Primary bone osteosarcoma in the pediatric age: State of the art

Cancer Treatment Reviews (2006) 32, 423– 436

available at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/ctrv

TUMOUR REVIEW

Primary bone osteosarcoma in the pediatric age: State of the art Alessandra Longhi a,*, Costantino Errani b, Massimiliano De Paolis b, Mario Mercuri b, Gaetano Bacci a a b

Chemotherapy Surgery of the Musculoskeletal, Oncology Department at Rizzoli Orthopaedic Institute, Bologna, Italy Orthopaedic Surgery of the Musculoskeletal, Oncology Department at Rizzoli Orthopaedic Institute, Bologna, Italy

Received 30 November 2005; revised 30 May 2006; accepted 31 May 2006

KEYWORDS

Summary 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. c 2006 Elsevier Ltd. All rights reserved.

Pediatric osteosarcoma; Chemotherapy; Surgery; Chemotherapy; New drugs

 Introduction

Osteosarcoma (OS) is the most common primary bone tumor in childhood and adolescence. It usually involves long bones and is a highly aggressive tumor that metastasizes primarily to the lung.1 Until 30 years ago, when surgery was the only

* Corresponding author. Present address: Sezione Chemioterapia, Istituto Ortopedico Rizzoli Via Pupilli 1, 40136 Bologna, Italy. Tel.: +39 051 6366374; fax: +39 051 6366277. E-mail address: [email protected] (A. Longhi).



therapy, most patients died within 1 year from diagnosis, and the overall 5-year survival rate was 10%. With the present protocols of neoadjuvant chemotherapy (4–6 cycles with the four most effective drugs before surgery and 9–13 cycles postoperatively) the 10-year disease free survival (DFS) is about 60% in patients with localized disease, and around 30% in patients with metastatic disease at diagnosis.2–4 The incidence of OS is about 3 new cases per million people per year. The median peak age is 16 years, and males are affected more than females with a ratio of 1.6:1; females have a peak incidence a little earlier than males due to the earlier onset of their growth spurt.5,6

0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2006.05.005

424

Etiology Exposure to radiation is the only proven exogenous risk factor but with a long interval, 10–20 years,7 so radiation-induced osteosarcoma is typical of adult age and is very rare. There is an association with a number of rare inherited syndromes8–12 like hereditary bilateral retinoblastoma, Li–Fraumeni syndrome, Bloom syndrome, Rothmund– Thomson syndrome or in association with multiple exostoses, and Paget’s disease. But the majority of osteosarcomas occur without a familial predisposition or a history of exposure to radiation. Several genetic alterations have been found to be associated with osteosarcoma.13 The retinoblastoma tumorsuppressor gene (RB) located on chromosome 13 has an essential role in the pathogenesis of OS.14,15 The RB gene is involved in retinoblastoma, a rare childhood tumor of the retina, in which there is always a mutation in the RB gene. Retinoblastoma patients have an increased incidence of extraocular second tumors and osteosarcoma is the most frequent second tumor. In patients with hereditary retinoblastoma the risk of developing an osteosarcoma can be up to 500 times more than in the healthy population.16,17 Genetic analysis of a high number of tumor cells from osteosarcoma patients showed homozygous loss of the RB gene and/or an altered RB gene product. The RB gene product is a nuclear phosphoprotein (pRb) that exerts a growth-suppressive effect on the cell cycle. The p53 tumor suppressor gene has also been involved in OS oncogenesis.18 Mutations of this gene have been found commonly in human carcinomas and in bone and soft tissue sarcomas. It encodes a p53 nuclear phosphoprotein that appears to function as a transcription factor. Amplification or over expression of MDM2 and CDK4 genes have been seen in osteosarcoma,19,20 suggesting that these genes are involved in tumor pathogenesis. The MDM2 gene encodes a protein that binds and inactivates the p53 protein; the CDK4 product is a cyclindependent kinase which may phosphorylate and inactivate pRb, the protein produced by the RB gene. C-myc and C-fos are proto-oncogenes that play an important role in the regulation of cell growth and they have been found to be amplified or over-expressed in osteosarcoma cells.21,22 Both genes encode transcriptional factors that control cell cycle progression, osteoblast and chondrocyte differentiation. Although it is clear that alterations of tumor suppressor genes and oncogenes occur in the genesis of osteosarcoma, it is not clear which event is first in this cascade of alterations. A viral etiology was suggested by evidence that bone sarcomas could be induced in animals by viruses.23 SV40 DNA (Simian DNA virus), an accidental contaminant of poliovirus vaccines used widely between 1955 and 1962, has been detected in some osteosarcoma cells.24 Long-term follow-up studies have not revealed recipients of SV40-contaminated poliovirus vaccines to be at an increased risk of cancer.25 Also trauma as an etiologic factor has been discarded. In fact, although the diagnosis is sometimes made after the occurrence of a trauma in the involved bone, no etiologic relationship with trauma has been found. A trauma, very

A. Longhi et al. common in this age group, reveals the disease but does not cause it. The peak of incidence of osteosarcoma during puberty when the growth spurt is highest26 and the observation that osteosarcoma is much more common in larger breeds of dogs, has raised the question of a correlation between the faster growing bone rate in puberty and the occurrence of osteosarcoma.27–29 Many studies have confirmed this hypothesis. Two recent studies29,30 showed that young osteosarcoma patients in growing age were taller than the normal population of the same age group.

Clinical presentation and diagnosis Pain is usually but not always the first symptom.1 It usually arises after strenuous exercise or a trauma, usually appearing 2–4 months before diagnosis,3 and progressing over time. Swelling appears later with a hard consistency mass. Pathologic fracture can occur. The laboratory findings may show an increase in alkaline phosphatase (AP) and in 30% of cases an increase in lactic de-hydrogenase.31 In the absence of metastases abnormal AP values are correlated with tumor volume and prognosis;32 mild anemia may also be present at diagnosis. Furthermore, the erythrocyte sedimentation rate (ESR) is often high and increases in the presence of relapse.33 At diagnosis, classic OS is localized in one bone site in 80% of cases and presents with metastases in about 20% of patients. The lung is the most common metastatic site, followed by bone.34 Other metastatic sites at diagnosis are very uncommon. Regional lymph node metastases are rare (<10%).35 In less than 10% of cases a skip metastasis can be detected.36 Skip metastases are nodular, small, and usually located in the same bone but also in the adjacent cross-joint bone and have been associated with poor prognosis.36 Eighty percent of osteosarcomas occur in the limbs, whereas 20% occur in the axial skeleton and pelvis Dahlin.37 It occurs primarily in the metaphysis or metadiaphysis of long bones, but tends to invade the epiphysis even in the presence of a growth plate. Usually, osteosarcoma arises from the medullary cavity of long bones and grows toward the cortex, sometimes invading the surrounding soft tissue. The femur is the most commonly affected bone (around 40%) followed by the tibia (20%) and humerus (10%).1 Flat bone and axial bone involvement is more frequent in older patients. In pediatric patients, axial skeleton involvement is less than 10%.38 Radiological findings of OS are quite typical. On a plain X-ray, the most common feature of OS is a combination of osteolytic and sclerotic appearance. Sometimes it is entirely eburneous with faded edges. Typically, OS starts intramedullary, but breaks the cortex and expands in the surrounding soft tissues. At the periphery of the area, where the tumor breaks the cortex, a triangle of immature bone can be seen (Codman’s sign). This is due to reactive bone produced acutely by periosteum. The soft tissue extension shows irregular, cloud-like radiodensities and/or stripes of increased density perpendicular to the cortex. The pure osteolytic form is typical of the telangiectatic variety. An isotope scan with technetium shows the intense hot spot of the tumor and any skip or distant bone metastases.

Primary pediatric bone osteosarcoma CT and MRI of bone lesions are important to study the extension of a tumor and the involvement of surrounding structures: vessels, nerves, soft tissues. MRI is the best technique to determine the medullary tumor borders, and the epiphyseal invasion and the skip metastases.39 CT with contrast medium allows accurate determination of intraand extra-osseous extension of bone tumor and reveals the relationship with vessels, but angiography is sometimes necessary. CT of the lung is part of the basal staging. Typical osteosarcoma lung metastases are usually peripheral, subpleural, round dense nodules of a few millimeters, sometimes with calcification inside, but different presentations are possible and differential diagnosis with benign nodules is not always possible with CT.40 Mediastinal lymph nodes are very rarely involved. Differential diagnosis includes also Ewing’s sarcoma, the second most common bone tumor in children and adolescents, which is usually located in the diaphysis of long bones, and has more lytic features.1 The sclerotic and mixed form of osteosarcoma poses few diagnostic problems. The differential diagnosis of the lytic form should include aneurysmal bone cyst that has radiological features similar to those of telangiectatic osteosarcoma. Other bone diseases to be included in the differential diagnosis are: bone fibrosarcoma, giant cell bone tumor, myositis ossificans. The latter is a benign pathology due to the formation of heterotopic bone in soft tissues. The biopsy should be carefully planned according to the site and definitive surgery and should be performed by an orthopedic surgeon familiar with the management of malignant bone tumors and experienced in the required techniques, preferably the surgeon who will perform the definitive surgical procedures.41 The results of a study from the Mayo clinic on 329 biopsies of musculoskeletal sarcomas showed that errors, complications and change in outcome were 2–12 times greater (P < 0.001) when the biopsy was performed in a referring institution instead of a treatment center. The biopsy can be an incisional (open) or needle (closed) biopsy. The latter can be a core biopsy or fine needle core (Trephine) biopsy. In experienced centers needle biopsy can yield high positive results. In a series of 208 patients, Stoker reported an adequate bioptic sample in 97%.42 Core biopsy is especially helpful in difficult areas such as the pelvis and vertebrae. If a core biopsy results inadequate, a small incisional biopsy should be performed. In children, incisional biopsy in general anesthesia is preferred. All biopsied sites must be removed en bloc when the tumor is resected. There are two systems of staging for OS: the Enneking surgical staging system43 or the American Joint Committee System.44 The Enneking staging system for malignant musculoskeletal tumors combines histologic grading and anatomical tumor extension. Most cases are Enneking stage IIB at presentation. Osteosarcoma is histologically characterized by the production of ‘‘tumor osteoid’’ or immature bone directly from a malignant spindle cell stroma. The current WHO histologic classification of OS45 recognizes three major subtypes of osteosarcoma: osteoblastic fibroblastic, and chondroblastic, reflecting the predominant type of matrix (osteoid, fibrous or chondroid matrix). Sometimes two different matrixes may exist and it is not easy to define the subtype (unclassifiable osteosarcoma). Histochemical tests show a high content of

