Anne McTiernan

Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials

BACKGROUND Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. PATIENTS AND METHODS Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. RESULTS Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. CONCLUSIONS Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.

Incidence and survival of malignant bone sarcomas in England 1979–2007

Primary malignant bone sarcomas (MBS) are rare and there are few studies examining their incidence and outcome. Here, the incidence and survival of all subtypes of MBS registered in England between 1979 and 2007 were analysed from patient registry data held by the National Cancer Intelligence Network (NCIN). Over 11,002 new cases of MBS were registered, an average of 379 per year. There was no change in incidence demonstrated over the study period (p = 0.08). Although a peak incidence is observed in adolescence, approximately half of MBS are diagnosed in patients over 50 years. An improvement in outcome of MBS was observed between those patients registered from 1979 to 1983 and 1983 to 1987 (p < 0.0001), but there has been no improvement since. In the most recent period studied (patients diagnosed 1998–2002) 5‐year survival was 55% in Ewing sarcoma, 70% in chondrosarcoma, 56% in chordoma and 43% in osteosarcoma. Patients diagnosed with osteosarcoma over the age of 40 years or with a non‐extremity tumour have a significantly inferior outcome; 22% 5‐year survival >40 years compared with 53% <40 years (p < 0.0001) and 16% non‐extremity tumour compared to 48% extremity tumour (p < 0.0001). This population‐based study has allowed us to confidently define the English incidence and survival rates of both the commoner bone tumours such as osteosarcoma, and rarer entities such as chordoma as well as groups with inferior outcome. The lack of significant improvement over recent decades for these diseases is cause for concern and further research.

Late relapse of osteosarcoma: Implications for follow-up and screening

Long‐term disease‐free survival in patients with localised osteosarcoma treated in large multicentre randomised trials is over 50%. Most relapses occur early, usually within 2–3 years. Relapse after 5 years is uncommon and has been infrequently described. Eight patients with osteosarcoma treated at The London Bone and Soft Tissue Tumour Service since 1986 developed recurrence of disease after 5 years, the latest 14 years after the initial diagnosis. Five patients developed pulmonary metastases, two patients isolated bone metastases and one patient intra‐abdominal metastases. Although a second complete remission was achieved in six patients, four patients relapsed again, all with pulmonary metastases. Two patients had co‐existent brain metastases. One of those with a second recurrence has achieved a further complete remission and remains well 50 months after the most recent treatment. A second patient is disease‐free 24 months after complete excision of an isolated pulmonary metastasis and one further patient is disease‐free 6 months after chemotherapy and pneumonectomy for pleural and pulmonary metastases. Five patients have died of disease with a median survival from the date of relapse of 17 months (2–68 months). Current data looking at long‐term outcome of patients with osteosarcoma is limited. Reports of late relapse are rare as numbers are small, thus long‐term surveillance of patients is essential. It is possible that sites of relapse are more unusual, and more extensive staging may be necessary when late relapse occurs.

Improving Outcomes After Relapse in Ewing's Sarcoma: Analysis of 114 Patients From a Single Institution

The outcome for patients with relapsed Ewings sarcoma is poor. A retrospective analysis was carried out to identify factors associated with improved survival. Between 1992 and 2002, 114 patients presented with relapsed or progressive disease. Median time to progression/relapse was 13 months (range, 2–128). Treatment at relapse included high dose treatment (HDT) in 29 patients, and surgery or definitive radiotherapy in 29. 2 and 5-year post relapse survival (PRS) was 23.5% and 15.2%, respectively. In multivariate analysis, the most significant factors associated with improved survival were disease confined locally or to the lungs (2-year PRS, 40% versus 6%; P < .001), relapse > 18 months from diagnosis (2-year PRS, 53% versus 8%; P < .001), HDT at relapse (2-year PRS, 62% versus 11%; P < .001), and surgery and/or radiotherapy at relapse (2-year PRS, 51% versus 14%; P < .001). First treatment failure in Ewings sarcoma is mostly fatal. Improved survival can be achieved in selective patients with aggressive treatment. These improvements are confined to those without bone or bone marrow metastases.

Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: A report from the European Osteosarcoma Intergroup

