered.
Adolescent↗
Osteoblastoma-like osteosarcoma. The Rizzoli Institute experience.
A series of 11 osteosarcomas that histologically resembles osteoblastoma was reviewed. The ages of the seven males and four females ranged from 19 to 47 yr (average 29). In six patients the roentgenograms showed cortical destruction and poorly defined borders on the lesion; this roentgenographic presentation was suggestive of malignancy. Histologically, the tumor permeation of the surrounding host tissue allowed us to differentiate osteoblastoma-like osteosarcoma from osteoblastoma. The differential diagnosis can be very difficult or even impossible on a small biopsy. The first diagnosis was considered benign in nine of our cases. Osteoblastoma-like osteosarcoma is a rare variety of osteosarcoma (1.1% of all osteosarcoma). It is a low-grade malignant lesion in which recurrence is the rule when adequate surgical margins were not achieved (five patients). Two of these patients died from tumors after inadequate surgical treatment of the primary tumor as well as of the recurrences. The six patients who were treated with wide surgical margins were alive without recurrence. One of them had lung metastasis, twice, treated with wide-wedge resection. Osteoblastoma-like osteosarcoma is a low-grade variety of osteosarcoma with characteristic histopathologic features. It needs to be recognized by the pathologist to achieve the right treatment which is wide surgical procedure.
Adult↗
[Osteosarcoma: magnetic resonance imaging of the effects of preoperative chemotherapy].
The effects of preoperative chemotherapy for osteosarcoma of the extremities were investigated with MR imaging. Forty-six patients affected with high-grade osteosarcomas of the extremities underwent MRI before and after two cycles of preoperative chemotherapy. At the end of treatment all tumors were resected and the rate of tumor necrosis was assessed on histologic sections. The MR images obtained before and after treatment were compared. Decreased tumor size, perilesional intramedullary edema and more marked lesion outline correlated well with positive histologic response to preoperative chemotherapy. Soft tissue edema and joint effusion did not change significantly and no clear correlation with histologic response was observed. Decreased signal intensity on T2-weighted images is likely to indicate response to chemotherapy. Likewise, poor response correlated with unchanged/increased signal intensity. Therefore, MRI appears a useful means to evaluate chemotherapy-induced changes in osteosarcomas of the extremities.
Adolescent↗
Complications and surgical indications in 144 cases of nonmetastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy.
From September 1986 to December 1989, 144 patients with osteosarcoma of the extremities were treated with combined surgery and neoadjuvant chemotherapy. The disease-free survival was 79% for good responders (necrosis greater than 90%) and 72% for poor responders (necrosis less than 90%), and the local recurrence rate was low. Improvement in long-term prognosis and the increase of limb-sparing surgery determine a higher rate of immediate and late complications. Most of the complications were observed in limb-salvage procedures; 63% of these procedures presented one or more complications. In nine rotationsplasties, there were four complications, and in 13 amputations no complications were observed. Therefore, 55% of patients were affected by surgical complications. Twenty-eight complications were considered minor (not requiring surgery), whereas 77 complications were major. Functional results, evaluated according to Enneking's new system, were higher than 50% in two thirds of the limb-salvage procedures. Complications in limb-salvage procedures are more influenced by the type of reconstruction than by the surgical procedure used. Probably the most troublesome consequence of surgical complications in osteosarcoma is the deviation or delay in administering postoperative chemotherapy, which jeopardizes survival.
Adolescent↗
The role of surgical therapy in patients with nonmetastatic Ewing's sarcoma of the limbs.
Of 131 patients with primary Ewing's sarcoma (ES) with extremity locations, treated between April 1972 and May 1987, 13 had amputation; 56 had a local resection with 31 (55%) requiring radiation therapy (RT) as an adjuvant to local therapy. Sixty-two of 131 patients (47%) had RT only. Local recurrences were reported in 5% of patients treated with surgery alone, 1% of the group treated with surgery and radiation therapy, 24% of patients treated with radiation therapy alone (46% for cesium-radiation therapy, and 12% with cobalt-radiation therapy).
Adolescent↗
[Osteosarcoma of the extremities metastatic at presentation. Results obtained with primary chemotherapy followed by simultaneous resection of the primary and metastatic lesion].
From September 1986 to September 1990 35 patients affected by osteosarcoma of the extremities with synchronous metastasis were treated with two cycles of high-dose methotrexate IV, cisplatin IA and adriamycin IV followed, in 22, by simultaneous resection of the primary and metastatic tumor. Six patients progressed and were not operated on, 7 patients with complete response of pulmonary nodules underwent surgical resection of the primary lesion. A complete histological examination of the resected specimens was always performed to evaluate the percentage of necrosis produced by chemotherapy on both the primary and metastatic tumor. After surgery the patients received 3 more cycles of the same drugs as used preoperatively plus ifosfamide. The histological response of the primary tumour was "good" (90% or more tumour necrosis) in 8 patients (27%) and "poor" (less than 90% of tumour necrosis) in 21 (73%) while in the 75 metastatic nodules the resulting necrosis was good in 18 (24%) and poor in 57 (74%). A good correlation between the histological response in the primary and metastatic tumour was observed. At an average follow-up of 30 months (R 12-60), 13 patients are alive, 10 disease-free, and 3 with uncontrolled disease. This data suggest that prognosis of osteosarcoma of the extremities with synchronous metastases remains poor even with a very aggressive treatment. Our results also seem to confirm the validity of the present strategy in the treatment of non metastatic osteosarcoma: to introduce new drugs postoperatively in patients poor responder can allows a better treatment of microscopic disease and can improve the prognosis for these patients.