425 alkaline phosphatase. The WHO classification recognizes two further histologic variants: telangiectatic and small cell osteosarcoma. The telangiectatic subtype is characterized by cyst-like spaces, filled with blood, which can simulate an aneurysmal bone cyst on plain films. Another rare subtype is the small cell osteosarcoma that can be mistaken for Ewing’s sarcoma due to the presence of small, round malignant cells in an osteoid matrix. Immunohistochemical assay can provide differential diagnosis. Small cell osteosarcoma is a highly aggressive subtype and is less responsive to chemotherapy treatment compared to the other types.46

Treatment of localized osteosarcoma Surgery is still the cornerstone of OS treatment, but alone it cannot cure patients. Until the 1970s, OS was treated by surgery (mostly amputation) or radiotherapy alone. Despite good local control, most patients died within a short time as a result of metastases, the first location of which was nearly always pulmonary. With surgery alone, the 5-year DFS was 12%, and 3 out of 4 patients died within 2 years of diagnosis. For this reason, in 1970 adjuvant chemotherapy was conceived. Doxorubicin (ADM) and Methotrexate (MTX) were the first drugs to be employed successfully.47–49 Other drugs, were used in the first pioneer studies, such as Vincristine, Bleomycin, and Dactinomycin, but later abandoned because of their scarce effectiveness.50,51 Cisplatin (CDP) and Ifosfamide (IFO) were subsequently added to ADM and MTX with a significant improvement in the 5-year DFS, of up to 70%.52,53 The goal of adjuvant chemotherapy was the eradication of micrometastases, that had already spread at the time of diagnosis, and even in patients with localized disease there was an improvement in DFS. In 1978, Rosen introduced neoadjuvant (preoperative) chemotherapy.54 The goals of neoadjuvant chemotherapy, besides the eradication of micrometastasis, were the destruction of primary tumor cells with reduction of tumor burden and the possibility to evaluate the histologic response to preoperative chemotherapy. Bone tumor necrosis after preoperative chemotherapy has been proved to be a prognostic factor and it correlates with DFS and overall survival (OS).55,56 Tumor necrosis is usually evaluated according to Huvos’ classification. Grade I: no necrosis, Grade II: necrosis between 50% and 90%, Grade III: necrosis >90% but <100%, Grade 4: total necrosis 100%.3 In a large monoinstitutional series of 1058 patients with localized OS of extremity 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. Prognosis was significantly correlated with the histologic response. The 5-year overall survival rate was 68% in good responders and 52% in poor responders (P = 0.0001) The rate of good responses and also the 5-year overall survival rates were significantly higher (P = 0.0001) in the fibroblastic and telangiectatic tumors and significantly lower in chondroblastic and osteoblastic tumors.57 Knowing the grade of tumor necrotic response to chemotherapy allowed postoperative treatment to be tailored according to different risk-groups. In the attempt to improve the cure rates of poor responder patients (patients with poor tumor necrosis), several

426

A. Longhi et al.

protocols included a postoperative intensification chemotherapy (higher doses, prolonged chemotherapy) but longterm follow ups of these patients showed no benefit from therapy intensification.2 At the same time conservative surgery was possible due to the development of better, more readily available prostheses (before 1980 prostheses were custom-made and required more time to be made) Traditional treatment for bone tumors used to be amputation; today advances in surgical techniques have made limb-salvage procedures a valid alternative method of treatment to amputation in 80–85% of cases, as reported in a recent review.58 In the ISG/SSG study (1997–2000) 92% of 182 patients with osteosarcoma of the extremity underwent limb salvage.59 Considering the advantages by facilitating limb salvage procedures and assessing chemotherapy-induced tumor necrosis, preoperative chemotherapy has become the standard approach of treatment. Since neoadjuvant therapy replaced adjuvant treatments the question whether one was better than the other arose. The only controlled study on this important problem was undertaken by the Pediatric Oncology Group between 1986 and 1993.60 One hundred patients were randomized to receive the same chemotherapy regimen with high doses (HD) MTX-CDP-ADM + bleomycin (B) + Cyclophosphamide (C) + Dacarbazine (D) used as adjuvant postoperatively or as neoadjuvant protocol. Number of amputations, DFS, and OS were the same in the two groups with no significant advantages of neoadjuvant vs. adjuvant chemotherapy. At the beginning of the 1990s, intra-arterial chemotherapy with CDP was employed in the preoperative phase together with systemic chemotherapy.61 The results, in terms of local control and tumor necrosis, were impressive but longer follow-up showed no advantages over systemic chemotherapy for DFS and OS.62 In COSS-86,63 171 patients with localized osteosarcoma of the extremity received preoperatively ADM, HDMTX, and CDP. They were randomized, according to three risk factors (tumor length, chondroid percentage, scintigraphy activity), in a low-risk and highrisk group. The high-risk group received also Ifosfamide preoperatively and CDP was stratified into intra-arterial vs. intravenous. The 10-year EFS of all 171 patients was 66% with no benefit of intra-arterial CDP vs. systemic CDP. Nowadays intra-arterial chemotherapy is seldom employed and only in few centers.64 In some recent protocols all four drugs active against osteosarcoma (CDP, ADM, MTX, and IFO) are employed in different combinations. The overall 5-year EFS ranges between 44% and 65% (Table 1). Other drugs have been used over the past years with varying results. Table 1

A study by the European Osteosarcoma Intergroup65 compared a short two-drug regimen (Cisplatin, Doxorubicin for 6 cycles) vs. a longer multidrug regimen (CDP, ADM, MTX, Actinomycin, VCR, BLEO, CTX for 18 cycles). No difference in tumor necrosis (Good responders 29%) and 5-year EFS was found between the groups, and the 5-year EFS was 44%. VCR, BLEO and Actinomycin were abandoned because they were not effective. In the Scandinavian Sarcoma Group VIII study (SSGVIII) 113 patients were treated with Doxo, CDP and MTX preoperatively. Poor responders (42%) received postoperatively Ifosfamide and Etoposide instead of ADM, MTX and CDP. The 5-year EFS was globally 63%, similar to previous studies, and the improvement was not significant for the poor responders who received IFO/Etoposide.66 In a pilot ISG study in 1996 high doses of Ifosfamide (15 g/m2) were administered starting from the preoperative phase to obtain increased tumor necrosis and EFS: a 5-year EFS of 73% was reported in an updated study.67 The toxicity was similar to other protocols with lower doses of Ifosfamide. Encouraged by these promising results the ISG/SSG I study (1997–2000), was started. The series consisted of 182 non-randomized patients with localized osteosarcoma. Preoperative chemotherapy consisted of 2 cycles of HDIFO (15 g/m2), 2 cycles of HDMTX (12 g/m2), and 2 cycles of CDP/ADM. In the postoperative phase poor responders received 3 more cycles of CDP, MTX, IFO). The total dose of Ifosfamide was 75 g/m2 as in the pilot study but the ADM dose was 330 mg/m2 compared to 420 mg/m2. The 5-year EFS of all groups was 64% (less than in the previous pilot study) despite a considerable toxicity, mainly hematological and renal.59 The lower dose of ADM might be the reason for the lower EFS. In consideration of these results a further protocol still in progress, ISG-OS1 (Italian Sarcoma Group-OS1) consisting of a two-arm randomized study has employed the same dose of Ifosfamide 30 g/m2 in both arms. The purpose of the reduced dose of Ifosfamide, compared to the previous protocol, is to have a less toxic effect, especially with regards to sterility. Recently, the results of a four-arm CCG-POG study on 677 osteosarcoma patients68 were reported. In this study MTX, Doxo, CDP ± IFO and ±MTP-PE (liposomal Muramyl Tripeptide Phosphatidyl ethanolamine, a biologic response modifier, and a monocyte activator)69 were added to conventional chemotherapy: the arm that received MTP together with Ifosfamide had better results (78% 3-year EFS) compared to the standard arm CDP-ADM-MTX (68%)

Most recent multicentric osteosarcoma protocols (1986–2000)

Study (reference)

Years

No. Pts

Drugs

5Y EFS (%)

COSS-86 [63] IOR-OS2 [2] POG-8651 [60] EOI-2 [65] SSGVIII [66] CCG-POG [68]

1986–1988 1986–1989 1986–1993 1986–1991 1990–1997 1993–1997

171 164 100 391 113 677

Doxo, CDP, MTX ± IFO Doxo, CDP, MTX, Ifo ± VP16 Doxo, MTX, CDP, Bleo, CTX ACT Doxo-CDP or MTX, Doxo, CDP Bleo, ACT, CTX, VCR MTX, CDP, Doxo ± IFO/VP16 MTX, CDP, Doxo ± IFO, ±MTP

62 65 63 44 63 63

Doxo = Doxorubicin, CDP = Cisplatin, MTX = Methotrexate, Bleo = Bleomycine, CTX = Cyclophosphamide, Act = Actynomicin, VCR = Vincristine, VP16 = Etoposide, IFO = Ifosfamide, MTP = Muramyl Trypeptide Phosphatidyl ethanolamine.

