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While surgery remains the cornerstone of treatment of bone and soft tissue sarcomas, chemotherapy has improved the 5-year overall survival in osteosarcoma and Ewing's sarcoma from 10% to 70% in localized disease. Patients with metastases at presentation treated with surgery combined with chemotherapy have a 3-year survival of 30-50%, but cure is still rare. The role of adjuvant chemotherapy in soft tissue sarcoma has yet to be determined, but it is likely that some patients will benefit. As some bone sarcomas do not respond to chemotherapy, surgery remains the only effective treatment, and there are no effective drugs to treat relapsing patients. Radiotherapy has both a curative role in combination with chemotherapy in soft tissue and Ewing's sarcoma and a palliative role in the other sarcomas. [ABSTRACT FROM AUTHOR]

Introduction: There have been no large-scale studies reporting the outcome of patients with osteosarcoma who first relapse with bone metastases, but there have been several case reports describing a much poorer prognosis for these patients than for those who relapse with lung metastases., Methods: We compared 52 patients with skeletal metastases as first relapse after neoadjuvant or adjuvant treatment for osteosarcoma of the extremity given at our institution between 1972 and 1999 with 371 contemporary patients treated with the same chemotherapy protocols, who first relapsed with lung metastases., Results: We found that the 52 patients with bone metastases had a higher rate of local recurrences (36% vs. 6%), a lower rate of remission (35% vs. 77%), and lower rates of 5-year event-free survival (11% vs. 27%) and overall survival (13% vs. 31%) (p < 0.01 for all comparisons)., Interpretation: The prognosis of patients who relapse with bone metastases--unless they have a single late-appearing metastasis--is worse than the prognosis of patients who first relapse with lung metastases. There was no difference in outcome between patients with single, resectable and late-appearing skeletal metastases and patients relapsing in the lung.

Background: Risk factors for local recurrence (LR) after osteosarcoma, such as surgical margins and histologic response to preoperative treatment, have been well documented, whereas the outcome for patients who locally recur has not been well established yet., Methods: Retrospective analysis of the management and outcome of 44 patients who developed LR after treatment of osteosarcoma of the extremities with neoadjuvant chemotherapy was performed in a single institution between 1983 and 1999., Results: In 24 patients (54.5%), LR was the first sign of recurrence; in 8 patients (18.2%) LR followed systemic recurrence and in 12 patients (27.3%), the 2 events, local and systemic recurrence, were concurrent. Of the 44 patients, 26 with local recurrences were free of disease, but only 5 were long-term event-free survivors, and 39 patients developed further recurrences: 37 died of the tumor and 2 were alive with uncontrolled disease at the time of last follow-up. The 5-year disease-free survival rate after the last recurrence was 15.9%; it was 25.9% for patients who achieved remission and 0% for the others. The only prognostic factor identified for post-LR disease-free survival was the presence of systemic recurrence at the time of diagnosis of LR or before (5-year postrecurrence event-free survival rate of 29.1% for patients without metastases at the time of local recurrence vs. 0% for those with metastases; P = .02)., Conclusions: These results confirm that patients with osteosarcoma of the extremities who develop LR are at a very significantly high risk of developing metastatic disease and dying of the tumor., (Copyright 2006 American Cancer Society.)

Our objectives were to evaluate the behavior of different doses of pre-operative methotrexate (MTX) pharmacokinetics, and assess correlations between the osteosarcoma histologic response and MTX serum peak concentrations. In total, 336 patients with osteosarcoma of the extremities were treated with three neoadjuvant protocols of chemotherapy including high-dose MTX (different doses for each protocol), cisplatin and doxorubicin (same doses in all protocols). The doses of MTX were 8 g/m2 in 124 patients, 10 g/m2 in 110 patients and 12 g/m2 in 102 patients. The mean value of peak serum MTX was 801 micromol/l (range 298-1831) with significant intra- and inter-patient variability. For patients treated with 8, 10 and 12 g/m2 it was 587, 735 and 1114 micromol/l, respectively (P < 0.0001). The histologic response to pre-operative chemotherapy was 90% or above tumor necrosis in 62.8% of patients and less than 90% in 37.2%. The grade of histologic response significantly correlated with the histologic subtype of the tumor, whereas no significant association was found between the mean peak of serum MTX and the histologic response. Thus, increasing the dose of MTX increases the MTX serum peaks, but does not correlate with the histologic response of the tumor.

