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Background: Patients with osteosarcoma and Ewing sarcoma have achieved longer survival over the past decades, but late side effects of chemotherapy and radiotherapy have become important concerns., Methods: The authors reviewed all patients with localized osteosarcoma or Ewing sarcoma who had been enrolled in the Italian Sarcoma Group neoadjuvant protocols from 1983 through 2006. Data were updated in December 2010 to determine 3 endpoints: the incidence of a secondary primary cancer (designated as "second malignant neoplasm" [SMN]), infertility, and cardiotoxicity., Results: Data were available on 883 patients with osteosarcoma and 543 patients with Ewing sarcoma. In the osteosarcoma group, there were 39 SMNs (4.4%) in 36 patients; in the Ewing sarcoma group, 15 patients (2.8%) experienced a single SMN each. The cumulative 10-year and 20-year incidence of an SMN (±standard error) was 4.9% ± 0.9% and 6.1% ± 1.2%, respectively, in the osteosarcoma group and 3.4% ± 0.9% and 4.7% ± 1.6%, respectively, in the Ewing sarcoma group. The most common SMN in the osteosarcoma group was breast cancer (n = 11), and the most common SMN in the Ewing sarcoma group was radiotherapy-induced osteosarcoma (n = 6). After 20 years, the risk of developing an SMN increased, whereas the risk of a recurrence of the primary tumor decreased. Permanent sterility was more common in males than in females. Doxorubicin cardiotoxicity occurred in 18 patients with osteosarcoma (2%) and in 7 patients with Ewing sarcoma (1.3%)., Conclusions: The awareness of late side effects in long-term survivors of primary bone cancers should encourage longer follow-up., (Copyright © 2012 American Cancer Society.)

Purpose: We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity., Patients and Methods: Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), and IFO 30 g/m(2)) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS)., Results: From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B., Conclusion: IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.

Despite advances in diagnostic imaging, the evolution of neoadjuvant chemotherapy and the refinements in limb-salvage surgery, the progression-free survival rate remains poor for patients with metastatic, recurrent or unresectable osteosarcoma. Different therapeutic strategies for these subgroups of patients have been employed to control disease and prolong survival. Treatment options are limited and controversial, including systemic and localized therapies. Surgical resection, whenever feasible, is still the standard treatment in advanced osteosarcoma. The role of chemotherapy is unclear while the use of radiotherapy, embolization and thermal ablation is increasing. New therapeutic experimental approaches and novel target therapies are needed to improve the outcome of these subgroups of patients.

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., (Copyright © 2009. Published by Elsevier Ltd.)

Background: The occurrence of high-grade osteosarcoma is rare in children aged 5 years or younger and only limited series or case reports have been described., Methods: The records of patients aged 5 years or younger with non-metastatic high-grade osteosarcoma of the extremities treated with surgery and adjuvant or neo-adjuvant chemotherapy at Rizzoli Institute between 1972 and 1999 were retrospectively evaluated in relation to gender, primary tumor site, histological subtype, surgical treatment, chemotherapy-induced tumor necrosis, 5- and 10-year event-free survival (EFS), and rate of local recurrence. Data were compared to patients aged 6-40 years entered with the same diagnosis and over the same time interval., Results: Data from 20 patients were collected. Comparing these data with those from 1,106 patients 6-40 years of age only two main differences resulted: the younger group showed a higher rate for fibroblastic subtype (P < 0.01) and for amputation surgery (P < 0.01). Among the two groups, no statistical difference was observed for the 5-year EFS (60% vs. 53.8%; P = 0.6) and 10-year EFS (60% vs. 52.1%; P = 0.5). The rate of local recurrence was 5.0% and 5.4%., Conclusions: These findings suggest that in non-metastatic osteosarcoma of the extremities outcome and clinical characteristics are similar among children 5 years of age or younger and older patients. However, in the younger group we have observed a significant higher rate of fibroblastic subtype as well as a significant higher rate of mutilating surgery. Pediatr Blood Cancer., (Copyright 2010 Wiley-Liss, Inc.)

