Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment (original) (raw)
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Cancer, 2016
BACKGROUND: Metronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated. METHODS: Patients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization. RESULTS: There were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n 5 139) or MAP alone (n 5 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic 5 0.724; P 5.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS.
Journal of Clinical Oncology, 2014
BACKGROUND: Metronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated. METHODS: Patients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization. RESULTS: There were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n 5 139) or MAP alone (n 5 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic 5 0.724; P 5.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS.
Factors Affecting Prognosis and Survival in Extremity Osteosarcoma
Indian Journal of Surgical Oncology
Background Osteosarcoma is a malignant bone tumor affecting mainly children and young adults and commonly involves extremities. The aim of this study was to assess the patient-related, tumor-related, and treatment-related factors affecting the overall survival in patients with non-metastatic extremity osteosarcoma. Methodology A retrospective, single institutional study of 100 patients with non-metastatic extremity osteosarcoma was done between 2014 and 2019. Age, sex, histologic type, tumor site, use of preoperative chemotherapy and its duration, response to chemotherapy, type of surgery, presence of local recurrence, occurrence of lung metastasis, and survival data were recorded. Survival analysis was done using Kaplan-Meier method. p < 0.05 by log-rank test was considered statistically significant. Statistical data were analyzed using SPSS v.25(IBM). Results The median age of presentation was 18 years with male sex preponderance. The most common site of presentation was distal femur, and commonest histological variant was osteoblastic osteosarcoma. Incidence of local recurrence was 9%, and lung metastasis was identified in 12% on follow-up. The 5-year overall survival (OS) was 65.5%, and 5-year local recurrence-free survival was 57.6%. The 5-year OS in neoadjuvant chemotherapy group was 80% compared to 39.5% in upfront surgery group (p = 0.015). The 5-year OS in patients with tumor necrosis > 90% and < 90% was 93.2% and 71.2%, respectively (p = 0.038). The 5-year OS in patients without lung metastasis was 76%, whereas none who developed lung metastasis has survived 5 years (p < 0.001). Conclusion The use of neoadjuvant chemotherapy, good response to chemotherapy, and the absence of lung metastasis on follow-up can independently predict better overall survival.
Annals of Oncology
To identify predictive factors of disease-free survival (DFS) in patients with non-metastatic osteosarcoma of the extremity, treated with primary chemotherapy and delayed surgery. The relationship between patient-related and treatment-related factors and prognosis was evaluated in 300 patients treated from 1986 to 1992 according to chemotherapy protocols based on high-dose methotrexate, cisplatin and doxorubicin, with the addition of ifosfamide in the post-operative phase. Univariate and multivariate analyses of prognostic factors for disease-free survival were performed. With a median follow-up of 9.2 (4.4-12) years, eight-year DFS was 59% (95% confidence interval (95% CI): 54-64.9). Univariate analyses showed that tumor volume > or = 150 ml (P = 0.002), histologic subtype (P = 0.028), age > 12 years (P = 0.044), high serum lactate dehydrogenase (P = 0.044) and alkaline phosphatase (P = 0.064) levels adversely affected DFS. Gender of patients and site of tumor did not influen...
Risk-Based Therapy for Localized Osteosarcoma
Pediatric Blood & Cancer, 2015
Background.-The outcome of localized osteosarcoma has remained constant over the past 30 years. Histological response to preoperative chemotherapy is the best predictor of outcome. Strategies to alter treatment based on histological response have not resulted in increased survival. Procedure.-Patients with localized osteosarcoma received preoperative chemotherapy with cisplatin, doxorubicin, and methotrexate. Patients whose tumors had a good histological response (≥90% necrosis) continued with the same treatment postoperatively. Patients with poor histological response (<90% necrosis) received three courses of melphalan 100 mg/m 2 on day −4, cyclophosphamide 2,000 mg/m 2 on days −3, and −2 followed by stem cell infusion. Results.-Fifty-two patients were enrolled. Median age was 14 years, and 56% of patients were male. The femur was the most common site. Forty patients underwent limb salvage surgery and amputation was performed in six patients. Forty-eight percent of tumors showed good histological response. Forty patients were evaluable for outcome; 18 patients with poor histologic response received high-dose chemotherapy. The 5-year event-free survival (EFS) and overall survival (OS) for patients treated on the high-dose chemotherapy arm were 28% (95% confidence interval [CI], 10-49) and 48% (95% CI, 23-69), respectively. The 5-year EFS and OS for patients treated on the standard chemotherapy arm were 62% (95% CI, 36-80) and 74% (95% CI, 44-90), respectively. All patients who received high-dose chemotherapy developed grade 3 or higher hematological toxicity. There were no treatment-related deaths.
