Explore the vast range of titles available.

Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma. In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18–25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18–25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223. Between April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8–50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7–5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5–65·9); 3-year event-free survival was 63·4% (55·2–70·9) for the control group and 57·1% (48·8–65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95–1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion). From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data. French National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant.

Background Whether current postoperative surveillance regimes result in improved overall survival (OS) of patients with extremity sarcomas is unknown. Questions/purposes We hypothesized that a less intensive followup protocol would not be inferior to the conventional followup protocol in terms of OS. We (1) assessed OS of patients to determine if less intensive followup regimens led to worsened survival and asked (2) whether chest radiograph followup group was inferior to CT scan followup group in detecting pulmonary metastasis; and (3) whether less frequent (6-monthly) followup interval was inferior to more frequent (3-monthly) followup in detecting pulmonary metastasis and local recurrence. Methods A prospective randomized single-center noninferiority trial was conducted between January 2006 and June 2010. On the basis of 3-year survival of 60% with intensive, more frequent followup, 500 nonmetastatic patients were randomized to demonstrate noninferiority by a margin (delta) of 10% (hazard ratio [HR], 1.36). The primary end point was OS at 3 years. The secondary objective was to compare disease-free survival (DFS) (time to recurrence) at 3 years. At minimum followup of 30 months (median, 42 months; range, 30–81 months), 178 deaths were documented. Results Three-year OS and DFS for all patients was 67% and 52%, respectively. Three-year OS was 67% and 66% in chest radiography and CT groups, respectively (HR, 0.9; upper 90% confidence interval [CI], 1.13). DFS rate was 54% and 49% in chest radiography and CT groups, respectively (HR, 0.82; upper 90% CI, 0.97). Three-year OS was 64% and 69% in 6-monthly and 3-monthly groups, respectively (HR, 1.2; upper 90% CI, 1.47). DFS was 51% and 52% in 6-monthly and 3-monthly groups, respectively (HR, 1.01; upper 90% CI, 1.2). Almost 90% of local recurrences were identified by patients themselves. Conclusions Inexpensive imaging detects the vast majority of recurrent disease in patients with sarcoma without deleterious effects on eventual outcomes. Patient education regarding self-examination will detect most instances of local recurrence although this was not directly assessed in this study. Although less frequent visits adequately detected metastasis and local recurrence, this trial could not conclusively demonstrate noninferiority in OS for a 6-monthly interval of followup visits against 3-monthly visits. Level of Evidence Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

ObjectivesInvestigating the effect of prognostic factors in a multistate framework on survival in a large population of patients with osteosarcoma. Of interest is how prognostic factors affect different disease stages after surgery, with stages of local recurrence (LR), new metastatic disease (NM), LR+NM, secondary malignancy, a second NM, and death.DesignAn open-label, international, phase 3 randomised controlled trial.Setting325 sites in 17 countries.ParticipantsThe subset of 1631 metastases-free patients from 1965 patients with high-grade resectable osteosarcoma, from the European and American Osteosarcoma Study.Main outcome measuresThe effect of prognostic factors on different disease stages, expressed as HRs; predictions of disease progression on an individual patient basis, according to patient-specific characteristics and history of intermediate events.ResultsOf 1631 patients, 526 experienced an intermediate event, and 305 died by the end of follow-up. An axial tumour site substantially increased the risk of LR after surgery (HR=10.84, 95% CI 8.46 to 13.86) and death after LR (HR=11.54, 95% CI 6.11 to 21.8). A poor histological increased the risk of NM (HR=5.81, 95% CI 5.31 to 6.36), which sharply declined after 3 years since surgery. Young patients (<12 years) had a lower intermediate event risk (eg, for LR: HR=0.66, 95% CI 0.51 to 0.86), when compared with adolescents (12–18 years), but had an increased risk of subsequent death, while patients aged >18 had a decreased risk of death after event (eg, for death after LR: HR=2.40, 95% CI 1.52 to 3.90; HR=0.35, 95% CI 0.21 to 0.56, respectively).ConclusionsOur findings suggest that patients with axial tumours should be monitored for LR and patients with poor histological response for NM, and that for young patients (<12) with an LR additional treatment options should be investigated.Trial registration numberNCT00134030.