Background: The evaluation variables influencing systemic and local recurrence and final outcome are extremely important in defining risk-adapted treatments for patients with nonmetastatic osteosarcoma of the extremity., Methods: A homogeneous group of 789 patients treated at a single institution between March 1983 and March 1999 with different protocols of neoadjuvant chemotherapy, with a minimum followup of 5 years, were retrospectively evaluated in relation to gender, age, serum levels of alkaline phosphatase, tumor site and size of the pathologic fracture, type of surgery, protocol of chemotherapy, surgical margins, and histologic response to preoperative treatment., Results: The 5-year event-free survival (EFS) and overall survival rates were 60.1% and 67.5%, respectively. Upon univariate analysis, EFS was significantly related to the age of patients, serum value of alkaline phosphatase, tumor volume, histologic subtype, type of surgery, surgical margins, histologic response to preoperative treatment, and chemotherapy protocol. Local recurrences (4.8%) were significantly correlated with surgical margins. The 5-year post-recurrence EFS survival was 17% and was significantly lower for patients who had a local recurrence and metastases than for those with metastases only. Patients who had a recurrence only in the lung had a post-recurrence survival rate significantly better than others, correlated with the number of metastatic nodules and the length of the disease-free interval., Conclusions: Upon multivariate analysis, age < or = 14 years, high serum levels of alkaline phosphatase, tumor volume > 200 mL, a two-drug regimen chemotherapy, inadequate surgical margins, and poor histologic response to treatment maintained independent prognostic values on the outcome of nonmetastatic osteosarcoma of the extremities. These factors must be considered when deciding risk-adapted treatments for osteosarcoma patients.

We aimed to identify pretreatment and treatment factors that may influence the outcome of Ewing's sarcoma family tumors of bone and enable customized therapy for future studies with a retrospective analysis of 579 patients with non-metastatic Ewing's sarcoma treated with combined adjuvant or neoadjuvant chemotherapy at a single institution between 1972 and 1998. We evaluated the prognostic significance of gender, age, site and volume of tumor, serum level of LDH, type of local treatment, type of chemotherapy and histologic response to preoperative treatment. The 5- and 10-year disease-free survival rates were 56.9% and 49.2% respectively. Multivariate analyses showed that all the evaluated factors, with exclusion of the tumor site, were significantly correlated with the 5-year disease-free survival. We concluded that the outcome of non-metastatic ESF of bone tumors is influenced by many clinical and treatment-correlated variables. In order to gain the greatest benefit from treatment, while reducing the morbidity, appropriate therapeutic strategies for different risk groups of patients should be selected. Criteria to stratify patients according to the risk of local or systemic relapse should not be based on a single prognostic factor, but should include all the variables that showed prognostic significance.

The relative risk of second tumors in patients with Ewing sarcoma is controversial, and little is known about their treatment and outcome. The purpose of the current study was to define the incidence and features of second tumors among 597 long-term survivors of nonmetastatic Ewing sarcoma treated with adjuvant and neoadjuvant chemotherapy, radiotherapy, and/or surgery. The authors found that the risk of secondary malignancy after adjuvant or neoadjuvant treatment of Ewing sarcoma is higher than that after other childhood or adolescent cancers only after radiotherapy. Based on this, postoperative radiotherapy should be avoided when surgery with adequate margins is feasible.

To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.

