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PubMed2006

Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group.

PURPOSE: The outlook for patients with osteosarcoma who present with synchronous regional bone metastases (skip metastases), either in the primary bone site or transarticular, is considered to be extremely poor. This study was conducted to further investigate the prognostic implication of skip metastases in osteosarcoma. PATIENTS AND METHODS: The authors retrospectively analyzed the collected data of 1,765 consecutive patients with newly diagnosed high-grade osteosarcoma of bone who were registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies and identified 24 patients (1.4%) with unequivocally proven skip metastases. All 24 patients were treated by an aggressive surgical approach coupled with polychemotherapy. Demographic, diagnostic, tumor, and treatment-related variables and response and survival data were analyzed. RESULTS: Skip metastases were identified preoperatively in 11 of 24 patients by bone scan, eight of 22 patients by plain x-ray, 15 of 18 patients by magnetic resonance imaging, and five of 10 patients by computed tomography. A complete surgical remission (CSR) of all clinically detectable tumor sites was achieved in 22 of 24 patients during front-line therapy. With a median follow-up time of 4.4 years (8 years for survivors) from diagnosis, 12 patients were alive, all of whom were in continuous CSR. Survival did correlate with location of skip metastases and histologic response to neoadjuvant chemotherapy. CONCLUSION: Synchronous regional bone metastases are rare in osteosarcoma, and preoperative detection relies on appropriate diagnostic imaging. Aggressive multimodal therapy holds the promise to achieve prolonged survival, especially in patients in whom these metastases occur within the same bone as the primary lesion and whose tumors respond well to chemotherapy.

Adolescent↗

PubMed2006

Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials.

BACKGROUND: The prognostic relevance of dose intensity in the treatment of osteosarcoma is still under discussion. The aim of this study was to investigate whether higher dose intensities of chemotherapy correlated with better outcomes. PROCEDURE: This study contains 917 consecutive Cooperative Osteosarcoma Study Group (COSS) patients <40 years with primary, high-grade central, nonmetastatic osteosarcoma of the extremities, who were in complete remission at least until day 200 after the start of chemotherapy. All COSS-protocols were based on a uniform treatment concept of aggressive polychemotherapy and definitive surgery. Chemotherapy dose intensity in the first 200 days of treatment (DI200) and possible correlations to overall and event-free survival were investigated. The study focused on methotrexate, doxorubicin, cisplatin, and ifosfamide, which are considered to be the most active drugs against osteosarcoma. Multivariate analyses including well-known prognostic factors were added to complete this investigation. RESULTS: Until day 200, patients received 80.7 +/- 26.1 g/m2 methotrexate (MTX); 242 +/- 69 mg/m2 doxorubicin (DOX); 324 +/- 133 mg/m2 cisplatin (DDP); and 13.9 +/- 9.8 g/m2 ifosfamide (IFO) (mean +/- SD). Median follow-up from day 200 was 6.6 (0.02-22.1) years. There was no correlation between a higher DI200 of any one drug and better outcomes in uni- or multi-variate analyses. Total treatment intensity did not show such correlations either. CONCLUSIONS: In an overall setting of intensive multidrug treatment of osteosarcoma, we could not prove that higher dose intensities correlate with better outcomes.

Adolescent↗

PubMed1993

Chemotherapeutic effect on osteosarcoma on basis of collagen analysis: a proposal of the induction of osteosarcoma differentiation.

The authors studied effect of chemotherapy on osteosarcoma by collagen analysis. As a result of this case study we propose the induction of osteosarcoma differentiation by chemotherapy. Treatment of a conventional osteosarcoma with two intra-arterial infusions of cisplatin and the T-12 protocol of Rosen resulted in sclerotic changes and good margination accompanied by the disappearance of the soft-tissue component from the X-rays. More than 90% tumour destruction was histologically demonstrated; tumour bone and osteoid increased after the chemotherapy, and the viable area of the tumour resembled an osteoblastoma. Before the chemotherapy, immunolocalization determined collagen types I and V to be diffusely present in the bone and osteoid. After the chemotherapy, the antibody to type I collagen was diffusely present, but the antibody to type V collagen occurred only on the surface of the increased bone and osteoid as in normal bone. When osteosarcoma cells were treated in vitro with methotrexate or cisplatin, collagen production increased significantly. It is thus believed that tumour cells were directly stimulated with these chemotherapeutic agents to produce collagen. The findings suggested that some anticancer agents might not only be cytotoxic to but also differentiate osteosarcoma cells.