Primary pediatric bone osteosarcoma

427

and the CDP, MTX, Doxo + Ifosfamide arm (61%). The difference in EFS according to treatment arm was significantly (P = 0.04) increased in the IFO + MTP arm, but additional clinical investigation will be necessary to explain the interaction of Ifosfamide and MTP. Analysis of the reported results indicates that a survival plateau of approximately 60% can be achieved by several different drug combinations (Table 1). The inclusion of additional drugs and treatment with complex combinations to all patients has not yielded a convincing survival benefit. These regimens probably overtreat a large number of patients, namely those who could have been cured by the previous less drastic regimens, and it increases the acute and delayed side-effects.70 The most toxic treatment involving additional anticancer agents should be reserved for high-risk or relapsing patients who would benefit from drugs, which they have not been previously exposed to, while waiting for new different drugs.

Chemotherapy toxicity Nearly a half of young adult survivors of childhood cancer have at least one major adverse outcome of their health status as a result of their cancer therapy.71 Early toxicity consists of hematological toxicity (manageable with growth factors), acute liver (MTX) and renal toxicity (CDP and IFO). Longer survival has led to the increase in late chemotherapy toxicity. The main late toxicities are: cardiac, second tumor, sterility, chronic renal failure and neurologic toxicities (mainly ototoxicity due to CDP). Clinically evident cardiac toxicity related to anthracycline chemotherapy has been reported in different childhood cancers, with an incidence ranging from 0% to 16%.72 Risk factors have been studied: the total dose of Doxo is the most important risk factor (0–15% of subclinical cardiac toxicity due to Doxo doses < 300 mg/m2). Also female gender and younger age are reported to be significant adverse risk factors.73 In one COSS study74 the incidence of congestive heart failure due Doxorubicin chemotherapy in 785 patients was 2.2%. In Rizzoli’s series of 755 patients 13 patients (1.7%) developed Doxorubicin cardiomyopathy (dose range 300– 480 mg/m2).75 All these patients experienced congestive heart failure. Seven of these 13 patients are alive: 3 with a transplanted heart. Of the 6 who died, two had acute cardiotoxicity, one died of metastatic disease and the other 3 of heart failure. The risk of developing a second malignant neoplasm (SMN) in survivors of childhood or adolescent cancers has been calculated to be 8–10% 20 years after primary cancer.76,77

Table 2

The risk of malignancies with aging results from the risk of cumulative cellular mutations. Exposure to mutagenic cytotoxic therapies results in an increased risk of secondary malignancy, particularly after alkylating agents and podophyllotoxins. The risk of SMN induced by cytotoxic agents is related to the cumulative dose of drugs. In 1996 Pratt published data on the incidence of Second Malignant Neoplasm (SMN) in 334 children, treated from 1962 to 1996 for osteosarcoma.78 The study showed a 10-year cumulative incidence of SMN of 2% ± 1% for patients with localized osteosarcoma and 8% ± 5% for those with metastatic disease at presentation. Another recent review from Memorial Sloan Kettering79 on 509 osteosarcoma patients, median age 16.6 years (3.1–74.4) reported a 10-year cumulative incidence of SMN of 3.1% ± 1.8%. In Rizzoli’s series75 17 second tumors (2.1% ) in 755 patients were reported with a median interval of 7 years (range 5–22) after chemotherapy. The most common second tumors reported after primary osteosarcoma are leukemia and, for solid tumors, brain cancer, soft tissue sarcoma, and breast cancer (Table 2). The interval from the end of chemotherapy and the occurrence of SMN is shorter for leukemia than for solid tumors (3–5 years vs. 10–20).75,78,79 Sterility was also a significant late side effect for male patients who received more than 30 g/m2 of IFO, as in the most recent protocols. When the total dose of ifosfamide was 60–75 g/m2 azoospermia was 100%.80 No sterility was observed in women younger than 35; in women age seems to be more correlated with sterility than alkylant dose.81 No congenital malformation was observed in siblings of these patients (male or female). Peripheral neuropathy manifests with paresthesias, and hearing loss for high frequencies due to CDP can occur at cumulative doses of 300–600 mg/m2.82 Cisplatin peripheral neuropathy is reduced when iv infusion is extended (72–48 h).59 Renal damage due to CDP is due to tubular damage and manifests with electrolyte wasting. Ifosfamide renal dysfunction manifests as a proximal tubulopathy associated with Fanconi-like syndrome,83 characterized by glycosuria proteinuria, hypophosphatemia, hypokalemia, renal tubular acidosis and reduced glomerular filtration rate. Renal damage by each single drug (CDP, Ifosfamide, MTX) can be increased by their combination.

Treatment of primary metastatic osteosarcoma and multifocal osteosarcoma About 20% of osteosarcomas are metastatic at presentation. For patients with a good performance status a multiple aggressive treatment with chemotherapy and surgery of

Second malignant neoplasms in osteosarcoma

Author

Period

No. pts

No. SMN

Interval median

Type of SMN

Pratt [78] Aung [79]

1962–1996 1973–2000

334 509

9 14

6,3 years 5,2 years

Longhi [75]

1983–2000

755

17

7 years

CNS, 3 sarcoma, melanoma, breast, stomach, colon, rectum CNS, AMLeulemia, Myelod. Syn 3 sarcomas, NHL, breast ca, parotid ca 2 AML, 3ALL, 1 CML, 3 breast ca CNS, lung ca, parotid ca, 3 sarcoma, skin ca, ovary

428 the primary tumor and all metastases is the standard therapy. However, despite aggressive treatment, mean 5-year EFS is 30% ranging from 16% (European Osteosarcoma Intergroup; 45 patient)84 to 53% (Pediatric Oncology Group; 30 pts).85 In a COSS study86 on 202 patients with metastases at diagnosis only 60 were alive after a median follow up of 1.9 years with a 5-year survival rate of 29% (SE = 3%). In this study multivariate analysis revealed that only the number of metastases at diagnosis and the completeness of surgical resection of all tumor sites were independent prognostic factors. At the author’s institution87 57 metastatic patients were treated with 6 cycles of preoperative chemotherapy (HDifo, CDP, Doxo, Mtx): 43 had only lung metastases, 3 had bone metastases, 9 had bone and lung metastases, and 2 patients had lymph node metastases only. After preoperative chemotherapy they underwent surgery both on primary tumor and metastases. Out of 57 patients 35 were freed of disease, while 22 never achieved a disease-free status. The 4-year EFS was 20%. In another study88 the combination of HDIFO and Etoposide was employed for 2 cycles before surgery in 41 metastatic patients. In 39 evaluable patients, this regimen showed a response rate of 59% ± 8%, despite significant associated toxicity (myelosuppression and renal toxicity). The projected 2 years progression-free survival was 39 ± 11. Prognosis of osteosarcoma that is metastatic at presentation is still poor and survival is related to the number and location of the metastases, and adequate surgical resections of all tumor sites. Multifocal osteosarcoma is a rare entity (0.5% of all high grade OS in our series) presenting with the synchronous appearance of multiple osteosarcoma localizations in the skeleton with or without pulmonary metastases. The highest incidence is at 5–15 years of age. The multiple localizations can involve vertebrae, ribs, sternum, skull, hand or foot, where OS is usually very uncommon. All lesions are extensively sclerotic. Whether it represents an early metastatic spread or a multicentric origin is unknown, the course is rapidly fatal despite treatment and prognosis depends on the number of metastases. Patients with no more than 2 bone localizations, who receive chemotherapy and surgery can experience a better prognosis. In our experience on 11 patients with multifocal OS at diagnosis 4 patients had only two localizations and received surgery on both. Their survival was double that of those with more than 2 localization (18 months vs. 9.1).89

Treatment of metastatic relapsed osteosarcoma Despite chemotherapy and surgical resection, 30–40% of patients with localized osteosarcoma of the extremities relapse, mostly within the first 3 years of diagnosis. Recurrence of osteosarcoma is most common in the lungs. The achievement of a complete remission of recurrent disease is the most important prognostic factor at first relapse with an overall survival after recurrence that ranges from 13% to 57%.90,91 Series on relapsed osteosarcoma are small and often heterogeneous including patients with different disease extensions (one or many metastases, resectable vs. unresec-

