Most cited article - PubMed ID 27569442
Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial
Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes.
- MeSH
- Biological Specimen Banks MeSH
- Sarcoma, Ewing * therapy pathology diagnosis MeSH
- Humans MeSH
- Biomarkers, Tumor MeSH
- Bone Neoplasms * therapy pathology MeSH
- Specimen Handling * methods standards MeSH
- Osteosarcoma * therapy pathology diagnosis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Practice Guideline MeSH
- Geographicals
- Europe MeSH
- Names of Substances
- Biomarkers, Tumor MeSH
The main objective of this study was to analyze changes in the antiproliferative effect of vitamin D3, in the form of calcitriol and calcidiol, via its combined application with all-trans retinoic acid (ATRA) in osteosarcoma cell lines. The response to treatment with calcitriol and calcidiol alone was specific for each cell line. Nevertheless, we observed an enhanced effect of combined treatment with ATRA and calcitriol in the majority of the cell lines. Although the levels of respective nuclear receptors did not correlate with the sensitivity of cells to these drugs, vitamin D receptor (VDR) upregulation induced by ATRA was found in cell lines that were the most sensitive to the combined treatment. In addition, all these cell lines showed high endogenous levels of retinoic acid receptor α (RARα). Our study confirmed that the combination of calcitriol and ATRA can achieve enhanced antiproliferative effects in human osteosarcoma cell lines in vitro. Moreover, we provide the first evidence that ATRA is able to upregulate VDR expression in human osteosarcoma cells. According to our results, the endogenous levels of RARα and VDR could be used as a predictor of possible synergy between ATRA and calcitriol in osteosarcoma cells.
- Keywords
- all-trans retinoic acid, calcidiol, calcitriol, osteosarcoma, retinoic acid receptor α, vitamin D receptor,
- MeSH
- Retinoic Acid Receptor alpha metabolism MeSH
- Calcifediol administration & dosage MeSH
- Calcitriol administration & dosage MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Osteosarcoma drug therapy metabolism MeSH
- Antineoplastic Agents administration & dosage MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Receptors, Calcitriol metabolism MeSH
- Drug Screening Assays, Antitumor MeSH
- Tretinoin administration & dosage MeSH
- Vitamins administration & dosage MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Retinoic Acid Receptor alpha MeSH
- Calcifediol MeSH
- Calcitriol MeSH
- Antineoplastic Agents MeSH
- Receptors, Calcitriol MeSH
- Tretinoin MeSH
- Vitamins MeSH
BACKGROUND: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials. METHODS: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients. RESULTS: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome. CONCLUSIONS: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.
- Keywords
- Chemotherapy, Cohort, Osteosarcoma, Outcomes, Surgery,
- MeSH
- Cisplatin administration & dosage MeSH
- Child MeSH
- Adult MeSH
- Doxorubicin administration & dosage MeSH
- Cohort Studies MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Methotrexate administration & dosage MeSH
- Survival Rate MeSH
- Adolescent MeSH
- Bone Neoplasms drug therapy mortality secondary MeSH
- Follow-Up Studies MeSH
- Osteosarcoma drug therapy mortality pathology MeSH
- Prognosis MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Names of Substances
- Cisplatin MeSH
- Doxorubicin MeSH
- Methotrexate MeSH