The Bone Tumor Center of the "Istituto Ortopedico Rizzoli" was established in 1955 with the aim of studying and treating the musculoskeletal tumors. Between 1959 and 2006, 1245 patients with high grade nonmetastatic osteosarcoma of the extremity were treated at our Institute. Most of them were enrolled in study protocols. In the "prechemotherapy era", the cure rate was 11%, with an amputation rate of 90%. Our first experience with adjuvant chemotherapy was in 1972. A total of 223 patients received adjuvant chemotherapy, with a disease-free survival (DFS) ranging from 45% to 53%, according to the chemotherapy protocol used. With the introduction of neoadjuvant chemotherapy, the resection rate increased and reached 94%, when high dose fosfamide was added to standard doses of methotrexate, cisplatin, and adriamycin. In the last few years, the results of treatment of nonmetastatic osteosarcoma of the extremity have reached a plateau (64% five-year DFS), and strategies of dose intensification are not able to improve the prognosis. Not only new active drugs, but also different approaches to the disease, are needed. In this regard, we are now investigating tumor microenvironment-targeted agents and chemotherapy protocols based on prospective biological stratification of patients. Collaborative projects with international groups and institutions are crucial for this rare disease.

Medical records of 133 patients, 10 years old or younger with primary high-grade nonmetastatic osteosarcoma of the extremities treated at the Rizzoli Institute between 1983 and 1999 with neoadjuvant chemotherapy were reviewed and compared with those of 782 patients aged 11 to 40 years treated in the same period with the same chemotherapy protocols. In comparison to the older group, the younger group had more females, more patients with normal lactic dehydrogenase levels, and more non-limb-salvage procedures (amputation or rotationplasty). Five-year event-free and overall survivals were essentially the same in the two groups (63% and 71% vs. 60% and 70%) as were the patients rescued after relapse and presently event-free (18% vs. 20%). The authors conclude that there does not seem to be any indication to treat preadolescent primary high-grade nonmetastatic osteosarcoma patients by alternative and/or more aggressive therapies.

Background and Methods: 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., Results: After neoadjuvant chemotherapy, metastases disappeared in 14 patients, 16 were judged unresectable by both our thoracic surgeons, 132 had primary tumors and lung metastases removed simultaneously. Removal of lung metastases was complete in 123 and incomplete in 9. Histologically lesions were benign in 32 patients. For the 100 patients simultaneously operated with histologically proven lung metastases, 5-year event-free survival (EFS) was 18.9%; 27.4% for the 91 who had a complete resection of pulmonary lesions and entered remission as opposed to none for 9 patients who had incomplete removal of lung nodules. Among these 91, 5-year EFS was significantly higher for patients with monolateral compared to bilateral lesions (27.1% vs. 7.9%, P < 0.02) and when only one to three metastatic nodules were present (40.0% vs. 13.3%, P < 0.0001)., Conclusions: These different results, demonstrate that our treatment had a reasonable survival outcome whereas other groups continue to have dismal prognosis. More efforts should be made to improve survival by identifying new active agents or novel approaches with cellular molecular targets., ((c) 2008 Wiley-Liss, Inc.)

A case of spontaneous regression of a pulmonary metastasis from high-grade osteosarcoma is reported. The metastasis developed 5 years after chemotherapy and amputation for a distal femur osteosarcoma. The sarcomatous nature of the lesion was histologically confirmed. No treatment was attempted owing to the patient's refusal. The patient was followed up every 3 months and a spontaneous regression of the lesion was documented. Seven years after the diagnosis of lung metastases, no pulmonary nodules or other signs of relapse are present.

Background: Indications and contraindications for limb salvage versus amputation for local treatment of osteosarcoma of the extremity are still controversial., Patients and Methods: Patients (1,126) with non-metastatic osteosarcoma of the extremity, treated in a single institution between 1972 and 1999 with different protocols of adjuvant and neoadjuvant chemotherapy were evaluated to establish factors that could influence local recurrence (LR) and outcome., Results: The 5-year event-free survival and overall survival were 55% and 66%. At a follow-up ranging between 5.5 and 32.5 years (mean18.6 years) of the 1,126 evaluated patients, 607 (54%) remained continuously disease-free and 519 relapsed. LR developed in 61 patients (5.4%) after a median time of 2.3 years (0.2-17). For this group of patients the 5-year post-relapse event-free survival and overall survival from the last relapse were, respectively, 11.4% and 16.4%. At the multivariate analyses only surgical margins and histologic response to preoperative treatment resulted to be independent prognostic factors for LR., Conclusion: Considering the risk of LR after surgery with inadequate surgical margins and poor prognosis of LR in osteosarcoma, limb salvage procedures should be performed only when adequate margins surgical margins can be achieved. In case of inadequate margins, an immediate amputation should be considered.