A. Longhi et al. table) and different treatments (only surgery vs. chemotherapy + surgery, mono vs. polychemotherapy). Often patients with solitary metastases receive only surgery,91,92 while patients with multiple lesions receive different types of treatment (chemotherapy, surgery, radiotherapy). Favorable prognostic factors are: the number and site of metastases, the length of disease-free interval after treatment for primary osteosarcoma and in lung metastases unilateral vs. bilateral localizations. The complete remission status after surgery is also an important prognostic factor.91–96 Further recurrences after the first relapse are frequent and subsequent post-relapse-free intervals are usually short. Hawkins92 reported the results of 59 relapsed osteosarcoma patients (43 lung, 8 bone, 7 others+lung), median time to relapse was 15 months. Eighteen patients received only surgery, whereas 41 received surgery and chemotherapy. In both groups the 4-year estimated EFS and Overall Survival were respectively 6% (95% CI, 0–12%) and 23% (95% CI, 10–36%). EFS was similar for patients treated with either surgery alone or chemotherapy with or without surgery, but survival was longer in patients treated with surgery alone, compared with patients treated with chemotherapy and surgery (47% vs. 13%, P = 0.005). However, the 18 pts who received surgery alone had only a solitary lesion (16 in the lung). Survival was closely associated with the achievement of a complete remission. In a study on 162 assessable patients with osteosarcoma at their first relapse91 the projected 5-year Post Relapse Free Survival for all 162 patients was 28%, ranging from 39% for those who reached a complete remission after surgery and 0% for those who failed to reach a complete remission after treatment. Prognostic factors that influenced Post-Relapse Survival were: site of relapse (lung 44% vs. all others 14%), relapse-free interval (patients with DSF >24 months had a better outcome), number of lung metastases (59% of PRFS with 1–2 nodules, 14% PRFS with >2 nodules). The use of second line chemotherapy gave a significant advantage in PRFS mainly to those patients with unresectable disease. The role of second line chemotherapy is still not well defined, partially due to lack of other effective drugs besides those employed in first-line neoadjuvant chemotherapy. Some studies93,94 reported no advantages from second line chemotherapy. However, in these studies chemotherapy was often administrated to patients with multiple and unresectable metastases. Saeter recently reported an improved overall survival in patients who received a ‘‘modern intensive chemotherapy’’ compared to those who received no or inadequate chemotherapy.95 A Coss study96 on 576 unselected relapsed osteosarcoma patients also reported that chemotherapy correlated with overall survival in patients who failed to achieve a second Complete Remission (P = 0.001) and correlated with EFS in those who achieved post-surgical CR (P = 0.016). Poly-chemotherapy compared to no chemotherapy or single agent chemotherapy correlated positively with overall survival (P = 0.012). Extrapulmonary localizations were not an adverse factor in this series; resectability was more important than location. There are no large-scale studies reporting the outcome of patients who first relapse with bone vs. lung metastases

Primary pediatric bone osteosarcoma but several case reports describe a much poorer prognosis for patients who relapse with skeletal metastases,97–99 others reported similar prognosis for lung and bone metastases.96,100,101 In a recent paper Bacci102 compared 52 patients with bone metastases as first recurrence (32 with a single bone lesion) with 371 patients who relapsed with lung metastases. The 5-year EFS was 11% in the bone metastases group vs. 27% in lung metastases group. Also overall survival was better for patients with lung localization (31% vs. 13%). Local recurrences occur approximately in 5–10% of patients. Some studies report a worse prognosis in patients with local recurrences in terms of increased risk of metastatic disease and death.103,104 Rodriguez-Galindo et al.104 reported a 5-year estimated PRFS (post-relapse free survival) of 19.2 ± 7.7(±1SE) in 26 patients with local recurrence. Other authors do not consider local recurrence as a worse prognostic factor compared to other metastatic localizations.105 Grimer et al. reported their experience in 96 patients with local recurrence after treatment for localized osteosarcoma: 18% had distant metastases before local recurrence and 23% had concurrent metastases. Two-year overall survival of all patients was 35%. However, the 5-year overall survival for those 57 with isolated local recurrence without metastases was 41% after adequate local treatment, while local recurrence plus distant metastasis had a worse prognosis.105 In order to improve the survival of metastatic patients different chemotherapy approaches have been considered. High dose chemotherapy (HDCT) with peripheral blood stem cell rescue (PBSCR) was employed in a few studies but results were disappointing, and now HDCT with PBCSR has been abandoned.106 In the study by Fagioli et al.,107 HDCT with stem cell rescue plus surgery was employed: 2 cycles of high dose carboplatin and etoposide followed by autologous stem cell rescue were administered to 32 metastatic osteosarcoma patients. Unfortunately, the 3-year OS was 20% and the 3-year DFS only 12%. High-dose samarium153-EDTMP, a radio-labeled phosphonate, used alone or in association with external radiotherapy, may provide significant pain control in patients with bone metastases.108,109

Radiotherapy Osteosarcoma is known to be quite resistant to RT. Anyway, in certain locations (pelvis, vertebra) where surgery is not feasible or for palliation in case of bone metastases or in multifocal osteosarcoma, radiotherapy can prolong survival and control pain. A recent study110 reported the results of radiotherapy in 41 patients who received 10–80 Gy for osteosarcoma located in the face/head (17 patients), spine (8), the pelvis (7), and in the trunk (1). The 5-year overall local control rate was 68% ± 8%. RT provided local control in osteosarcoma patients when surgical resection was inadequate or impossible, and was more effective when the residual disease was microscopic or minimal. Machak et al.111 reported a series of 31 patients with osteosarcoma of the extremities who refused amputation as local treatment. Besides chemotherapy they received

429 60 cGy as local treatment. After a median follow up of 39 months 20 patients were alive (65%) and 16 were free of disease. The estimated overall control rate at 5 years was 56%. Whelan reviewed the use of Prophylactic Lung Irradiation (PLI) as employed in the 1970s with the aim of reducing lung metastases after surgery on primary bone osteosarcoma.112 PLI has been shown, at best, to be as effective as the early adjuvant chemotherapy regimens. The combination of chemotherapy and radiation increases toxicity but appears to offer no additional benefit over single modality treatment. For metastatic OS, the surgical resection of lung metastases remains the treatment of choice. The role of radiotherapy in lung post-metastasectomy has not been established.

New experimental drugs Some studies have been published on drugs not commonly used in first line treatments of osteosarcoma. Some of them are quite promising. Topotecan, employed in 26 metastatic OS patients at presentation followed by multiagent chemotherapy, did not show an effective improvement over traditional chemotherapy.113 Gemcitabine was employed alone with minimal response,114 but in one study it was employed together with Docetaxel in 35 patients with different sarcomas and a RR of 43% was reported.115 Ecteinascididin-743 has been employed alone in pretreated recurrent osteosarcoma patients with unremarkable results.116 Further studies of ET743 in combination with other drugs are ongoing. Immunomodulation has been investigated in a few studies. Since the 1980s, some studies have employed interferon, alone or in combination with chemotherapy, with encouraging results.117,118 A recent paper, from Karolinska Hospital,119 reported the long-term results of 89 osteosarcoma patients treated from 1971 to 1990 after surgery only with Interferon as single agent adjuvant therapy for 18 months to 5 years. With a median follow up of 12 years (range 2–16) the 10-year metastasis free survival is 39%. These results are similar to results obtained in certain chemotherapy protocols employed in the 1980s. In one study120 four courses of IL2 were administrated together with polychemotherapy in 18 pediatric osteosarcoma patients. NK counts and activity significantly correlated with clinical outcome, suggesting a possible role of the natural killer (NK) cells in the control of osteosarcoma. Chemotherapy did not influence the modification of NK cells, LAK and NK activities induced by IL 2. EURAMOS 1 (European American Osteosarcoma Study Group) is a recent ongoing intergroup study that employs preoperative chemotherapy with MTX, ADM (Doxo), and CDP (MAP). After surgery good responders are randomized to receive the same MAP regimen or MAP plus Interferon a as maintenance therapy. Poor responders are randomized to receive MAP or MAP plus Ifosfamide and etoposide. The introduction of Interferon a is based on the above-mentioned pioneer Scandinavian studies that demonstrated a clear activity of this immunomodulator as maintenance therapy (the EURAMOS protocol is reported in Ref.66, pp. 94–95).

430 Liposomal muramyl tripeptide phosphatidylethanolamine (MTP) was employed successfully in dogs with osteosarcoma. This encouraged phase I and II studies. So far 11 clinical studies have been performed and 3 were on osteosarcoma patients.69 The largest study was the one by Meyers as mentioned above.68 L-MTP-PE is an activator of monocytes and macrophages and induces the secretion of different cytokines (IL 1, IL 6, TNFa). The presence of the IGF1 receptor on osteosarcoma cells has suggested the use of a growth hormone antagonist, such as somatostatin, in the treatment of osteosarcoma patients. A pilot study on 21 osteosarcoma patients (12 localized, 6 metastatic) employed a somatostatine analogue at different doses with no significant response.121 Gene therapy is now being more widely used and some preclinical studies seem encouraging. A recent report showed the effectiveness of p53 gene therapy via a transferrin–liposome–p53 complex administrated with a 60% growth inhibition in vitro and reduction of tumor volume in animals.122 Endostatin, an inhibitor of angiogenesis, was administrated combined with liposome to experimental animal with orthotopic osteosarcoma.123 A delay of tumor growth, histologically confirmed, was observed compared to the control group. Other biologic therapies are under evaluation in preclinical studies and we hope that in the future we can offer osteosarcoma patients some of these new treatments to improve their survival.