Adolescent↗

PubMed2002

Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup.

Large randomised trials are mandatory when one wants to examine the effects of different aspects (such as the treatment modality) of a pathological condition on the overall outcome. This is especially true when studying a disease in which there is a multifactorial influence on progression and outcome such as osteosarcoma. Data on 570 patients with biopsy-proven primary central osteosarcoma of an extremity included in two consecutive studies of the European Osteosarcoma Intergroup (EOI) were analysed in order to evaluate if the histological subtype of the biopsy specimen correlated with the subtype of osteosarcoma represented in the resected specimen, if there was a relationship between the histological subtype and overall survival and if there was a relationship between the histological subtype and histological response to chemotherapy. High-grade osteosarcoma, as defined by established criteria, was subtyped as either conventional, chondroblastic, teleangiectatic, small cell, fibroblastic, osteoclast rich, anaplastic and sclerotic/osteoblastic well differentiated. A panel of experienced pathologists with a special interest in bone pathology was appointed to review the histological diagnosis and to assess the tumour response to chemotherapy on the resected specimen of each patient entered into the trials. Subtyping on the biopsy specimen proved to be highly representative for the subtype of the whole tumour. In 102 patients for which subtyping was performed on the biopsy and the resected specimens, there were only two discrepancies. Of the 568 patients for whom subtype was available, 404 (71%) were of the conventional type, 54 (10%) were chondroblastic, 53 (9%) had fibroblastic tumours and the remainder consisted of rare subtypes. A good response to preoperative chemotherapy was defined as 90% or more necrosis. The proportion of patients responding well to chemotherapy differed significantly between subtypes (Chi-square test statistics=11.44, P=0.01 on 3 degrees of freedom (d.f.)). In comparison with the conventional subtype, there was a higher proportion of good responders in the fibroblastic group and a lower proportion of good responders in the chondroblastic group. Good responders had a significantly better survival than patients who responded poorly to the pre-operative chemotherapy (logrank statistic=25.20, P<0.01 on 1 df). Survival did not differ significantly according to subtype (logrank statistic=2.72, P=0.44 on 3 df), although there was a suggestion that patients with chondroblastic tumours experienced a better long-term survival. This large set of prospectively-collected data provides important information on the relationship between pathological subtype, histological response and survival. Histological response has a known prognostic effect on survival, and we have shown that the rates of response differ by subtype. There is some evidence from this study that the specific histological subtypes, i.e. the chondroblastic subtype, experience better survival. However, despite this large multi-institutional study, we have insufficient numbers of non-conventional tumours to examine this unambiguously for these subsets.

Adolescent↗

PubMed2002

Establishment of human osteosarcoma cell lines with high metastatic potential to lungs and their utilities for therapeutic studies on metastatic osteosarcoma.

Relevant animal models for metastasis of osteosarcoma is needed to understand the biology and to develop the treatment modality of metastasis of human osteosarcoma. Therefore, we screened six human osteosarcoma cell lines for metastatic ability in nude mice. The HuO9 cell line was identified as being metastatic to the lung after intravenous injection. We established two sublines, HuO9-M112 and HuO9-M132, with high metastatic potential to the lung from the parental HuO9 cells by in vivo selection. There were no differences between these two sublines and the parental cells in the growth rate in vitro and the tumorigenicity after subcutaneous injection in nude mice, however, mice injected with the metastatic sublines became moribund earlier than mice injected with the parental HuO9 cells did. Thus, adriamycin (ADR) and recombinant interleukin-12 (IL-12) were administered to mice injected with the HuO9-M112 subline to suppress experimental lung metastases. Production of lung colonies was significantly suppressed and the prognoses of mice were significantly improved by both ADR and IL-12 treatments. These results indicate that both ADR and IL-12 are effective agents against pulmonary metastatic osteosarcoma, and that these sublines are useful for studies on the biological behavior and treatment of pulmonary metastatic osteosarcoma.