The overall survival of patients with osteosarcoma of the extremity with localized disease has greatly improved in recent decades and today about half of them are long-term survivors (i.e. more than 10 years). Owing to the increased number of long-term survivors, late side effects of combined chemotherapy are more evident and have been better studied. Doxorubicin-induced cardiac toxicity is still an important and ominous side effect even if the percentage of affected patients is low. In this study, we report the incidence of clinically symptomatic cardiac toxicity induced by doxorubicin, in our series of 755 patients with localized osteosarcoma of the extremity, who had been treated from 1983 to 2000 with different protocols at our institution. Thirteen (1.7%) patients developed a clinically symptomatic cardiac toxicity (New York Heart Association class II-IV). Six of them died. Of the seven still alive, three needed a heart transplant. The case report of these 13 patients is described in detail. A higher incidence of cardiac toxicity was noted in women patients (eight women=2.5% and five men=1.1%). Cumulative dose and dose intensity (cumulative dose/week of treatment) are the most important risk factors in developing doxorubicin-related cardiomyopathy.

Background: It is unclear whether adult patients with high-grade non-metastatic osteosarcoma of the extremities, treated with neoadjuvant chemotherapy according to protocols designed for adults, have a different outcome than younger patients treated with conventional protocols., Patients and Methods: From 1994 through 1999, we treated 34 patients with non-metastatic osteosarcoma of the extremities. These patients were aged mean 50 years (41-60), and received 4 cycles of multidrug chemotherapy (1 preoperatively and 3 postoperatively). Each cycle consisted of a combination of Cisplatin/Adriamycin, Ifosfamide/Cisplatinum and Ifosfamide/Adriamycin. 30 patients had limb salvage and 3 underwent amputation. During preoperative treatment, 1 died of toxicity. 16 patients had a good histological response to chemotherapy (> or = 90% tumor necrosis) and 17 had a poor response., Results and Interpretation: With a median follow-up of 8 (5-11) years, 19/33 patients remained continuously disease-free and 14 relapsed (10 with metastases, 3 with local recurrence and metastases, and 1 with local recurrence alone). After further treatments, 2/14 relapsed patients are alive and disease-free, 11 died of tumor, and 1 is alive with uncontrolled disease. 5-year event-free survival and overall survival were 56% and 70%, respectively. These results, which are similar to those of 296 patients under 40 years of age who were treated with conventional chemotherapy (5-year EFS 59% and 5-year OS 70%), indicate that neoadjuvant chemotherapy improves prognosis and also reduces amputations in patients aged over 40 with osteosarcoma of the extremities.

Purpose: Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO., Patients and Methods: Between 1983 and 1998, we treated 20 RIO patients, ages 4-36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times., Results: Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7-22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group., Conclusion: Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.01).

We evaluated the rate of second malignancies in 1205 patients with osteosarcoma of the extremity treated at our Institution with different protocols of adjuvant and neoadjuvant chemotherapy. Twenty-six patients (2.15%) developed a second malignant neoplasm at a median of 7.6 years (1 to 25 y) after primary osteosarcoma treatment. Of these, 2 developed a third cancer which were not considered in the series. Second neoplasms were leukemia (10), breast (7), lung (2), kidney (2), central nervous system cancer (2), soft tissue (1), parotid (1), and colon (1). The rate of second neoplasms was significantly higher in female patients, and the latent period shorter in hematologic tumors compared with solid tumors. Ten of these 26 patients are disease free at a median of 7.7 years (range 1 to 15 y) after the last treatment. The rate of second malignancies observed in the osteosarcoma group was significantly higher than that observed in the control group of 1160 patients with benign tumors treated in the same period at our Institute (2.2% vs. 0.8%, P<0.009). Our study showed that the risk of second neoplasm within 15 years increased and then leveled off and that although secondary solid tumors could be explained as unrelated cases, leukemias seem to be over represented.