Surgery In the past 20 years, the use of amputation has progressively decreased and more patients have been treated by local resection and functional reconstruction of the limb in almost 90% of cases.124,125 The type of surgical procedure depends not only on tumor stage, and response to adjuvant treatments, but also on the patient’s age, gender, general condition, life expectancy and quality of life. The percentage of local recurrence is strictly correlated to resection margins and to response to chemotherapy.126 Surgeons who perform tumor resection must follow the principles of oncologic surgery meticulously: the tumor must be removed with wide or radical, non-contaminated surgical margins.127 When surgical margins are inadequate (marginal, intralesional or contaminated), the risk of local recurrence is very high and a local recurrence considerably worsens prognosis.128 Surgery can be limb-salvage or amputation. The imaging technique is essential to the preoperative evaluation in relation to the tumor size, neurovascular bundles and joint involvement.129 Studies of osteosarcoma have shown an increase of local recurrence in patients undergoing limb-salvage surgery (10%), but not an increase in mortality.130 Chemotherapy is mainly responsible for the low risk of local recurrence in limb-salvage surgery. A recent study has examined the rate of local recurrence in patients with osteosarcoma and has shown that the margins of excision and the responsiveness of the primary tumor to chemotherapy represent important prognostic factors.131 The main surgical challenge is how to reconstruct the limb after resection of the tumor, and, in the pediatric

A. Longhi et al. age, how to preserve a useful functioning limb and avoid a discrepancy at the end of the growth. Today amputation is still the safest and most suitable option in some children.132 The indications are: tumors of large dimensions infiltrated in the main neurovascular bundles, patients in whom a wide excision of the tumor is not possible, and when removal of the tumor with adequate margins sacrifices various compartments, with consequent functional loss of the limb.133 Amputation, after conservative surgery, must be taken into consideration when local recurrence occurs and for serious secondary complications, such an infection, that would postpone or suspend chemotherapy and thus compromise prognosis.134,105 Sarcomas of the foot and ankle must be discussed separately. For these sites, a below-the-knee amputation is always the most efficient oncologic treatment; it guarantees a better functional result than most alternative reconstructions.135 For tumors of the femur or proximal tibia, the indication can be a surgical procedure half way between limb amputation and limb salvage, rotationplasty. This technique is a valid alternative to limb amputation for all age groups, but is the treatment of choice in sarcomas about the knee in children under seven years of age.136,137 There are no other acceptable reconstruction alternatives for this small subgroup of patients. Rotationplasty has the best results in pediatric patients, who adapt quickly to the motion pattern and where functional advantages (running and jumping) are appreciated.138 By this technique, the tumor is removed, the tibia and foot are rotated 180° and reattached to the remaining portion of the femur, and the ankle is fixed so that at the end of growth it will be at the same level as the other knee. The rotated ankle will replace the knee and the foot will act as leg stump, but without causing the typical trophic problems of amputation stumps (ulcerations, phantom limb syndrome).139 In conservative surgery, the choice of reconstruction of the resected bone segment depends on different factors: site, residual muscular and bone tissue (lesion extension), patient age, patient expectation, psychological and physical condition of the patient, patient lifestyle, and the need for adjuvant therapy. Major reconstruction options are:140 special modular prosthesis, massive osteoarticular allograft, composite prosthesis, massive intercalary allograft, vascularized fibula, allograft plus vascularized fibula. A modular prosthesis141 is used to reconstruct a joint segment or rarely an entire bone segment. These prostheses are available in various sizes and are assembled in the operating theatre according to specific needs. The advantages of this reconstruction are: a relatively easy reconstruction technique, fast mobilization, good function; the disadvantages are related to the difficulty of suturing the soft tissues (shoulder rotator cuff, gluteus and ileo-psoas for the proximal femur, patella tendon for the knee) to the metal prosthesis. This reconstruction technique is indicated in adolescents at the end of growth and when the tumor is located in the proximal femur, distal femur, proximal tibia, proximal and distal humerus; the whole humerus or femur can be replaced with a single implant.142 The long-term results of this kind of reconstruction have shown that the endoprosthetic survival is 86%, 80% and 69% at 3, 5 and 10 years’ follow-up.143 The trend for endoprosthetic survival from the best to worst was proximal femur, proximal

Primary pediatric bone osteosarcoma humerus, distal femur, proximal tibia and distal humerus. The complications include mechanical failure, local recurrence (6.8%), aseptic loosening, dislocation, infection, and endoprosthetic malalignment. Expandable prostheses can be used in pediatric age and can be lengthened over time, thus correcting limb-length discrepancy. The functional results in children are similar to those reported for adults, according to the average Musculoskeletal Tumor Society rating.144 However, more operations are needed not only for lengthening, but also for managing the complications of expandable component fractures, infection, wear, and loosening. The use of a closed expandable prosthesis is a non-invasive system to lengthen a child’s limb without having to perform an operation, and so the incidence of complications associated with lengthening can be reduced.145,146 Reconstruction with massive osteoarticular allograft147 is a good option because it allows reconstruction of bony mass and joint function similar to the original. In the upper limb it is indicated for shoulder and elbow reconstruction, and in the lower limb for the distal femur and the proximal tibia. The advantages are that the soft tissues can be reinserted (shoulder rotator cuff, gluteus and ileo-psoas, patella tendon) in the graft with better functional results. The joint surface slowly tends to deteriorate with the onset of arthrosis and joint instability after many years and can be replaced. Osteoarticular allografts are mostly indicated in young patients to reconstruct the proximal humerus, distal radius and in selected cases the distal humerus; in the lower limb to reconstruct the distal femur or the proximal tibia when the resection spares the periarticular muscles and the joint capsule. The long-term results of allografts used in children have shown many complications:148 non-unions of the bones in 34% of patients, allograft fractures in 27% and a deep infection in 16%. Furthermore, limb-length discrepancies greater than 2 cm have been reported in 35% of the patients.149,150 The allograft composite prosthesis151 combines the advantages of allografts (reinsertion of the soft tissues, biological consolidation of the host bone) with those of prostheses (stable joint, no complications, such as fractures or joint resorption and arthrosis). The composite prosthesis is indicated in the proximal femur, proximal tibia and occasionally in the proximal humerus, generally when resection spares most of the muscles in the district. The combination of a massive allograft and prosthesis, can also be used in pelvic reconstruction after periacetabular resections. The disadvantages of this technique are the risk of infection and slow healing during chemotherapy.152 Intercalary bone allograft is the most frequently used type of diaphyseal reconstruction and the allograft can be filled with bone cement to increase its mechanic resistance.153 Results of intercalary allografts use have been reported by Ortiz-Cruz E and colleagues,154 who found that there were no significant differences in the overall outcome with regards to the patient’s age, gender, and anatomical site and length of the graft. Functional results were satisfactory but there were some complications related to the allograft. The main problem was a high rate of non-union (33%) and more operations were needed. Other complications were infection and allograft fracture; furthermore the chemotherapy had an adverse effect on the survival of the allograft.155

431 The intercalary bone allograft can combined with a vascularized fibula to accelerate fusion with the host bone and favor long-term revitalization.156 This technique allows anatomic and biological reconstruction of large diaphyseal segments and avoids complications connected to using the allograft alone: pseudoarthrosis and fracture. The combination of a massive allograft and a vascularized fibula for the reconstruction of intercalary skeleton defects is particularly used in long intercalary resections of the femur and tibia, where residual bone stumps are small in size. Viable bone (vascularized fibula) in the implant guarantees fast fusion of osteotomies even without a rigid fixation. This technique combines the advantages of a vascularized fibula with those of a massive allograft.157 In our experience, reconstruction with vascularized fibula alone does not guarantee sufficient stability and is too weak to support body weight in a brief time. Today, in orthopaedic oncology, vascularized fibula alone is indicated only in growing patients who have to undergo a diaphyseal resection of the humerus, radius or ulna.158 In children with distal radius, proximal humerus, or proximal femur resections, the growing vascularized fibula can be used explanted with the whole epiphysis including growth cartilage to avoid limb discrepancies at the end of growth.159,160 Follow-up studies to investigate surgical outcomes have shown that the functional results after limb-salvage surgery are similar to or a little better than after amputation.161,162 Although amputation is a more lasting and easier solution, the patient usually prefers a limb-salvage surgery.163 A recent study has shown how the initial cost of limb-salvage surgery is higher, but in the long term the costs of amputation exceed those of limb-salvage.164

Prognostic factors Many studies have been performed to determine the most reliable prognostic factors. Significant prognostic factors are: first of all metastatic vs localized disease with a difference in 5-year EFS of 60–70% vs. 20–30%, tumor necrosis after preoperative chemotherapy, tumor site (limbs vs. axial skeleton), surgical margins, and tumor volume. Coss55 studied 1702 patients over 18 years and found that significant prognostic factors were: primary metastases vs. localized (10-year EFS of 26% vs. 64.4%, P < 0.0001), tumor necrosis after chemotherapy (poor necrosis 47.2% vs. good necrosis 73.4%), P < 0.0001), tumor site (axial 29% vs. extremity 61.7%, P < .0001), surgical margins (incomplete 14.6% vs. complete 64.8%, P < 0.0001), as well as extremity tumor,tumor volume, and location within the limb. All these prognostic factors were significant with multivariate analysis. In another Rizzoli Institute prognostic factors were evaluated on 300 patients with localized osteosarcoma of the extremity treated from 1986 to 1992.165 With a median follow-up of 9.2 years (4.4–12), 8-year DFS was 59% (95% confidence interval). Univariate analyses showed that tumor volume > or = 150 ml, histologic subtype, age >12 years, high serum lactate dehydrogenase and alkaline phosphatase levels, poor histologic response, and type of surgery (limb sparing vs. amputation) adversely affected DFS. After multivariate analyses, tumor volume > or =

432 150 ml (P = 0.028), age > 12 years (P = 0.051), and histologic subtype (P = 0.052) retained prognostic significance. In an attempt to identify prognostic factors related to age groups166 a group of 317 preadolescent patients (<12 years) were compared with an adult group of 819 patients to determine any differences in prognostic factors related to age and we found that most preadolescents were female (58% vs. 38%, P < 0.0001) with abnormal levels of LDH, and their tumors were mostly located in the extremities, while the adult group showed more non-extremity locations.