Animals↗

PubMed1996

Chondromyxoid fibroma-like osteosarcoma: a distinct variant of low-grade osteosarcoma.

Chondromyxoid fibroma-like osteosarcoma is a recently described, extremely rare subtype of low-grade osteosarcoma. Two such cases were encountered among 102 cases of osteosarcoma seen in the Prince of Wales Hospital, Hong Kong, between 1984 and 1994. The first patient, a 39-year-old woman, presented with a mass in her right maxilla which was resected and mistaken as a myxoma. The tumour recurred locally four years later and she now has extensive local recurrent disease six years after initial presentation and is amenable to support treatment only. The second patient, a 28-year-old man, had a pelvic tumour which recurred in the form of a polypoid left atrial tumour and pulmonary nodules six years after operation. The left atrial tumour recurred one year after operation, and led to sudden death of the patient seven years after initial presentation. Radiologically, the tumours in both cases appeared as expansile osteolytic lesions with erosion of adjacent bone and infiltration into soft tissue. Histologically, they consisted of lobules of spindle, stellate or polygonal tumour cells showing mitotic activity and with moderate nuclear pleomorphism and hyperchromatism, set in a highly myxoid stroma superficially mimicking chondromyxoid fibroma. The histological hallmark was the direct production of osteoid by tumour cells. Chondromyxoid fibroma-like osteosarcoma merits recognition as a distinct variant of low-grade osteosarcoma for which early appropriate surgery is indicated.

Adult↗

PubMed2002

Extraskeletal osteosarcoma histologically mimicking parosteal osteosarcoma.

An extraskeletal osteosarcoma histologically mimicking parosteal osteosarcoma arising in a 63-year-old female is described. The intramuscular lesion in the left lower thigh was a 7 x 4 cm, well-defined mass with marked central calcification and ossification. The tumor was composed predominately of a centrally located osteocartilaginous component and a peripheral, non-osseous fibrous component. The former was characterized by a complex interanastomosing pattern of woven-bone trabeculae with small osteocytes and a minor cartilaginous element. The intratrabecular stroma consisted of benign-appearing fibroblasts. The peripheral fibrous part was characterized by fascicular and interlacing proliferations of spindle cells with mild atypia, rare mitosis and low to moderate cellularity. There were a few scattered foci of proliferating pleomorphic cells, constituting 5% of the tumor, indicating high-grade transformation. There was no evidence of zoning phenomena, cortical erosion, periosteal reaction or intramedullary involvement. The patient is well without recurrence or metastasis at 12 months follow up. This soft tissue neoplasm, mimicking parosteal osteosarcoma, should be distinguished from other bone-forming tumors or tumor-like lesions with which they may be confused. Pathologists and physicians should know the existence of this type of extraskeletal osteosarcoma and treat it as a high-grade extraskeletal osteosarcoma.

Bone Neoplasms↗

PubMed1988

Primary osteosarcoma of toe phalanx: first documented case. Review of osteosarcoma of short tubular bones.

A case of a sclerosing variant of osteosarcoma of a toe phalanx is reported in a 28-year-old man. This represents the first reported case of osteosarcoma of any kind at this site. This is based on a review of 4,214 cases of conventional osteosarcoma. The reason for the extraordinary rarity in toe or hand phalanges is unknown although osteosarcoma is the second most common primary tumor of bone. Since the neoplasm had minimal signs of cytologic anaplasia, it was originally mistaken for and treated as an osteoid osteoma. The lesion recurred and extended into soft tissues. Reevaluation revealed the tumor to be an osteosarcoma, sclerosing variant with "normalization" of nuclei. The lesions that this tumor should be distinguished from are osteoid osteoma and osteoblastoma.

Adult↗

PubMed2002

Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols.