We investigated the renal function of pediatric and adult patients who had been submitted to chemotherapy with high-dose methotrexate (MTX), cisplatin and high-dose ifosfamide (IFO). We observed 43 osteosarcoma patients aged 4--34 years (median 16 years). The median received cumulative doses of MTX, cisplatin and IFO were 60.1 g/m, 598 mg/m and 73.5 g/m. Renal function was assessed by measurement of creatinine clearance, renal threshold for phosphate (Tmp/GFR), urinary alpha1-microglobulin (A1M):creatinine ratio, urinary albumin:creatinine ratio, 24-h glycosuria and proteinuria. The median interval between chemotherapy completion and first renal function assessment was 2 months (range 2--4 months); assessments were then performed at a median interval of 16 months (range 9--49 months). A significant decrease of TmP/GFR was observed only in the pediatric group (under 18 years): the percentage of patients with TmP/GFR<1 mmol/l increased from 21% (six of 28) at the end of treatment to 46% (13 of 28) at the late assessment. Glycosuria in 10 (67%) of 15 adults and 21 (75%) of pediatric patients was detected with an increased incidence compared to the early post-chemotherapy assessment (13% adults and 29% children). A significant increase of the albumin:creatinine ratio and A1M:creatinine ratio was observed only in adults. Overall, 21 patients had a reduced glomerular function at the latest evaluation, associated with glycosuria in 15 patients (71%), proteinuria in 14 (67%) and TmP/GFR<1 mmol/l in 11 (52%). We conclude that strict monitoring of renal function should be recommended in pediatric and adult patients after chemotherapy with high-dose MTX, cisplatin and high-dose IFO.

The medical records of patients with high-grade osteosarcoma observed at the authors' institution between 1972 and 1999 were reviewed to study whether osteosarcoma in preadolescent patients has a different biology and a worse prognosis than in older patients. To assess epidemiologic differences, the first analysis evaluated 1,603 patients regardless of tumor stage and site and treatment received. In the second analysis, only 1,136 patients (317 preadolescent and 819 older patients) with nonmetastatic extremity osteosarcoma, treated with the same protocols of chemotherapy, were evaluated to assess differences in prognosis and in the pattern of relapse. Most preadolescents were female (56% vs. 44%, P < 0.0001), and most tumors were located in the extremity (95% vs. 5%, P < 0.001). The 5-year event-free survival (60% [95% CI 53-67%] vs. 58% [95% CI 46-63%]), the overall survival (67% vs. 65%), the rate of amputation (24% vs. 25%), time (21 vs. 22 months) and type of first relapse (systemic 98% vs. 95%, local 2.3% vs. 4.7%) the site of first metastases (pulmonary, 87% vs. 89%), and good histologic response to preoperative treatment (65% vs. 63%) were essentially the same. The authors concluded that there is no need to employ different therapies for the two groups.

Background: Underrecognition and undertreatment of depression in primary care has been regarded as a major public health problem. In contrast, some studies found that among patients labeled as depressed by primary-care physicians (PCPs), a relevant proportion do not satisfy international diagnostic criteria for depression. The aims of this study are: (1) to assess disparity between PCP diagnosis and research diagnosis of depression; (2) to compare antidepressant treatment in concordant and discordant cases of depression., Methods: Data are gathered from a national survey on depressive disorders in primary care, conducted with the collaboration of 191 PCPs. Three hundred and sixty-one PCP patients were evaluated, and their psychiatric diagnosis was established by the 'unaided' PCPs and by using a research interview for depression., Results: PCPs recognized 79.4% of cases of depression and prescribed antidepressants to 40.9% of them. Yet, 45.0% of patients labeled as depressed by the PCPs were not cases of depression according to ICD-10 criteria; 26.9% of false-positive cases received an antidepressant. Globally, 35% of antidepressants for 'depression' were prescribed to false-positive cases., Conclusions: Underrecognition and undertreatment of depression in primary care seem to be less alarming. Conversely, PCP diagnoses of depression appear to be more inclusive than psychiatric diagnostic criteria. A possible consequence of this apparently more inclusive diagnostic threshold may be an excessive use of antidepressants. These changes require a corresponding change in research, toward efficacy and safety of the treatment of milder cases, and in education, toward the distinction between the management of mild and severe cases of depression., (Copyright (c) 2005 S. Karger AG, Basel.)

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.