Conclusions A lot of progress has been made in the treatment of osteosarcoma over the last 30 years, due to chemotherapy development and surgery improvement. A multi-disciplinary approach has increased the number of conservative procedures (85%) and the probability of a better prognosis up to a 70% 5-year DFS for non-metastatic patients. We think that the best approach to osteosarcoma can be obtained in specialized centers with a very skilled multidisciplinary team and the possibility to evaluate statistically the data from large series of patients. Without this approach the improvements obtained in the past 30 years would not have been possible. For relapsing patients, new effective drugs are needed and new therapeutic targets and new strategies must be explored.

References 1. Campanacci M. Bone tumors. 2nd ed. Lippincott-Verlag; 1999., p. 1418–68. 2. Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the IOR/OS2 protocol: an update report. J Clin Oncol 2000;18:4016–27. 3. Huvos A. Bone tumors :diagnosis, treatment and prognosis. 2nd ed. Philadelphia: WB Saunders; 1991. 4. Bielack S, Kempf-Bielack B, Schwenzer D, et al. Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients. Klin Padiatr 1999;211:260–70. 5. Rytting M, Pearson P, Raymond AK, et al. Osteosarcoma in preadolescent patients. Clin Orthop 2000;373:39–50. 6. Fraumeni JF. Stature and malignant tumors of bones in childhood and adolescence. Cancer 1967;20:967–73. 7. Longhi A, Barbieri E, Fabbri N, et al. Radiation-induced osteosarcoma arising 20 years after the treatment of Ewing’s sarcoma. Tumorigenesis 2003;89(5):569–72. 8. Fuchs B, Pritchard DJ. Etiology of osteosarcoma. Clin Orthop 2002;397:40–52. 9. Swaney JJ. Familial osteogenic sarcoma. Clin Orthop 1973; 97:64–8. 10. Smith JW, Ali K, Caces JN. Familial cancer: the occurrence of bone cancer in male members of a family in multiple generations. Clin Res 1980;28:869–73. 11. German J. Bloom’s syndrome. The first 100 cancers. Cancer Genet Cytogenet 1997;93:100–6. 12. Wang LL, Gannavaparu A, Kozinets CA, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund–Thomson syndrome. J Natl Cancer Inst 2003;95:669–74.

A. Longhi et al. 13. Hansen MF. Molecular genetic considerations in osteosarcoma. Clin Orthop 1991;270:237–40. 14. Scholtz RB, Biol D, Kabisch H, et al. Studies of the RB1 gene and p53 gene in human osteosarcoma. Pediatr Hematol Oncol 1992;9:125–37. 15. Drya TP, Rappaport JM, Epstein J. Chromosome 13 homozygosity in osteosarcoma without retinoblastoma. Am J Hum Genet 1986;38:59–66. 16. Thomas DM, Carty SA, Piscopo DM, et al. The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol Cell 2001;8(2):303–16. 17. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in children in the United States. Sex-, race-, and 1year age-specific rates by histologic type. Cancer 1995;75: 2186–2195. 18. Masuda H, Miller C, Koeffer H, et al. Rearrangement of the p53 gene in human osteogenic osteosarcomas. Proc Natl Acad Sci USA 1987;84:7716–9. 19. Ragazzini P, Gamberi G, Benassi MS, et al. Analysis of SAS gene and CDK4 and MDM2 proteins in low grade osteosarcoma. Cancer Detect Prev 1999;23:129–36. 20. Khatib ZA, Matsushime H, Valentine M, et al. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res 1993;15:5535–41. 21. Barrios H, Castresana JS, Ruiz J, et al. Amplification of the cmyc proto-oncogene in soft tissue sarcomas. Oncology 1994; 51:13–7. 22. Van den Berg S, Rahmsdorf HJ, Herrlich P, et al. Overexpression of the c-fos increases recombination frequency in human osteosarcoma cells. Carcinogenesis 1993;14:925–8. 23. Finkel MP, Biskis BO, Jinkins PB. Virus induction of osteosarcomas in mice. Science 1966;151(711):698–701. 24. Mendoza SM, Konishi T, Miller CW. Integration of SV40 in human osteosarcoma DNA. Oncogene 1998;17(19):2457–62. 25. Engels EA. Cancer risk associated with receipt of vaccines contaminated with simian virus 40: epidemiologic research. Expert Rev Vaccines 2005;4(2):197–206. 26. Gelberg KH, Fitzgerald EF, Hwang S, Dubrow R. Growth and development and other risk factors for osteosarcoma in children and young adults. Int J Epidemiol 1997;26:272–8. 27. Withrow SJ, Powers BE, Straw RC, Wilkins RM. Comparative aspects of osteosarcoma. Dog versus man. Clin Orthop Related Res 1991;270:159–68. 28. Tjalma RA. Canine bone sarcoma: estimation of relative risk as a function of body size. J Natl Cancer Inst 1966;36:1137–50. 29. Cotterill SJ, Wright CM, Pearce MS, Craft AW. Stature of young people with malignant bone tumors. Pediatr Blood Cancer 2004;42:59–63. 30. Longhi A, Pasini A, Cicognani A, Baronio F, Pellacani A, Baldini N, et al. Height as a risk factor for osteosarcoma. J Ped Hem Oncol 2005;27(6). 31. Link MP, Goorin AM, Horowitz, et al. Adjuvant chemotherapy of high grade osteosarcoma of the extremity. Update results of Multi-Institutional Osteosarcoma Study. Clin Orthop:8–14. 32. Bacci G, Longhi A, Ferrari S, et al. Prognostic significance of serum alkaline phosphatase in osteosarcoma of the extremity treated with neoadjuvant chemotherapy: recent experience at Rizzoli Institute. Oncol Rep 2002;9:171–5. 33. Hannisdal E, Solheim OP, Theodorsen L, Host H. Alterations of blood analyses at relapse of osteosarcoma and Ewing’s sarcoma. Acta Oncol 1990;29(5):585–7. 34. Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am 1997;44:973–89. 35. Jeffree GM, Price CHG, Sissins HA, et al. The metastatic spread of osteosarcoma. Br J Cancer 1975;32:87–107. 36. Sajadi KR, Heck RK, Neel MD, Rao BN, Daw N, RodriguezGalindo C, et al. The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res(426):92–6.

Primary pediatric bone osteosarcoma 37. Dahlin DC. Osteosarcoma of bone and a consideration of prognostic variables. Cancer Treat Rep 1978;62:189–92. 38. Link MP, Gebhardt MC, Meyers PA. Osteosarcoma in principles and practice of pediatric oncology. 4th ed. Lippincott; 2002., p. 1051–89. 39. Aisen AM, Martel W, Braunstein EM, et al. MRI and CT evaluation of primary bone and soft tissue tumours. Am J Roentgenol 1986;146:749–56. 40. Picci P, Vanel D, Briccoli A, et al. Computed tomography of pulmonary metastases from osteosarcoma: the less poor technique. A study of 51 patients with histological correlation. Ann Oncol 2001;12(11):1601–4. 41. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited: members of the Musculoskeletal Tumor Society. J Bone Joint Surg Am 1996;78:656–63. 42. Stoker DJ, Cobb JP, Pringle JA. Needle biopsy of musculoskeletal lesions. A review of 208 procedures. J Bone Joint Surg Br 1991;73(3):498–500. 43. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 1980;153:106–20. 44. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed. New York: Springer Verlag; 2002. 45. Raymond AK, Ayala AG, Knuutila S. Conventional osteosarcoma. In: Kleihues P, Sobin L, Fletcher C, et al., editors. WHO Classifications of Tumours: Pathology and genetics of Tumors of Soft tissue and Bone. Lyon, France: IARC Press; 2002. p. 264–70. 46. Nakajima H, Sim FH, Bond JR, Unni KK. Small cell osteosarcoma of bone. Review of 72 cases. Cancer 1997;79:2095–106. 47. Campanacci M, Bacci G, Bertoni F, et al. The treatment of osteosarcoma of the extremities: twenty year’s experience at Istituto Rizzoli. Cancer 1981;48:1569–81. 48. Enneking WF. Advances and treatment of primary bone tumors. J Fla Med Assoc 1979;66:28–30. 49. Rosemburg SA, Chabner BA, Young RC. Treatment of osteogenic sarcoma.Effect of adjuvant high-dose Methotrexate after amputation. Cancer Treat Rep 1979;63:739–51. 50. Meyers PA, Heller G, Healey J, et al. Chemotherapy for non metastatic osteogenic sarcoma :the MSKCC experience. J Cin Oncol 1992;10:5–15. 51. Avella M, Bacci G, Mc Donald DJ. Adjuvant chemotherapy with six drugs (adriamycin, methotrexate, cisplatinum, bleomycin, cyclophosphamide and dactinomycin) for non metastatic high grade osteosarcoma of the extremities. Results of 32 patient and comparison to 127 patients concomitantly treated with the same drugs in neoadjuvant form. Chemioterapia 1988;7: 133–137. 52. Kraker J, Voute PA. Experience with ifosfamide in paediatric tumors. Cancer Chemother Pharmacol 1989;24:S28–9. 53. Bacci G, Ferrari S, Longhi A, et al. High dose ifosfamide in combination with high-dose methotrexate, doxorubicin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma/Scandinavian Group Pilot study. J Chemother 2002;14:198–206. 54. Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumour to preoperative chemotherapy. Cancer 1982;49(6):1221–30. 55. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities and trunk:an analysis of 1702 patients treated with neoadjuvant Cooperative Osteosarcoma Study Group Protocols. J Clin Oncol 2002;20:776–90. 56. Glaser DB, Lane JM, Huvos AG, et al. Survival, prognosis, and therapeutic response in osteogenic sarcoma. The Memorial Hospital experience. Cancer 1992;69:698–708.