PURPOSE: To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease. PATIENTS AND METHODS: A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions. RESULTS: Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival > or = 40, 41.6%; < 40, 60.2%; P =.012), tumor site (axial, 29.2%; limb, 61.7%; P <.0001), and primary metastases (yes, 26.7%; no, 64.4%; P <.0001), and for extremity osteosarcomas, also size (> or = one third, 52.5%; < one third, 66.7%; P <.0001) and location within the limb (proximal, 49.3%; other, 63.9%; P <.0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; P <.0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; P <.0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors. CONCLUSION: Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.

Adolescent↗

PubMed1996

Intracortical low grade osteosarcoma. A unique case and review of the literature on intracortical osteosarcoma.

The thirteenth case of an intracortical osteosarcoma is presented. According to the authors' knowledge, this case appears to be the first report of an intracortical low grade osteosarcoma of the fibrous dysplasia-like variant in the femur. All other cases (except one small cell variant) reported in the literature were histologically diagnosed as high grade osteoblastic or sclerotic variants. The finding of both a low grade and a small cell variant of osteosarcoma supports the concept that intracortical osteosarcoma rather represents a distinct entity defined by location than an early detected conventional medullary osteosarcoma.

Child↗

PubMedDate not supplied

BK virus-induced osteosarcoma (Os515) as a model of human osteosarcoma.

BK virus was isolated by Gardner et al in 1971 from the urine of an immunosuppressed patient with a kidney allograft. Antibodies to this virus are ubiquitous in the general populations worldwide, but the oncogenic capacity of BKV in humans had not been reported. The virus transformed in vitro permissive human and non-permissive animal cells, and the transformed cells had the T antigen. Intracerebral and intravenous inoculation of BKV in newborn hamsters induced malignant tumours (mainly ependymomas, malignant insulinomas, and osteosarcomas). Subcutaneous and intraperitoneal routes were also effective. The virus was only rescued from a few tumours by fusion with human embryonic cells or Vero cells. Brain tumours appeared earlier and osteosarcomas developed in animals which survived for more than 6 months. Many of the osteosarcomas were bony and grew slowly with frequent lung metastases, and a few osteosarcomas were soft and grew rapidly without lung metastases. Experimental targeting chemotherapy with doxorubicin (DX)-containing immunoliposomes was performed against Os515 osteosarcoma. In in vitro experiments, DX-Lip-MoAb29 showed a more significant inhibitory effect on cultured Os515 cells than free Dx and DX-Lip. DX-Lip DNP had less effect. In in vivo experiments, DX-Lip-MoAb29 suppressed the growth of Os515 tumour isografts in hamsters and prolonged the survival of recipients more significantly than free DX.

Animals↗

PubMed2005

Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma.

PURPOSE: The aims of this analysis were to investigate the clinical features of extraskeletal osteosarcoma (ESOS) and examine the outcome after multi-modal therapy. METHODS: The co-operative osteosarcoma study-group database was searched for patients with extraskeletal osteosarcoma. Eligible patients were included in a retrospective analysis of patient, tumour and treatment related variables and outcome. As for conventional osteosarcoma, scheduled treatment included surgery and multi-agent chemotherapy. RESULTS: Seventeen eligible patients were identified with a median age of 44 years (range, 3-65 years). The thigh was the commonest tumour site. Two patients had a history of previous malignancies and two had primary metastases. Median follow-up was 3.2 years (range: 0.6-7.4 years) and at last follow-up, 11 patients were alive in complete remission, 3 patients were alive with disease and 3 patients had died of their disease. Three-year overall actuarial and event-free survival rates were 77% and 56%, respectively. Patients with macroscopically complete surgical remission had an improved overall survival (P = 0.0004). CONCLUSIONS: The patients in this retrospective study had a surprisingly good survival rate. This may be due to the combination of multi-agent chemotherapy with surgery, and we recommend this approach in the treatment of ESOS.

Adolescent↗

PubMed2003

Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

PURPOSE: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. PATIENTS AND METHODS: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. RESULTS: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. CONCLUSION: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.

Adolescent↗

PubMed1979

A large parosteal osteosarcoma with transformation to high-grade osteosarcoma: a case report.