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.

The aim was to evaluate the clinical impact of P-glycoprotein in primary non-metastatic high-grade osteosarcoma patients, treated with neoadjuvant chemotherapy protocols. P-glycoprotein was assessed by immunohistochemistry on paraffin-embedded tissue samples collected at time of diagnosis from 94 osteosarcoma patients, treated with the Italian Sarcoma Group/Scandinavian Sarcoma Group 1 (ISG/SSG 1) protocol. P-glycoprotein-positivity at diagnosis was found in 53/94 ISG/SSG 1 cases (56%) and emerged as the single factor significantly associated with an unfavourable outcome from survival and multivariate analyses. A comparative analysis of the subgroup of 94 patients considered for P-glycoprotein evaluation and the whole series of ISG/SSG 1 patients showed that this marker retained its prognostic value also in the latter group. In osteosarcoma patients treated with doxorubicin-based chemotherapy protocols, P-glycoprotein overexpression at diagnosis is an important adverse prognostic factor for outcome. P-glycoprotein evaluation can therefore constitute the basis for stratifying, at diagnosis, osteosarcoma patients for whom alternative treatments may be considered.

The current combination treatment, chemotherapy and surgery, has significantly improved the cure rate and the survival rate of primary bone osteosarcoma. The 5-year survival rate has increased in the last 30 years from 10% to 70%. Even in patients with poor prognosis, such as those with metastases at diagnosis, the 5-year survival rate has reached 20-30% due to chemotherapy and the surgical removal of metastases and primary tumor. However, the most effective drugs are still the same as those employed over the last 20 years as front line neoadjuvant or adjuvant chemotherapy: Doxorubicin, Cisplatin, Methotrexate, Ifosfamide. No standard, second line therapy exists for those who relapse. At relapse, due to the lack of new non-cross-resistant drugs, surgery is still the main option when feasible. Other drugs have been employed in relapsed patients with poor results. This article reviews the state of the art of treatment for bone osteosarcoma in the pediatric age.

The aim of this study was to identify predictive factors of late relapse in nonmetastatic osteosarcoma patients treated at the Rizzoli Institute from 1983 to 1997. Clinical features of patients who had late (>4 y of follow-up) or earlier recurrence were compared. Late relapse was reported in 24 (3.7%) of the 648 patients who entered the studies. A surgical complete remission was achieved in 19 (79%) patients. The 5-year probability of postrelapse survival was 65% for the complete remission patients (48% in the entire group), which was significantly better than that of the patients (5-year postrelapse survival 20%) with an early relapse. Sex, site, and size of the tumor, histologic subtype, alkaline phosphatase and lactate dehydrogenase serum levels, type of surgery, and histologic response did not significantly differ between patients with late or early relapse. No clinical predictive factors of late relapse were identified and a prolonged follow-up is recommended for all patients.

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.

Around 1148 patients with non-metastatic osteosarcoma of the extremity were treated in a single institution between 1972 and 1999 with 4 different protocol of adjuvant and 7 different protocols of neoadjuvant chemotherapy. The rate of limb salvage increased from 20% to 71%. The 5-year event-free survival (EFS) and overall survival (OS) were 57% and 66%, respectively. The 10-year EFS and OS were 52% and 57%, respectively, and the results significantly correlated with serum alkaline phosphatase levels; the type of chemotherapy (adjuvant vs neoadjuvant); and with histologic response to pre-operative treatment. Aggressive chemotherapy and surgery could cure about the 60% of patients with osteosarcoma of the extremity. However, since local or systemic relapses, myocardiopathies and a second malignancy are possible even 5 or more years since the beginning of treatment, a long-term follow-up is recommended.

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.