Aims: The study evaluated the correlation between pretreatment serum lactate dehydrogenase (LDH) levels with the stage of disease and its clinical prognostic value., Methods: Pretreatment serum LDH of 1421 patients with osteosarcoma of the extremity were assessed to investigate whether the enzyme correlates with the stage of the tumor. In 860 assessable patients with localized disease, treated according to 10 different protocols of adjuvant (four) and neoadjuvant chemotherapy (six), we also evaluated the correlation between the serum levels of LDH and outcome., Results: According to the stage of disease, the rate of high serum level of LDH was significantly higher in 199 patients with metastatic disease at presentation than in 1222 patients with localized disease (36.6% vs 18.8%; P < 0.0001). In these patients, the 5-year disease-free survival was 39.5% for patients with high LDH levels and 60% for those with normal values. The 5-year disease-free survival correlated with serum level of LDH at univariate and multivariate analysis, although it lost its significance when histologic response to chemotherapy was also considered in the multivarite analysis., Conclusions: Serum LDH has a prognostic value and it should be considered in evaluating the results of therapeutic trials of chemotherapy, as well as defining a category of patients at high-risk of relapse to be treated with a more aggressive regimen.

Background: Investigation of the relation between primary tumor and metastatic disease is necessary for the identification of predictive factors for postrecurrence survival (PRS) in patients with recurrent osteosarcoma., Methods: Cellular levels of P-glycoprotein, ErbB-2, p53, and Bcl-2 expression were evaluated in primary tumor biopsy and metachronous pulmonary metastasis specimens from 19 patients with high-grade osteosarcoma. Results were analyzed for differences between primary tumor and pulmonary metastases and for correlations between expression patterns and survival., Results: Positive staining in lung metastases was noted in 68%, 53%, 32%, and 84% of patients for P-glycoprotein, ErbB-2, p53, and Bcl-2, respectively. These percentages were higher than those observed in primary tumor specimens for all genetic markers evaluated, with a significant difference in the percentage of patients with positive staining for P-glycoprotein (68% vs. 32%; P = 0.05) and a near-significant difference in the percentage of patients with positive staining for Bcl-2 (84% vs. 53%; P = 0.08). Patients with ErbB-2 expression in the primary tumor were more likely to have multiple metastases and shorter recurrence-free intervals compared with patients in whom ErbB-2 expression was not observed, whereas differences in P-glycoprotein, p53, and Bcl-2 expression were not related to differences in metastatic pattern. PRS was influenced by p53 expression levels in pulmonary metastases, with patients who had negative staining for p53 having a significantly better PRS rate relative to patients with positive staining for p53 (3-year PRS rate: p53-negative, 64%; p53-positive, 17%; P = 0.008)., Conclusions: In the current study of patients with high-grade osteosarcoma, most patients exhibited increased cellular expression of P-glycoprotein, ErbB-2, and Bcl-2 in recurrent pulmonary metastases compared with primary tumor. Further studies aimed at investigating the relation between altered p53 expression in lung metastases and postrecurrence survival are recommended., (Copyright 2004 American Cancer Society.)

We retrospectively studied 790 patients with osteosarcoma treated by neoadjuvant chemotherapy at a single institution between 1983 and 2000 according to different protocols, all including a high dose of methotrexate (HDMTX), to determine the incidence of delayed clearance of HDMTX, and identify patients at high risk for this kind of toxicity. Chemotherapy was administered according to 7 different protocols, successively activated, in which HDMTX was associated with other drugs (cisplatin, adriamycin, ifosfamide) in different combinations. The doses of MTX ranged between 7.5 to 12 g/m(2) and patients received from 1 to 10 cycles with MTX for a total number of 4219 cycles. The incidence of delayed clearance of MTX (plasma values of the drug at 24 h >5 microM/l) was 8.6% per patient and 1.6% per cycle of treatment. In 51 cases the delayed clearance of MTX was "mild" (plasma values of MTX at 24 h between 5 and 19 microM/l) and in 18 cases "severe" (plasma values of MTX at the 24 h >20 microM/l). The delayed clearance of MTX was significantly correlated with the age of patients (16% for patients over 20 vs. 6% for younger patients: p=0.0001) and was significantly more frequent during the first cycles of chemotherapy (7% during the first 3 cycles of treatment vs. 2% during subsequent cycles). There was also a significant correlation (p=0.0001) between the plasma values of MTX at the end of the infusion and at 18 h and the delayed clearance of the drug. In addition to support treatment by increased hydration and sodium bicarbonate, all patients who experienced the delayed clearance of MTX were treated solely with a high dose of leucovorin (HDLV), which was started at the first 18 h. Significant neutropenia and/or thrombocythopenia, increase of serum creatinine, mucositis of varying degrees and vomiting occurred in most cases of severe delayed clearance of MTX, but all patients completely recovered. We conclude that in spite of adequate hydration and urine alkalinization and the use of pharmacokinetically guided leucoverin rescue, delayed clearance of MTX may still occur and that its incidence is higher in older patients and during the first cycles of treatment. However, if "rescue" treatment is started early, the consequent morbility is tolerable and these patients can be rescued using only HDLV, without the need for extracorporeal removal.