This case of a large (31 cm) parosteal osteosarcoma had x-ray documentation 4 1/2 years before treatment. When the tumor began enlarging rapidly, treatment was sought. The tumor histologically showed typical parosteal osteosarcoma as well as malignant cartilage, osteoid, and undifferentiated sarcoma. The case shows one course a parosteal osteosarcoma can take over a 7-year untreated period. The significance of high-grade sarcoma and intramedullary involvement is discussed. When unequivocal high-grade osteosarcoma is present, it should be treated with radical resection and adjuvant multi-drug chemotherapy.

Bone Neoplasms↗

PubMed2004

Mutation analysis of the apoptotic "death-receptors" and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines.

Apoptosis is a key mechanism of the organism that regulates embryogenesis and development, maintains homeostasis of the immune system and removes potentially hazardous cells. A dysregulation of apoptosis signaling may thus disturb the balance of cell survival and cell death, leading to the development of several diseases including cancer. In order to determine whether osteosarcomas display an increased frequency of genetic alterations that affect apoptosis signaling, we analyzed the death domains of the death receptor genes CD95/Fas/Apo1, TNFR1, DR3/Apo3/WSL-1/LARD/TRAMP, DR5/TRAIL-R2/TRICK2/KILLER, DR6 and the complete coding sequences of the death receptor gene DR4/TRAIL-R1 and the genes of the adaptors TRADD and FADD/MORT-1. The investigation included 15 osteosarcoma tumor samples, 3 osteosarcoma cell lines (SAOS-2, HOS and MG63) and peripheral blood from 20 donors as controls. We were able to identify 4 different sequence variations within the DR4 gene located on exons 3, 4, 5 and 10 (death-domain). No alterations have been detected in the other genes or exons investigated. Except the sequence variant affecting exon 4, the alterations were homozygous in 15% of the tumor samples and cell lines, whereas the same alterations found in the control group were heterozygous or even not detectable. Three out of 4 alterations are located in the receptor's extracellular cysteine rich domain, which contains the ligand binding area and 1 on exon 10 coding for the death-domain. They may thus exert influence on ligand-receptor interactions and subsequent apoptosis induction. Our findings suggest that homozygous genetic alterations within the DR4 gene may be implicated in the formation of osteosarcoma.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Platinum agents in the treatment of osteosarcoma: efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines.

BACKGROUND: Cisplatin (cDDP), when used either alone or, more often, in combination with other agents, especially adriamycin, achieves a high response rate in osteosarcoma. Its use, however, is limited by severe nephro- and neuro-toxicity. Second generation platinum compounds, most notably carboplatin (CBDCA), have been developed in order to attempt to reduce these dose-limiting toxicities, and thus improve the therapeutic ratio. Studies evaluating the role of combination CT containing CBDCA vs. cDDP have demonstrated differing results depending on the tumor type tested and its role in the treatment of osteosarcoma has yet to be clarified. PROCEDURE: In this study, we compared the in vitro anti-tumor activity of cDDP and CBDCA in a panel of three human osteosarcoma cell lines (HOS, MG63, and U2OS). RESULTS: cDDP and CBDCA (0-20 micromol) showed marked variation in cytotoxicity among the three cell lines. EC(50) values for CBDCA in HOS and MG63 cells were approximately two-fold higher than for cDDP and the ratio of AUC(CBDCA) to AUC(cDDP) varied from 1.8 in the HOS cell line to 2.3 in the MG63 cell line. Exposure of MG63 and HOS cells to either cDDP or CBDCA (1.67 and 13.5 micromol) caused a G2/M cell cycle arrest by 24 hr. Also evident was a sub G1 peak indicative of cell death by apoptosis. U2OS cells were relatively resistant to the cytotoxic effects of both drugs, although a cell cycle arrest in response to DNA damage was observed. This suggests that unlike MG63 and HOS cells, U2OS cells have either a more efficient repair pathway for platinum-induced DNA damage or are able to evade apoptosis. Examination of apoptotic events and cellular recovery demonstrated that both an 8-16-fold higher concentration and longer treatment period for CBDCA compared with cDDP was required to produce equivalent cell death and a loss of the ability of single cell clones to form colonies in both the HOS and MG63, but not the U2OS cell line. CONCLUSIONS: Our findings suggest that CBDCA at a two- to four-fold higher concentration than cDDP has potential therapeutic activity in platinum sensitive osteosarcomas, particularly when cDDP cytotoxicity compromises therapeutic efficacy.