Background: Surgical resection of lung metastases is widely accepted in osteosarcoma patients. Few data exist on treatment of recurrent pulmonary metastases. The authors of the current study retrospectively analyzed patients with osteosarcoma who received surgery for recurrent lung metastases., Methods: From 1980 to 2001, 127 metastasectomies were performed on 94 patients. Criteria of eligibility were no metastases beyond the lung, no local recurrence, possibility of achieving complete resection of metastases without causing respiratory insufficiency, acceptable operative risk. Data were statistically elaborated with survival analysis according to Kaplan-Meier method of univariate analysis, life tables and Gehan statistic model, and multivariate analysis using Cox regression test. Results were considered in terms of time from first (DFI1) and second (DFI2) metastasectomy., Results: Of 94 patients operated upon twice, 59 (62.7%) died. Thirty-five (37.3%) are alive; 31 (32.9%) of these are continuously disease-free. The 3- and 5-year event-free actuarial survival curve from first metastasectomy was 45%, and 38%, respectively, whereas from the second metastasectomy, it was 33% and 32%, respectively. According to a Cox regression model, DFI1 has a risk of death of 0.974 times and DFI2 of 0.972 times for every additional month of survival. In multivariate analysis, Cox regression test showed the best predictive model of local recurrence and number of metastases (P = 0.0014)., Conclusions: The authors concluded that patients persistently free of the primary osteosarcoma who developed recurrent resectable metastatic disease of the lung should be considered for reoperation a second, third, or fourth time, as these patients had similar DFI curves after five-years., (Copyright 2005 American Cancer Society)

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.

Expression of HER2 was evaluated by immunohistochemical techniques in 84 osteosarcoma (OS) and 113 Ewing's sarcoma (ES) paraffin-embedded tumour biopsies. HER2 gene status was also assessed in a panel of cell lines as well as in vitro efficacy of trastuzumab (a humanised antibody directed against HER2) as single agent or in combination with the insulin-like growth factor I receptor (IGF-IR) IR3 antibody. Overexpression of HER2 was present in 32% of OS and 16% of ES and was significantly associated with the increased expression of P-glycoprotein, a surface molecule responsible for multidrug resistance. Event-free survival analyses revealed a prognostic value for HER2 and/or P-glycoprotein expression in OS, but not in ES. However, despite its prognostic relevance, no therapeutic effectiveness was observed pre-clinically for trastuzumab-driven therapy, in both OS or ES cell lines, unless the antibody was associated with anti-IGF-IR targeting strategies. Therefore, the therapeutic potential of trastuzumab in these neoplasms may be better exploited in combined treatments with anti-IGF-IR approaches.

Previous investigations have suggested that osteosarcoma may be associated with a taller stature, but the relationship between height and osteosarcoma remains controversial. Height at diagnosis was evaluated in a continuous series of 962 osteosarcoma subjects treated between 1981 and 2001. Patients diagnosed during growth (group 1) were separated from those diagnosed in adulthood (group 2). Height (H) and final height (FH) were expressed as standard deviation scores (SDS), calculated by national reference data. Group 1 subjects were above the 50th centile and their mean H-SDS values (0.31 +/- 1.1) were significantly higher than the mean FH-SDS values (P < 0.0001) of the group 2 subjects, both in males and females. In contrast, the mean FH-SDS (0.01 +/- 1.1) of group 2 did not differ from that of the reference population. The highest incidence of osteosarcoma was at 12.5 years in females, 14.5 years in males. These data confirm previous observations of an association between osteosarcoma development and height, at least in growing individuals. The higher incidence during the pubertal spurt, in the anatomic sites of greater growth and in taller individuals, suggests that growth factors play an important role in the pathogenesis of this bone cancer.

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.

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.

The fourth case in the literature is presented of a patient with the rare association of hyperparathyroidism and osteosarcoma. A 56-year-old woman presented with hyperparathyroidism and a lesion in the tibia. Initial diagnosis was brown tumor. Histology, however, revealed osteosarcoma, and the patient was treated accordingly. The experimental induction of osteosarcoma by parathormone in rodent studies makes this finding alarming, considering the increasing use of parathormone in the treatment of osteoporosis. The mechanism by which osteosarcoma is induced in humans cannot be explained based on current knowledge of mechanisms of action of parathyroid hormone.

Second malignant neoplasms (SMNs) after treatment of children and adolescent cancers have been extensively studied. Lung cancer as an SMN is rare in all type of primary cancer in children and in osteosarcoma as well. The authors reviewed all cases of osteosarcomas treated at their institution from 1975 to 2000 and found 22 cases of SMN, only 1 involving lung cancer. The authors describe this latter case, a 17-year-old girl with a localized osteosarcoma of the tibia who developed simultaneously lung metastases of osteosarcoma and a primitive lung adenocarcinoma only 18 months from the diagnosis. Lung cancer is unusual in youths as a primary malignancy or as a second primary malignancy. The occurrence of a primitive lung cancer together with lung metastases from osteosarcoma is even more unusual, and examination of all new lung nodules is highly recommended.