Aim Chemotherapy-induced toxicity is an independent prognostic indicator in several cancers. We aimed to determine whether toxicity was related to survival and histological response in high-grade localised extremity osteosarcoma. We undertook a retrospective analysis of patients treated within three consecutive randomised controlled trials (RCTs) of the European Osteosarcoma Intergroup. Methods Between 1982 and 2002, 533 patients were randomised to six cycles of doxorubicin 75 mg/m2 and cisplatin 100 mg/m2. Toxicity data were collected prospectively and graded according to the World Health Organisation (WHO) criteria. Standard univariate and multivariate models were constructed to examine the relationship between reported toxicity, survival, and histological response. Results Five- and 10-year overall survival was 57% (95% confidence interval (CI) 52–61%) and 53% (49–58%), respectively. Grades 3–4 oral mucositis (hazard ratio (HR) 0.51, 95% CI 0.29–0.91), grades 1–2 nausea/vomiting (HR 0.37, 95% CI 0.16–0.85), grades 1–2 thrombocytopenia (HR 0.49, 95% CI 0.27–0.87), good histological response (HR 0.42, 95% CI 0.27–0.65), and distal tumour site (HR 0.45, 95% CI 0.28–0.71) were associated with improved survival in multivariate analysis. The only factors that were independently associated with histological response were older age (odds ratio (OR) 0.18, 95% CI 0.04–0.72) and chondroblastic tumour (OR 0.28, 95% CI 0.10–0.77), both being associated with a significantly lower chance of achieving a good response. Conclusion Chemotherapy-induced toxicity predicts survival in patients with localised extremity osteosarcoma. Investigation of the pharmacogenomic mechanisms of constitutional chemosensitivity underlying these observations will present opportunities for personalising treatment and could lead to improved outcomes.

A Phase II Study of Docetaxel for the Treatment of Recurrent Osteosarcoma

PURPOSE: To determine the response and toxicity of docetaxel in recurrent osteosarcoma and related spindle cell tumours of bone. PATIENTS AND METHODS: Fourteen patients, 10 males and four females, were enrolled, median age 30.5 years (range, 17-46). Diagnosis was: conventional osteosarcoma, 12 patients; periosteal osteosarcoma, one patient; and malignant fibrous histiocytoma of bone, one patient. Initial chemotherapy had been with doxorubicin and cisplatin in 10 patients, and multiagent regimens in four. Nine had been treated with second line chemotherapy before receiving docetaxel. Thirteen patients had lung metastases and one intra-abdominal disease. Docetaxel 100 mg/malpha(2) was given as a 1-h infusion every 3 weeks. Response was assessed every two cycles to a maximum of six. RESULTS: A total of 43 cycles were given, median of two per patient (range 1-6). Thirteen patients were evaluable for response. A single partial remission was seen, for a response rate of 8%. Two patients had stable disease, and one patient a mixed response. Forty cycles were evaluable for toxicity. The principle toxicity was haematological, with a median neutrophil count of 0.9 (range 0-9.6). There were four episodes of neutropenic sepsis (10%). The only non-haematological toxicity >/=grade 3 was stomatitis, occurring in just one patient. There were no toxic deaths. CONCLUSION: Docetaxel at this dose and schedule is well tolerated, but is not associated with significant activity in patients with relapsed osteosarcoma.

A Phase II Nonrandomised Open-Label Study of Liposomal Daunorubicin (DaunoXome) in Advanced Soft Tissue Sarcoma

Thirty four patients with advanced soft tissue sarcoma not previously treated with an anthracycline were treated with DaunoXome 100mg/m2 every 3 weeks. Thirty-three patients were evaluable for toxicity. Grade 3-4 neutropenia was seen in 20 patients (60.6%), complicated by febrile neutropenia in 2 (6.1%). Other grade 3 toxicities were rare. Among 32 patients assessable for response, one patient had a partial response, giving a response rate of 3.13% (95% confidence interval, 0.08–16.22%). Seven patients (21.9%) had stable disease, and 24 patients (75.0%) had disease progression. The median time to progression for all patients was 42 days (95% CI, 39–49) and the progression-free rate at 3 months was 12.5%. In conclusion, DaunoXome at this dose and schedule is well tolerated in patients with advanced soft tissue sarcoma, but is not associated with significant activity. Further studies at this dose and schedule cannot be recommended in this disease.

A phase I/II study of doxorubicin, ifosfamide, etoposide and interval methotrexate in patients with poor prognosis osteosarcoma

The prognosis for patients with metastatic or axial‐skeletal osteosarcoma is poor. A phase I/II study was conducted of intensive chemotherapy with interval methotrexate, to assess the feasibility, response rate and toxicity in this group of patients.

A Phase II Study of Docetaxel in Patients with Relapsed and Refractory Ewing's Tumours

Purpose. The prognosis for patients with Ewings tumours who have metastases at presentation or who are refractory to standard chemotherapy regimens remains poor. There is therefore a need to evaluate the role of new agents. This report describes the initial results of a prospective phase II trial of docetaxel in patients with progressive or refractory Ewings tumours. Patients and methods. Fourteen patients with Ewings tumours who had all relapsed or progressed after treatment with multi-drug cytotoxic therapy were treated with docetaxel 100 mg/m2 infused over 1 h, three weekly for a maximum of six cycles. Nine patients received granulocyte colony-stimulating factor with all cycles. Results. A partial response was observed in one patient and stable disease in two. The remaining patients progressed on treatment. The major toxicity was myelosuppression and infection with 36% patients experiencing grade 3 or 4 neutropenia and/or infection. Conclusion. Docetaxel appears to have some activity in Ewings tumours even in heavily pre-treated patients. Further evaluation of its efficacy at an earlier stage of the disease is warranted.