Antineoplastic Combined Chemotherapy Protocols↗
Osteosarcoma of the extremity metastatic at presentation: results achieved in 26 patients treated with combined therapy (primary chemotherapy followed by simultaneous resection of the primary and metastatic lesions).
From September 1986 to December 1989, 26 selected patients with high-grade osteosarcoma of the extremities metastatic at presentation were treated with primary chemotherapy (high doses of methotrexate, -cisplatinum and adriamycin) followed by surgery. Twenty-one cases underwent resections of the primary and metastatic tumor at the same time; owing to the disappearance of lung metastases after preoperative chemotherapy in 3 cases, only the primary tumor was operated on. Due to progression of the disease in 2 patients, no surgery was performed. Histologic examination of the resected specimen was performed to evaluate the percentage of necrosis produced by chemotherapy on the primary and metastatic tumor. After surgery, the patients received further chemotherapy with the same drugs used preoperatively plus ifosfamide and VP-16. The histologic response of the primary tumor was good (> 90% tumor necrosis) in 25% of the cases; in the resected metastatic nodules, 23% had good responses. A discrepancy between the histologic response of the primary and secondary tumor was observed in only 15% of the cases. These results seem to confirm the validity of the strategy (widely used today in the neoadjuvant treatment of non-metastatic osteosarcoma) of changing the postoperative treatment when the histologic response of the primary tumor is poor. At an average follow-up of 3.5 years, only 6 patients remained disease-free; 19 patients relapsed and 1 patient died for adriamycin cardiotoxicity. Of the 19 relapsed patients, 16 died and 3 are still alive but with uncontrolled disease. These results are much worse than those obtained in 144 cases of non-metastatic osteosarcoma of the extremities treated in the same period with the same preoperative chemotherapy (77% with good response in the primary tumor and 78% with continuous disease-free survival). The data suggest that a very effective neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremities gives disappointing results in osteosarcoma of the extremities which is metastatic at presentation.
Adolescent↗
Effect of intra-arterial versus intravenous cisplatin in addition to systemic adriamycin and high-dose methotrexate on histologic tumor response of osteosarcoma of the extremities.
In neoadjuvant treatment of osteosarcoma of the extremities intra-arterial (IA) instead of intravenous (IV) administration of cisplatinum (CDDP) has been advocated to improve local response and consequently increase the percentage of limb salvages and the cure rate. Since the major local advantages from the IA use of CDDP have been recently questioned, a comparative prospective study was performed at the Rizzoli Institute between July 1990 and September 1991. Preoperative chemotherapy consisted of two cycles of high-dose methotrexate (HDMTX), followed 6 days later by CDDP and adriamycin (ADM), HDMTX and ADM were delivered intravenously while CDDP was delivered according to previous randomization, either intra-arterially or intravenously. Of the 79 patients who entered the study 40 received CDDP IA and 39 CDDP IV. The percentage of clinical and radiological response of the tumor as well as the percentage of limb salvage procedures performed was the same in the two groups. However the rate of good histological response (tumor necrosis greater than 90%) was significantly higher in the group of patients who received IA CDDP than in the patients who received the drug intravenously (77.5% vs 46%: p less than 0.01). No differences in terms of local or systemic side effects were found in the two groups. A longer follow-up is necessary to establish if this improved good response rate achieved with IA CDDP will lead to an improved cure rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The treatment of localized osteosarcoma of the extremities: the Italian experience. Studies of the National Research Council.
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Bone Neoplasms↗
Limb sparing versus amputation in osteosarcoma. Correlation between local control, surgical margins and tumor necrosis: Istituto Rizzoli experience.
Three hundred fifty-five patients with osteosarcoma were surgically managed at the Istituto Ortopedico Rizzoli between 1983 and 1988. Three hundred two patients performed two cycles of neoadjuvant chemotherapy according to two different protocols consecutively activated; the remaining 53 patients were immediately operated on without neoadjuvant treatment. Follow-up ranged from 19 to 88 months, with a mean of 51 months. Demolitive surgery was performed in 116 patients (33%), while conservative in 239 patients (67%). A radical margin was achieved only in patients undergoing amputations: no radical surgical margins were achieved by local resection: 174 resected patients (73%) had wide margins, while 34 (14%) had marginal margins; 20 patients had contaminated margins and 11 patients (5%) had intralesional margins. Wide or marginal margins were achieved in 208 (87%) of the patients managed by local resection. Local recurrence was identified in 24 of 355 patients (7%). Incidence of local recurrence is strictly related to surgical margin, but above all, to tumor necrosis induced by neoadjuvant chemotherapy. In fact, neoadjuvant chemotherapy makes limb salvage feasible in the majority of cases without increasing the risk of local recurrence: in the group of patients immediately operated on without neoadjuvant chemotherapy, the incidence of local recurrence is dramatically high even when the surgical margins are adequate.