433 57. Bacci G, Bertoni F, Longhi A, Ferrari S, Forni C, Biagini R, et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer 2003;97:3068–75. 58. Wafa H, Grimer RJ. Surgical options and outcomes in bone sarcoma. Expert Rev Anticancer Ther 2006;6(2):239–48. 59. Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: A Joint Study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 2005;23:8845–52. 60. Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 2003;21: 1574–80. 61. Jaffe N, Prudich J, Knapp J, et al. Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate. J Clin Oncol 1983;1:428–31. 62. Bielack SS, Bieling P, Erttmann R, et al. Intraarterial chemotherapy for osteosarcoma: does the result really justify the effort? Cancer Treat Res 1993;62:85–92. 63. Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998;9(8): 893–9. 64. Cullen JW, Jamroz BA, Stevens SL, et al. The value of serial arteriography in osteosarcoma: delivery of chemotherapy, determination of therapy duration, and prediction of necrosis. J Vasc Interv Radiol 2005;16(8):1107–19. 65. Souhami RL, Craft AW, Van der Eijken JW, et al. Randomized trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997;350(9082):911–7. 66. Smeland S, Muller C, Alvegard TA, et al. SSGVIII study: prognostic factors for outcome and role of replacement salvage chemotherapy for poor histologic responders. Eur J Cancer 2003;39:488–94. 67. Bacci G, Ferrari S, Longhi A, et al. High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma Group/ Scandinavian Sarcoma Group Pilot study. J Chemother 2002;14:198–206. 68. Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and highdose methotrexate. J Clin Oncol 2005;23:2004–11. 69. Nardin A, Lefebvre ML, Labroquere K, et al. Liposomal muramyl tripeptide phosphatidylethanolamine: Targeting and activating macrophages for adjuvant treatment of osteosarcoma. Curr Cancer Drug Targets 2006;6:123–33. 70. Bruland OS, Pihl A. On the current management of osteosarcoma. A critical evaluation and a proposal for a modified treatment strategy. Eur J Cancer 1997;33(11):1725–31. 71. Offinger KC, Hudson MM. Long term complications following childhood and adolescent cancer:foundations for providing Risk-based health care for survivors. CA Cancer J Clin 2004;54:208–36. 72. Kremer LC, van Dalen EC, Offringa M, et al. Frequency and risk factors of anthracycline-induced clinical heart failure in children. A systematic review. Ann Oncol 2002;13:503–12. 73. Lipshultz SE, Stuart SR, Lipsitz SR, et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. NEJM 1995; 332(26):1738–43.

434 74. Geidel S, Garn M, Gravinghoff L, et al. Cardiomyopathy after osteosarcoma treatment: a contribution to the cardiotoxicity of adriamycin. Klin Padiatr 1991;203(4):257–61. 75. Longhi A, Ferrari S, Ferrari C, et al. Late side effects of osteosarcoma neoadjuvant chemotherapy: the experience at Rizzoli Institute. In: Proceedings of the Annual Meeting of ASCO 2006, Abstract 9508. 76. Meadows AT, Baum E, Fossati-Bellani F, et al. Second malignant neoplasms in children: an update from Late Effects Study Group. J Clin Oncol 1985;3(4):532–8. 77. Hawkins MM, Draper GJ, Kingston JE, et al. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer 1984;56:339–47. 78. Pratt CB, Meyer WH, Luo X, et al. Second malignant neoplasms occurring in survivors of osteosarcoma. Cancer:80960–5. 79. Aung L, Gorlick RG, Shi W, et al. Second malignant neoplasms in long-term survivors of osteosarcoma: Memorial Sloan-Kettering Cancer Center Experience. Cancer 2002;95:1728–34. 80. Longhi A, Vitali G, Macchiagodena M, et al. Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol 2003;25(4):292–6. 81. Longhi A, Porcu E, Petracchi S, et al. Reproductive functions in female patients treated with adjuvant and neoadjuvant chemotherapy for localized osteosarcoma of the extremity. Cancer 2000;89(9):1961–5. 82. Cvitkovic E. Cumulative toxicity from Cisplatin therapy and current cytoprotective measures. Cancer Treat Rev 1998;24:265–81. 83. Arndt C, Morgenstern B, Hawkins D, et al. Renal function following combination chemotherapy with Ifosfamide and Cisplatin in patient with osteogenic sarcoma. Med Pediatr Oncol 1999;32:93–6. 84. Voute PA, Souhami RL, Nooij M. A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary axial,skeletal and metastatic osteosarcoma: European Sarcoma Intergroup (EOI). Ann Oncol 1999;10:1211–8. 85. Harris MB, Gieser P, Goorin AM, et al. Treatment of metastatic osteosarcoma at diagnosis: a Pediatric oncology group Study. J Clin Oncol 1998;16:3641–8. 86. Kager L, Zoubek A, Potschger U, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 2003;21:2011–8. 87. Bacci G, Briccoli A, Rocca M, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol 2003;14:1126–34. 88. Goorin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 2002;20:426–33. 89. Longhi A, Fabbri N, Donati D, et al. Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 2001;13:324–30. 90. Martini N, Huvos AG, Mike V, et al. Multiple pulmonary resections in the treatment of osteogenic sarcoma. Ann Thorac Surg 1971;12(3):271–80. 91. Ferrari S, Briccoli A, Mercuri M, et al. Postrelapse survival in osteosarcoma of the extremities: prognostic factors for longterm survival. J Clin Oncol 2003;21:710–5. 92. Hawkins DS, Arndt CA. Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer 2003;98(11):2447–56. 93. Tabone MD, Kalifa C, Rodary C, et al. Osteosarcoma recurrence in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol 1994;12:2614–20.

A. Longhi et al. 94. Pastorino U, Gasparini M, Tavecchio L, et al. The contribution of salvage surgery to the management of childhood osteosarcoma. J Clin Oncol 1991;9:1357–62. 95. Saeter G, Hoie J, Stenwig AE, et al. Systemic relapse of patients with osteogenic sarcoma:prognostic factors in long term survival. Cancer 1995;75:1084–109. 96. Bielack BK, Bielack SS, Jurgens H, et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005;23(3):559–68. 97. Huth JF, Eilber FR. Patterns of recurrence after resection of osteosarcoma of the extremity: strategies for treatment of metastases. Arch Surg 1989;124:122–6. 98. Wuisman P, Enneking WF. Prognosis for patients who have osteosarcoma with skip metastases. J Bone Joint Surg (Am) 1990;72:60–8. 99. Kalberrmatten DF, Windisch W, Siebenrock KA. High grade metachronous osteosarcoma. A case report over a 23 year period. Acta Orthop Belg 2000;66:507–13. 100. Jaffe N, Pearson P, Yasko AW, et al. Single and multiple metachronous osteosarcoma tumours after therapy. Cancer 2003;98:2457–66. 101. Aung L, Gorlick R, Healey JH, et al. Metachronous skeletal osteosarcoma in patients treated with adjuvant and neoadjuvant chemotherapy for nonmetastatic osteosarcoma. J Clin Oncol 2003;21:342–8. 102. Bacci G, Longhi A, Bertoni F, et al. Bone metastases in osteosarcoma patients treated with neoadjuvant or adjuvant chemotherapy. Acta Orthop 2006;77(3). 103. Bacci G, Ferrari S, Mercuri M, et al. Predictive factors for local recurrence in osteosarcoma:540 patients with extremity tumors followed for minimum 2,5 years after neoadjuvant chemotherapy. Acta Orthop Scand 1998;69(3):230–6. 104. Rodriguez-Galindo C, Shah N, McCarville MB, et al. Outcome after local recurrence of osteosarcoma: St’Jude Children’s Research Hospital experience (1970–2000). Cancer 2004;100(9):1928–35. 105. Grimer RJ, Sommerville S, Warnock D, et al. Management and outcome after local recurrence of osteosarcoma. Eur J Cancer 2005;41(4):578–83. 106. Sauerbrey A, Bielack S, Kempf-Bielack B, et al. High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma. Bone Marrow Transplant 2001;27:933–7. 107. Fagioli F, Aglietta M, Tienghi A, et al. High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J Clin Oncol 2002;20:2150–6. 108. Franzius C, Bielack S, Flege S, Eckar, et al. High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin 2001;40:215–20. 109. Anderson PM, Wiseman GA, Dispenzieri A, et al. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol 2002;20:1953–4. 110. Delaney TF, Park L, Goldberg SI, et al. Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 2005;61:492–8. 111. Machak GN, Trachev SI, Solovyev YN, et al. Neoadjuvant chemotherapy and local radiotherapy for high grade osteosarcoma of the extremities mayo. Clin Proc Febr 2003;78:147–55. 112. Whelan JS, Burcombe RJ, Janinis J, et al. A systematic review of the role of pulmonary irradiation in the management of primary bone tumours. Ann Oncol 2002;13(1):23–30. 113. Seibel N, Krailo M, Sato J. Phase II window of Topotecan in newly diagnosed Metastatic Osteosarcoma CCG 7943. In: Proceedings of the ASCO 2001; Abstract 1509.