We compared the residual ovarian function and the fertility of two groups of female patients treated at different times at the authors' institution by neoadjuvant chemotherapy for localized osteosarcoma of the extremities. From 1997 to 2000, one group of 31 females received neoadjuvant treatment according to the IOR 6 protocol, which included high-dose ifosfamide, high-dose methotrexate, adryamycin, and cis-platinum. In this group of patients an oral contraceptive (OC) was given in an attempt to prevent post-chemotherapy ovarian failure. Another group of 90 patients was treated between 1974 to 1995 with the same antiblastic drugs according to similar protocols (IOR 1-IOR 5). These patients did not receive OC or other treatment to protect ovarian function. There were no significant differences between the two groups of patients. Early chemotherapy-induced menopause occurred in 3 out of 19 postpubertal patients who received the OC and in 3 out of 71 postpubertal patients in the control group. In the OC group there were 2 cases of thrombophlebitis. No delay in menarche was seen in prepubertal patients. From statistical evaluation we underline that age and alkylant doses are the most important predictive factors for early menopause and that oral contraceptives during chemotherapy do not protect ovarian function in patients receiving high-dose alkylant based chemotherapy.

In 560 patients with high-grade osteosarcoma of the extremity treated with 5 different protocols of neoadjuvant chemotherapy at a single institution between 1983 and 1995, the pre-treatment serum alkaline phosphatase (SAP) was examined to evaluate whether the enzyme levels had a clinical value in predicting the course of the disease. SAP was normal in 302 (54%) patients and high in 258 (46%). High levels of SAP was observed significantly and independently more frequently in male patients over 14-years-old, and in tumours larger than 150 ml and of osteoblastic subtypes. The 5-year event-free survival (EFS) and overall survival (OS) for all patients were respectively 60 and 68%. With multivariate analysis only two factors were independently correlated with the 5-year EFS: SAP levels (p=0.002) and the grade of chemotherapy-induced necrosis (p=0.0001). The authors conclude that in planning randomized clinical trials of neoadjuvant treatment for osteosarcoma, patients should be stratified according to SAP levels, and that when tailoring the aggressiveness of postoperative chemotherapy to the risk of relapse, in addition to the histologic response to preoperative treatment, the SAP levels should also be considered.

Background: In osteosarcoma, as in other tumors, the presence of metastases at presentation is generally considered a consequence of late diagnosis. To verify this, the authors investigated whether there was a relationship between the stage of the disease at presentation and several clinical and pathologic characteristics, including the interval between the onset of first symptoms or signs and the final diagnosis., Patients and Methods: One thousand seventy-one patients with high-grade osteosarcoma of the extremity were observed between 1980 and 1999. Of these, 891 had a localized tumor and 180 had metastases at the time of diagnosis., Results: Compared with patients with localized disease, patients with detectable metastases at the time of diagnosis had higher serum levels of alkaline phosphatase, larger primary lesions, and tumors often located in the femur and humerus. In terms of time to diagnosis, the interval between the onset of first symptoms and the final diagnosis was significantly shorter in patients with metastases than in patients with localized tumor. This surprising finding probably reflects a more rapid growth of the tumor., Conclusions: These results suggest a different biologic phenotype and aggressiveness of the tumor in a subgroup of patients and that the stage of the disease at presentation depends more on the properties of these tumors than on late diagnosis.