Adolescent↗
Primary chemotherapy and delayed surgery for osteosarcoma of the extremities with synchronous metastases.
From September 1986 to September 1989 11 patients affected by osteosarcoma of the extremities with synchronous metastases were treated with two cycles of high-dose methotrexate i.v., cisplatin i.a. and adriamycin i.v. followed by simultaneous resection of the primary and metastatic tumor. A complete histological examination of the resected specimens was always performed to evaluate the percentage of necrosis produced by chemotherapy on both the primary and metastatic tumor. After surgery the patients received 3 more cycles of the same drugs as used preoperatively plus ifosfamide. The histological response of the primary tumor was 'good' (90% or more tumor necrosis) in 4 patients and 'poor' (less than 90% of tumor necrosis) in 7, while in the 34 metastatic nodules the resulting necrosis was good in 8 and poor in 26. A good correlation between the histological response in the primary and metastatic tumor was observed, particularly for poor responders (91% of poor responses also in metastatic nodules). At an average follow-up of 42 months, only 3 patients are alive, 2 disease-free, and one with uncontrolled disease. These data suggest that the prognosis of osteosarcoma of the extremities with synchronous metastases remains poor, even with a very aggressive treatment. Our results also seem to confirm the validity of the present strategy in the treatment of non-metastatic osteosarcoma: introducing new drugs post-operatively in poor responding patients can allow a better treatment of microscopic disease and can improve the prognosis for these patients.
Adolescent↗
Expression of MDR1 and GST-pi in human soft tissue sarcomas: relation to drug resistance and biological aggressiveness.
Human soft tissue sarcomas (HSTS) in adults are a family of mesenchymal tumors characterized by high biological aggressiveness and general refractoriness to chemotherapy. A series of 36 HSTS, 24 untreated and 12 homogeneously treated with a presurgical chemotherapeutic regimen consisting of doxorubicin (intra-arterial) and iphosphamide (intra-vein), was analyzed for expression of MDR1 and the glutathione-S-transferase-pi (GST-pi) gene in order to identify molecular phenomena which may be implicated in the chemoresistance displayed by these tumors. The MDR1 gene was expressed in a greater percentage of drug-treated tumors and at higher levels than in untreated ones. By contrast, chemotherapeutic treatment has no effect on GST-pi mRNA expression. The GST-pi expression level (EL) was much higher in the HSTS with biologically aggressive features. In fact, significant correlations were observed between GST-pi and histologic grade (p = 0.01); aneuploidy (p less than 0.01); and histone H3 EL (p = 0.01), suggesting a possible causal relationship between GST-pi activity and biological aggressiveness in HSTS.
Adult↗
Osteosarcoma and other cancers of bone.
Because of great improvements in survival and reduction in amputations in patients with osteosarcoma, investigators in the various fields involved in diagnosis and care of these patients are making greater efforts to contribute to better knowledge of the disease and the effects of treatment. Recent developments include basic studies on genetic abnormalities, evaluation of the role of modern imaging in predicting chemo-induced tumor necrosis and in defining tumor margins, and research into new agents, with new combinations and schedules for increasing prognosis and reducing side effects. Major efforts are also being made by surgeons in the difficult field of reconstruction after bone resections.
Acetylmuramyl-Alanyl-Isoglutamine↗
Osteoblastoma of the spine.
Osteoid osteomas and osteoblastomas have similar histologic characteristics, although their clinical course in the spine may be significantly different. At the authors' institution, spinal osteoblastomas constituted 46% (30/65) of all osteoblastomas treated. Sixteen of the lesions occurred in the lumbar spine (53%), eight in the thoracic spine, and six in the cervical spine. In all regions of the spine, the posterior elements and pedicles were more frequently involved than the vertebral body. Twenty patients had pain or other symptoms for more than 12 months before diagnosis. Six of eight patients had thoracic lesions that demonstrated neurologic involvement. Twelve patients presented with painful scoliosis. Fourteen patients had lesions with well-circumscribed margins confined within the vertebral structure (Enneking Stage 2), and 16 had ill-defined margins with soft-tissue extension (Enneking Stage 3). Well-defined lesions were treated with curettage, with excellent results in 12 of 14 patients. The more extensive lesions were treated by intralesional excision (15/16) and adjuvant radiation therapy (9/16).
Adolescent↗
Tumours of the patella.
We report 15 cases of primary tumours and pseudotumours of the patella. The radiographic features and the surgical treatment of the different histological types are described in relation to Enneking's surgical staging and data derived from the literature.
Adolescent↗