Background: High-dose methotrexate (HDMTX)-induced renal dysfunction can be life threatening, because it delays methotrexate (MTX) excretion, thereby exacerbating the other toxicities of MTX. HDMTX-induced nephrotoxicity has been managed with high-dose leucovorin, dialysis-based methods of MTX removal, thymidine, and with the recombinant enzyme, carboxypeptidase-G2 (CPDG2), which cleaves MTX to inactive metabolites. The objectives of the current study were to estimate the current incidence of HDMTX-induced renal dysfunction in patients with osteosarcoma and to compare the efficacy and recovery of renal function for dialysis-based methods of MTX removal with treatment using CPDG2., Methods: The literature was reviewed for osteosarcoma trials, use of dialysis-based methods for MTX removal, and reports of MTX-induced nephrotoxicity, including information regarding recovery of renal function. Clinical trial databases of select osteosarcoma studies were reviewed. The efficacy of CPDG2 and renal recovery after CPDG2 rescue was obtained from the database of a compassionate-release trial., Results: Approximately 1.8% of patients with osteosarcoma (68 of 3887 patients) who received HDMTX developed nephrotoxicity Grade >/= 2. The mortality rate among those patients was 4.4% (3 of 68 patients). Dialysis-based methods of MTX removal were used frequently but had limited effectiveness in removing MTX compared with the rapid reductions > 98% in plasma MTX concentrations achieved with CPDG2. CPDG2 did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis-based methods., Conclusions: HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma who are treated on clinical protocols with optimal supportive care. For patients with delayed MTX excretion and high plasma MTX concentrations, CPDG2 should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently., (Copyright 2004 American Cancer Society.)

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.)

Purpose: The aim of this study was to compare the results in terms of histologic response to primary chemotherapy of two sequential studies in osteosarcoma patients preoperatively treated with methotrexate, doxorubicin, cisplatin, and ifosfamide, given at different doses., Patients and Methods: Between January 1993 and March 1995, 171 patients with osteosarcoma of the extremity were treated according to a protocol of neoadjuvant chemotherapy with preoperative methotrexate, cisplatin, doxorubicin, and ifosfamide. From April 1995 to December 1999, 196 osteosarcoma patients were preoperatively treated with the same drugs at higher doses. Postoperatively, patients received the same treatment in both studies used, but poor responders (tumor necrosis <95%) had more cycles of treatment than good responders., Results: Comparing the two chemotherapy regimens, there were no significant differences in terms of good histologic response to chemotherapy (69% vs. 62%), 5-year event-free survival (60% vs. 65%), 5-year overall survival (74% vs. 80%), and rate of local recurrence (6% vs. 4%). The 5-year event-free survival was significantly related to the serum level of alkaline phosphatase before treatment (77% for patients with normal values vs. 46% for patients with high values) and the degree of histologic response to preoperative chemotherapy (69% for good responders vs. 54% for poor responders)., Conclusions: Increasing the doses of preoperative chemotherapy does not improve the rate of good histologic response and survival in osteosarcoma of the extremity. The degree of necrosis induced by preoperative treatment probably reflects an innate sensitivity to chemotherapy, which is not altered by increasing drug doses.