One hundred and forty-four patients with osteosarcoma of the extremity treated with neoadjuvant chemotherapy at the authors' institution between 1986 and 1989 were retrospectively analyzed to evaluate the relationship between the dose-intensity of chemotherapy actually received (RDI) and the prognosis. Preoperative chemotherapy consisted of high-dose methotrexate i.v., cisplatin i.a., and doxorubicin i.v. After surgery "good responder" patients (90% or more tumor necrosis) had a 31-weeks of chemotherapy with the same drugs, while "poor responder" patients (less than 90% tumor necrosis) received a 40 weeks treatment with ifosfamide and etoposide added to the three drugs used preoperatively. Due to delays and dose-reductions, only 17 patients (12%) received the treatment exactly as scheduled by the protocol, 66 (46%) received a dose-intensity between 90 and 99%, and 61 (42%) a dose-intensity between 63 and 89%. At a follow-up ranging between 10 and 13 years, 97 patients (67%) remained continuously free of disease, 45 relapsed, and two died of doxorubicin-induced cardiopathy. The continuous disease-free survival (CDFS) was not related to patients' gender and age, tumor histology, site and size, serum value of alkaline phosphatase, type of surgery and histologic response to chemotherapy. According to the RDI, CDFS resulted significantly higher for those 81 patients who received 90% or more of the scheduled dose-intensity than for those 61 who had less than 90% of the scheduled dose-intensity (76.5% v.s. 57.3%; p<0.02). These results seem to suggest that in neoadjuvant treatment of osteosarcoma the dose-intensity of chemotherapy is crucial for outcome, therefore every effort should be made to avoid reductions of doses and/or delays in performing the cycles of chemotherapy.

Patients with metastatic Ewing's sarcoma of bone have a poor prognosis. A relation between clinical characteristics and presence of metastatic disease at diagnosis in patients with Ewing's sarcoma of bone was investigated. Data from 618 patients [136 (22%) with metastases at diagnosis] registered at the authors' institution between April 1972 and December 1997 were collected. The distribution of several clinical and hematologic parameters in patients with metastases and those without metastases was analyzed, and clinical risk factors of metastatic disease at presentation were analyzed by means of multivariate logistic regression analysis. All the variables significant at the univariate analysis (age, fever, site, volume, lactic dehydrogenase, anemia, and interval between onset of symptoms and diagnosis) were considered in the multivariate analysis. Pelvic location of the tumor, high level of lactic dehydrogenase, presence of fever, an interval between onset of symptoms and diagnosis less than 3 months, and age older than 12 years were found to be risk factors of clinically evident metastatic disease. In the subset of patients with no risk factors the rate of metastatic disease at presentation was only 4%; in case of contemporary presence of two factors it was 23%, although it was almost double (44%) if three or four factors were present. Only six patients were positive for five factors and all of them had metastases at presentation. The parameters identified are clinical markers of Ewing's sarcoma having a particularly aggressive metastatic behavior.

Purpose: To provide an estimate of long-term prognosis for patients with osteosarcoma of the extremity treated in a single institution with neoadjuvant chemotherapy and observed for at least 10 years., Patients and Methods: Patients with nonmetastatic osteosarcoma of the extremity were preoperatively treated with high-dose methotrexate, cisplatin, and doxorubicin (ADM). Postoperatively, good responders (90% or more tumor necrosis) received the same three drugs used before surgery, whereas poor responders (less than 90% tumor necrosis) received ifosfamide and etoposide in addition to those three drugs., Results: For the 164 patients who entered the study between September 1986 and December 1989, surgery was a limb salvage in 136 cases (82%) and a good histologic response was observed in 117 patients (71%). At a follow-up ranging from 10 to 13 years (median, 11.5 years), 101 patients (61%) remained continuously free of disease, 61 relapsed, and two died of ADM-induced cardiotoxicity. There were no differences in prognosis between good and poor responding patients. ADM-induced cardiotoxicity (six patients), male infertility (10 of the 12 assessable patients), and second malignancies (seven patients) were the major complications of chemotherapy. Despite the large number of limb salvages performed, only four local recurrences (2.4%) were registered., Conclusion: With an aggressive neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with nonmetastatic osteosarcoma of the extremity and amputation may be avoided in more than 80% of them. Because local or systemic relapses, myocardiopathies, and second malignancies are possible even 5 years or more after the beginning of treatment, a long-term follow-up is recommended for these patients.