Antineoplastic Agents↗

PubMed1997

Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup.

BACKGROUND: A previous trial by the European Osteosarcoma Intergroup (EOI) suggested that a short intensive chemotherapy regimen with doxorubicin and cisplatin might produce survival of operable, non-metastatic osteosarcoma similar to that obtained with complex and longer-duration drug regimens based on the widely used T10 multi-drug protocol. We undertook a randomised multicentre trial to compare these two approaches. METHODS: 407 patients with operable, non-metastatic osteosarcoma were randomly assigned the two-drug regimen (six cycles [18 weeks] of doxorubicin 25 mg/m2 on days 1-3 and cisplatin 100 mg/m2 on day 1) or a multi-drug regimen (preoperatively vincristine, high-dose methotrexate, and doxorubicin; postoperatively bleomycin, cyclophosphamide, dactinomycin, vincristine, methotrexate, doxorubicin, and cisplatin; this protocol took 44 weeks). Surgery was scheduled for week 9 for the two-drug group and week 7 for the multi-drug group. Analyses of survival and progression-free survival were by intention to treat. FINDINGS: Of 407 randomised patients, 391 were eligible and have been followed up for at least 4 years (median 5-6 years). Toxic effects were qualitatively similar with the two regimens. However, 188 (94%) of 199 patients completed the six cycles of two-drug treatment, whereas only 97 (51%) of 192 completed 18 or more of the 20 cycles of the multi-drug regimen. The proportion showing a good histopathological response (> 90% tumour necrosis) to preoperative chemotherapy was about 29% with both regimens and was strongly predictive of survival. Overall survival was 65% at 3 years and 55% at 5 years in both groups (hazard ratio 0.94 [95% CI 0.69-1.27]). Progression-free survival at 5 years was 44% in both groups (hazard ratio 1.01 [0.77-1.33]). INTERPRETATION: We found no difference in survival between the two-drug and multi-drug regimens in operable, non-metastatic osteosarcoma. The two-drug regimen is shorter in duration and better tolerated, and is therefore the preferred treatment. However, 5-year survival is still unsatisfactory and new approaches to treatment, such as dose intensification, are needed to improve results.

Adolescent↗

PubMed1999

A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI).

BACKGROUND: Despite advances in the treatment of primary limb osteosarcoma, the outcome of patients with primary metastatic and axial skeletal disease remains poor. The European Osteosarcoma Intergroup have assessed a combination chemotherapy regimen consisting of ifosfamide (IFOS) 3 g/m2/dl-2, doxorubicin (DOX) 25 mg/m2/dl-3 i.v. bolus and cisplatin (CDDP) 100 mg/m2/dl. PATIENTS AND METHODS: One hundred nine previously untreated patients with primary osteosarcoma were registered. Eligibility was confirmed in 103. At presentation, 45 eligible patients had metastatic disease, 15 axial skeletal primary tumours and 43 non-metastatic limb tumours. RESULTS: The major toxicities were myelosuppression (90%, grade 3 or 4) and nausea and vomiting (74%, grade 3 or 4). Overall mean relative dose intensity (RDI) was 80% (88% CDDP, 75% IFOS, 81% DOX). Clinical response as measured by reduction in tumour volume occurred in 36% (95% confidence interval (95% CI): 27%-47%) of primary tumours. Response of pulmonary metastases to chemotherapy was seen in 33% (95% CI: 19%-49%). Good histological response (> or = 90% necrosis of the tumour) occurred in 33% (95% CI: 22%-45%) of resected tumours. Five-year survival was 62% in limb-non-metastatic, 41% in axial skeletal and 16% in limb metastatic patients. CONCLUSIONS: This regimen is active in osteosarcoma but does not appear to be more active than the two-drug CDDP-DOX regimen currently recommended by EOI.

Adolescent↗