Primary pediatric bone osteosarcoma 114. Okuno S, Edmonson J, Mahoney M, et al. Phase II trial of gemcitabine in advanced sarcomas. Cancer 2002;94:3225–9. 115. Leu KM, Ostruszka LJ, Shewach D, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 2004;22:1706–12. 116. Laverdiere C, Kolb EA, Supko JG, et al. Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer 2003;98:832–40. 117. Kotz R, Plattner E, Ramach W, Flener R, Bodo G. Interferon/ controlled study in 3-year survival of patients with osteosarcoma. Arzneimittelforschung 1982;32:446–8. 118. Strander H, Aparisi T, Blomgren H, et al. Adjuvant interferon treatment of human osteosarcoma. Recent Results Cancer Res 1982;80:103–7. 119. Muller CR, Smeland S, Bauer HC, et al. Interpheron-alpha as the only adjuvant treatment in high-grade osteosarcoma:Long term results of the Karolinska Hosp series. Acta Oncol 2005;44:475–80. 120. Luksch R, Perotti D, Cefalo G, et al. Immunomodulation in a treatment program including pre- and post-operative interleukin-2 and chemotherapy for childhood osteosarcoma. Tumorigenesis 2003;89:263–8. 121. Mansky PJ, Liewehr DJ, Steinberg SM, et al. Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: significant reduction of insulin-like growth factor-1 serum levels. J Pediatr Hematol Oncol 2002;24:440–6. 122. Nakase M, Inui M, Okumura K, Kamei T, Nakamura S. Tagawa p53 gene therapy of human osteosarcoma using a transferrinmodified cationic liposome. Mol Cancer Ther 2005;4:625–31. 123. Dutour A, Monteil J, Paraf F, et al. Endostatin cDNA/cationic liposome complexes as promising therapy to prevent lung metastases in osteosarcoma: study in human-like rat orthotopic tumor. Mol Ther 2005;11:311–9. 124. Mercuri M, Capanna R, Manfrini M, et al. Management of malignant bone tumors in children and adolescents. Clin Orthop 1991;264:156–68. 125. Springfield D. Surgery for bone and soft-tissue tumors. Philadelphia: Lippincott-Raven; 1997., p. 265–74. 126. Velez-Yanguas MC, Warrier RP. The evolution of chemotherapeutic agents for the treatment of pediatric musculoskeletal malignancies. Orthop Clin North Am 1996;27:545–9. 127. Malawer MM, Chou LB. Prosthetic survival and clinical results with use of large-segment replacements in the treatment of high grade bone sarcomas. J Bone Joint Surg Am 1995;77:1154–65. 128. Picci P, Sangiorgi L, Bahamonde, et al. Risk factors for local recurrences after limb-salvage surgery for high grade osteogenic sarcoma of the extremities. Ann Oncol 1997;8:899–903. 129. Schima W, Amann G, Stiglbauer R, et al. Preoperative staging of osteosarcoma: efficacy of MRI imaging in detecting joint involvement. Am J Roentegenol 1994;163:1171–5. 130. Abudu A, Sferopoulus NK, Tillman RM, Carter SR, Grimer RJ. The surgical treatment and outcome of pathological fracture in localized osteosarcoma. JBJS B 1996;78:694–8. 131. Grimer RJ, Taminiau AM, Cannon SR. Surgical outcomes in osteosarcoma. J Bone Joint Surg Br B 2002;84:395–400. 132. Rougraff BT, Simon MA, Kneisl JS, Greenberg DB, Mankin HJ. Limb salvage compared with amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am 1994;76:649–56. 133. Bacci G, Ferrari S, Longhi A, Donati D, Manfrini M, Giacomini S, et al. Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 2003;74(4):449–54. 134. Jeys LM, Grimer RJ, Carter SR, et al. Risk of amputation following limb salvage surgery with endoprosthetic replace-

435

135.

136.

137. 138.

139.

140. 141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152. 153.

154.

155.

156.

ment, in a consecutive series of 1261 patients. Int Orthop 2003;27:160–3. Gherlinzoni F, Picci P, Bacci G, Campanacci D. Limb sparing versus amputation in osteosarcoma. Correlation between local control, surgical margins and tumor necrosis: Istituto Rizzoli experience. Ann Oncol 1992;3(Suppl. 2):S23–7. Kotz R, Salzer M. Rotation-plasty for childhood osteosarcoma of the distal part of the femur. J Bone Joint Surg Am 1982;64:959–69. Winkelmann WW. Rotationplasty. Orthop Clin North Am 1996;27:503–23. Hillmann A, Hoffmann C, Gosheger G, et al. Malignant tumour of the distal part of the femur or the proximal part of the tibia: Endoprosthetic replacement or rotationplasty? J Bone Joint Surg Am 1999;81:462–8. Fuchs B, Kotajarvi BR, Kaufman KR, Sim FH. Functional outcome of patients with rotationplasty about the knee. Clin Orthop 2003;415:52–8. Grimer RJ. Surgical options for children with osteosarcoma. Lancet Oncol 2005;6(2):85–92. Bradish CF, Kemp HB, Scales JT, Wilson JN. Distal femoral replacement by custom-made prostheses: clinical follow-up and survivorship analysis. J Bone Joint Surg Br 1987;69:276–84. Chao EY, Fuchs B, Rowland CM, et al. Long-term results of segmental prosthesis fixation by extracortical bone-bridging and ingrowth. J Bone Joint Surg Am 2004;86:948–55. Torbert JT, Fox EJ, Hosalkar HS, Ogilvie CM, Lackman RD. Endoprosthetic reconstructions: results of long-term followup of 139 patients. Clin Orthop Relat Res 2005;438:51–9. Eckardt JJ, Kabo JM, Kelley CM, et al. Expandable endoprosthesis reconstruction in skeletally immature patients with tumors. Clin Orthop 2000;373:51–61. Gitelis S, Neel MD, Wilkins RM, Rao BN, Kelly CM, Yao TK. The use of a closed expandable prosthesis for pediatric sarcomas. Chir Organi Mov 2003;88(4):327–33. Neel MD, Wilkins RM, Rao BN, Kelly CM. Early multicenter experience with a non-invasive expandable prosthesis. Clin Orthop 2003;415:72–81. Rodl RW, Ozaki T, Hoffmann C, Bottner F, Lindner N, Winkelmann W. Osteoarticular allograft in surgery for highgrade malignant tumours of bone. J Bone Joint Surg Br 2000;82(7):1006–10. Brigman BE, Hornicek FJ, Bebhardt MC, Mankin HJ. Allografts about the knee in young patients with high grade sarcoma. Clin Orthop 2004;421:232–9. Finn HA, Simon MA. Limb-salvage surgery in the treatment of osteosarcoma in skeletally immature individuals. Clin Orthop Relat Res(262):108–18. Alman BA, De Bari A, Krajbich JI. Massive allografts in the treatment of osteosarcoma and Ewing sarcoma in children and adolescents. J Bone Joint Surg Am 1995;77(1):54–64. Gitelis S, Piasecki P. Allograft prosthetic composite arthroplasty for osteosarcoma and other aggressive bone tumors. Clin Orthop 1991;270:197–201. Hejna MJ, Gitelis S. Allograft prosthetic composite replacement for bonetumors. Semin Surg Oncol 1997;13(1):18–24. Gerrand CH, Griffin AM, Davis AM, Gross AE, Bell RS, Wunder JS. Large segment allograft survival is improved with intramedullary cement. J Surg Oncol 2003;84(4):198–208. Ortiz-Cruz E, Gebhardt MC, Jennings LC, et al. The results of transplantation of intercalary allografts after resection of tumors: A long-term follow-up study. J Bone Joint Surg Am 1997;79:97–106. Gebhardt MC, Flugstad DI, Springfield DS, Mankin HJ. The use of bone allografts for limb salvage in high-grade extremity osteosarcoma. Clin Orthop 1991;270:181–96. Chang DW, Weber KL. Use of a vascularized fibula bone flap and intercalary allograft for diaphyseal reconstruction after

436

157.

158. 159.

160.

161.

A. Longhi et al. resection of primary extremity bone sarcomas. Plast Reconstr Surg 2005;116(7):1918–25. Ceruso M, Falcone C, Innocenti M, Delcroix L, Capanna R, Manfrini M. Skeletal reconstruction with a free vascularized fibula graft associated to bone allograft after resection of malignant bone tumor of limbs. Hand Chir Mikrochir Plast Chir 2001;33:277–82. Manfrini M. The role of vascularized fibula in skeletal reconstruction. Chir Organi Mov 2003;88:137–42. Innocenti M, Ceruso M, Manfrini M, et al. Free vascularized growth-plate transfer after bone tumour resection in children. J Reconstr Microsurg 1998;14:137–43. Manfrini M, Innocenti M, Ceruso M, Mercuri M. Original biological reconstruction of the hip in a 4-year-old girl. Lancet 2003;361:140–2. Nagarajan R, Neglia JP, Clohisy DR, Robison LL. Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications? J Clin Oncol 2002;20:4493–501.

162. Rougraff BT, Simon MA, Kneisl JS, et al. Limb salvage compared with amputation for osteosarcoma of the distal end of the femur. A long term oncological, functional and quality of life study. J Bone Joint Surg Am 1994;76: 649–56. 163. Felder-Puig R, Formann K, Mildner A, et al. Quality of life and psychosocial adjustment of young patients after treatment of bone cancer. Cancer 1998;83:69–75. 164. Grimer RJ, Carter SR, Pynsent PB. The cost-effectiveness of limb salvage for bone tumours. JBJS B 1997;79:558–61. 165. Ferrari S, Bertoni F, Mercuri M, Picci P, Giacomini S, Longhi A, et al. Predictive factors of disease-free survival for nonmetastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001;12:1145–50. 166. Bacci G, Longhi A, Bertoni F, Bacchini P, Ruggeri P, Versari M, et al. Primary high-grade osteosarcoma: comparison between preadolescent and older patients. J Pediatr Hematol Oncol 2005;27:129–34.