To investigate somatostatin receptors (SSTRs) in primary or metastatic high-grade osteosarcoma, 18 patients (12 without metastases, 4 with synchronous lung, and 2 with metachronous bone metastases) underwent SSTR scintigraphy. After intravenous (i.v.) injection of 200-250 MPq of 111In-pentreotide, images were recorded at 4 and 24 hours. All patients underwent 99mTc-methylene diphosphonate (MDP) bone scan (BS). Scans were interpreted both with qualitative evaluation and with semiquantitative image processing, by means of tumor-to-background ratio modification over time. Primary tumor: SSTR scintigraphy was positive in 12 (75%) patients: 10 (83%) of the 12 nonmetastatic patients, and 2 (50%) of those with synchronous metastases. Metastases: SSTR scintigraphy was positive only in one (17%) of the six patients with metastatic disease. No relation was found between SSTR scintigraphy results and gender, histologic subtype, site, and size of the tumor. After primary chemotherapy, 15 patients underwent surgery of primary tumor; a good histologic response was found in 7 (64%) of the 11 patients with positive SSTR scintigraphy versus 1 (25%) of the 4 patients with negative SSTR scintigraphy. High-grade osteosarcoma exhibits somatostatin receptors, usually detectable in the primary tumor, but not in the metastatic lesions. The different expression of somatostatin receptors observed in primary and metastatic lesions, and in patients with tumors having different chemosensitivity, could indicate a possible relation between somatostatin receptors and biological behavior of the tumor.

We report the case of a 17 years old female with a Ewing's sarcoma of the left femur treated with limb sparing surgery followed by local radiotherapy of 45 Gy and adjuvant chemotherapy with vincristine, doxorubicine, cyclophosphamide, actinomycin D. The patient received neoadjuvant chemotherapy for osteosarcoma and a left femur resection with endoprosthesis replacement. The patient is alive and free of disease 4 years after the treatment of this second malignant neoplasm (SMN). This case shows that radioinduced SMN can occurr with relatively low doses of RT (<50 Gy) and that it may occur very late.

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 (3-20) 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 rates were 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.

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.

Background: In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy., Methods: The authors investigated whether the subtypes correlated with histologic response to chemotherapy in 1058 patients with osteosarcoma of the extremities who were treated with neoadjuvant chemotherapy over the last 20 years. The tumors were classified as osteoblastic (70%), chondroblastic (13%), fibroblastic (9%), and telangiectatic (6%). At diagnosis, 911 patients had localized disease and 147 had resectable lung metastases., Results: The response to preoperative chemotherapy was good (90% or more tumor necrosis) in 59% of patients and poor (< 90% tumor necrosis) in 41% of patients. The rate of good responses was significantly higher (P = 0.0001) in the fibroblastic (83%) and telangiectatic (80%) tumors and significantly lower in chondroblastic tumors (43%). Prognosis was significantly correlated with the histologic subtypes. The 5-year overall survival rate was significantly higher (P = 0.0001) in fibroblastic (83%) and telangiectatic (75%) tumors than in osteoblastic (62%) and chondroblastic (60%) tumors. In all subtypes, except for the chondroblastic subtype, the 5-year overall survival rate was significantly higher (P = 0.0001) in good responders P = 0.0001 (68%) than in poor responders (52%)., Conclusions: The authors concluded that the histologic subtype of primary central high-grade osteosarcoma of the extremity was strictly correlated with histologic response to chemotherapy and probably, as a consequence, also with prognosis. Further studies are needed to establish whether these results justify a specific therapeutic approach based on the histologic subtype of the tumor., (Copyright 2003 American Cancer Society.)

Purpose: To evaluate fertility in male patients with osteosarcoma after chemotherapy including high doses of alkylating agents., Patients and Methods: Postchemotherapy fertility was evaluated in 96 male patients who received chemotherapy at the authors' institution from 1976 to 1996 for localized bone osteosarcoma of the extremities. Four drugs were administrated (doxorubicin, cisplatin, methotrexate, ifosfamide) at different doses according to six different protocols. Eleven patients were prepubertal and 85 were postpubertal at the time of chemotherapy. The median age of these patients at the time of chemotherapy was 17 years (range 10-42), the median age at the time of the interview was 27 years (range 19-53), and the median follow-up from the end of chemotherapy was 9 years (range 4-17)., Results: Of the 96 patients, 26 underwent sperm analysis and 20 showed oligo- or azoospermia. Patients who received high-dose ifosfamide showed a higher incidence of azoospermia. Six patients were normospermic and received no ifosfamide or lower doses of ifosfamide. Eight patients fathered a total of 12 children. No birth defects or congenital anomalies were observed in their offspring., Conclusions: The rate of sterility was related to ifosfamide dosage. It appears that pubertal maturation is not affected by chemotherapy. No congenital malformations were seen in the children of the few patients who fathered children.

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.

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.

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.