What has changed in the last 25 years in osteosarcoma treatment? a single center experience
The Turkish Journal of Pediatrics
Background. Osteosarcoma is the most common type of primary malignant bone tumor in the extremities. The main purpose of this study was to determine clinical features, prognostic factors, and treatment results of patients with osteosarcoma at our center. Methods. We retrospectively analyzed the medical records of children with osteosarcoma between the years 1994-2020. Results. 79 patients were identified (54.4% male, 45.6% female). The most common primary site was the femur (62%). Twenty-six of them (32.9%) had lung metastasis at diagnosis. The patients were treated between 1995-2013 according to the Mayo Pilot II Study protocol, while the others were treated with the EURAMOS protocol between the years 2013-2020. Sixty-nine patients underwent limb salvage surgery as a local treatment, whereas seven underwent amputation. The median follow-up time was 53 months (2.5-265 months). The event-free survival (EFS) and overall survival (OS) rates at 5 years were 52.1% and 61.5%. The 5-year EFS and OS rates were 69.4% and 80% in females; 37.1% and 45.5% in males (p=0.008/p=0.001). The 5-year EFS and OS rates of the patients without metastasis were 63.2% and 66.3%; with metastasis 28.8% and 51.8% (p=0.002/p=0.05). For good-responders, the 5-year EFS and OS rates were 80.2% and 89.1%; while for poor-responders, 35% and 46.7% (p=0.001). Mifamurtide was used in addition to chemotherapy as of the year 2016 (n=16). The 5-year EFS and OS rates were 78.8% and 91.7%, respectively for the mifamurtide group; 55.1% and 45.9%, respectively for the non-mifamurtide group (p=0.015, p=0.027). Conclusions. Metastasis at diagnosis and poor response to preoperative chemotherapy were the most important predictors of survival. Females had a better outcome than males. In our study group, the mifamurtide group's survival rates were significantly higher. Further large studies are needed to validate the efficacy of mifamurtide.
Increased survival, limb preservation, and prognostic factors for osteosarcoma
Cancer, 1991
Preoperative intraarterial (IA) cisplatin (CDP) was administered to 92 patients with nonmetastatic osteosarcoma. The ages of the patients ranged from 4 to 28 years. Sixty-four patients (70%) received 2 or 3 preoperative courses and 28 (30%) received 4 or more. Sixty-two specimens were available for pathologic examination to assess the degree of tumor necrosis. More than 90% tumor destruction was observed in 16 of 42 patients (38%) who received 1 to 3 preoperative courses as opposed to 17 of 20 (85%) who received 4 or more courses. Patients who received 4 or more courses had a &fold probability of achieving more than 90% tumor necrosis, and 68% underwent conservative surgery. Of those who received 3 or less courses, 23% underwent conservative surgery. Postoperatively, patients were treated with intravenous (IV) CDP alternating with doxorubicin (ADR) (Adriamycin, Adria Laboratories, Columbus, OH). Pulmonary metastases developed in 36 patients, bone metastases in 2, and local recurrence in 6. Two patients died of cardiac failure without evidence of disease. Thus, 46 patients (50%) were continuously free of disease 18 to 78 months after diagnosis. Univariate and multivariate analyses showed that male sex, low grade preoperative chemotherapy-induced necrosis, and nonosteoblastic histologic condition were prognostic factors predictive of recurrence, while male sex and large tumor size were prognostic factors predictive of death. These results are comparable with those reported by other centers and are superior to our previous experiences that yielded survival rates of 5% to 10%. A substantial number of patients also had the opportunity to achieve tumor removal with conservative surgery. Cancer 68:733-737,1991.
The bone & joint journal, 2015
A poor response to chemotherapy (≤ 90% necrosis) for osteosarcomas leads to poorer survival and an increased risk of local recurrence, particularly if there is a close margin of excision. We evaluated whether amputation confers any survival benefit over limb salvage surgery (LSS) with narrow margins in patients who respond poorly to chemotherapy. We only analysed patients with an osteosarcoma of the limb, a poor response to chemotherapy and close margins on LSS (marginal/intralesional) or primary amputation: 360 patients (36 LSS (intralesional margins), 197 LSS (marginal margins) and 127 amputations) were included. Local recurrence developed in 13 (36%) following LSS with intralesional margins, and 39 (20%) following LSS with marginal margins. There was no local recurrence in patients who underwent amputation. The five-year survival for all patients was 41% (95% confidence interval (CI) 35 to 46), but for those treated by LSS with marginal margins was 46.2% (95% CI 38 to 53), 36.3% ...