Citrus aurantium is rich in flavonoids, which may prevent osteosarcoma progression, but its related molecular mechanism remains unclear. Flavonoids were extracted from C. aurantium and purified by reparative HPLC. Each fraction was identified by using electrospray ionisation mass spectrometry (ESI-MS). Three main components (naringin, naringenin, and hesperetin) were isolated from C. aurantium. Naringenin inhibited the growth of MG-63 cells, whereas naringin and hesperetin had no inhibitory function on cell growth. ROS production was increased in naringin- and hesperetin-treated groups after one day of culture while the level was always lowest in the naringenin-treated group after three days of culture. 95 osteosarcoma patients who underwent surgery were assigned into two groups: naringenin group (NG, received 20 mg naringenin daily, n=47) and control group (CG, received 20 mg placebo daily, n=48). After an average of two-year follow-up, osteosarcoma volumes were smaller in the NG group than in the CG group (P>0.01). The rate of osteosarcoma recurrence was also lower in the NG group than in CG group. ROS levels were lower in the NG group than in the CG group. Thus, naringenin from Citrus aurantium inhibits osteosarcoma progression and local recurrence in the patients who underwent osteosarcoma surgery by improving antioxidant capability.

Background While research on exercise interventions during anticancer treatment is well-established in adults, only very few studies exist in children. However, pediatric patients experience great limitations to being physically active, and appropriate interventions are desired. Procedure The present study aimed at investigating the effects of individualized exercise interventions during inpatient stays on pediatric patients with a malignant bone tumor. The parameter of interest was physical activity (PA). Patients’ PA during home stays was assessed 6 weeks as well as 3, 6, 12, and 18 months post-surgery. Patients were distinguished into an intervention group and a control group. All patients received endoprosthetic replacement of the affected bone in the same institution. Results A constant increase in all PA parameters was observed during follow-up. Exercise interventions were possible and appeared worthwhile. The intervention group showed better PA results at all measurements; however, no significant differences between groups were found. Furthermore, differences decreased especially after the cessation of the intervention. General problems in reaching appropriate power and compliance were observed. Conclusions Individualized exercise interventions in pediatric bone tumor patients are possible and appear to be beneficial. Such interventions should be implemented in adjuvant care; however, future research is needed to understand more about the effects of different interventions.

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. 407 patients with operable, non-metastatic osteosarcoma were randomly assigned the two-drug regimen (six cycles [18 weeks] of doxorubicin 25 mg/m 2 on days 1–3 and cisplatin 100 mg/m 2 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. 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% Cl 0·69–1·27]). Progression-free survival at 5 years was 44% in both groups (hazard ratio 1·01 [0·77–1·33]). 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.

According to the current treatment protocol of the Cooperative Osteosarcoma Study (COSS), monitoring preoperative chemotherapy response and estimating grade of tumor regression in patients with osteosarcoma is mandatory before surgical removal of the tumor, particularly if a limb salvage procedure is intended. In addition, response to neoadjuvant chemotherapy is considered as an important prognostic indicator. The aim of this prospective study was to assess the usefulness of 2-(18F) fluoro-2-deoxy-D-glucose (FDG) PET in the noninvasive evaluation of neoadjuvant chemotherapy response in osteosarcoma. In 27 patients with osteosarcoma, we determined tumor-to-background ratios (TBRs) of FDG uptake with PET, before and after neoadjuvant chemotherapy according to COSS 86c or COSS 96 protocols, respectively. We compared changes in glucose metabolism of osteosarcomas with the histologic grade of regression in the resected specimen, according to Salzer-Kuntschik, discriminating responders (grades I-III; n = 17) and nonresponders (grades IV-VI; n = 10). The decrease of FDG uptake in osteosarcomas expressed as a ratio of posttherapeutic and pretherapeutic TBRs showed a close correlation to the amount of tumor necrosis induced by polychemotherapy (P < 0.001; Spearman). With a TBR ratio cutoff level of 0.6, all responders and 8 of 10 nonresponders could be identified by PET. In addition, lung metastases of osteosarcoma were detected with FDG PET in 4 patients. FDG PET provides a promising tool for noninvasive evaluation of neoadjuvant chemotherapy response in osteosarcoma. This could imply consequences for the choice of surgical strategy, because a limb salvage procedure cannot be recommended in patients nonresponsive to preoperative chemotherapy unless wide surgical margins can safely be achieved.

The analysis of chondroblastic osteosarcoma (CBO) was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2019).​ A cohort of 317 surgically treated CBO patients was analyzed, with 261 (82.3%) receiving adjuvant chemotherapy and 56 (17.7%) classified as no/unknown chemotherapy recipients. The median diagnosis year of CBO patients was 2005 and the median follow-up time was 5.25 years (63 months).​​ Kaplan-Meier analysis demonstrated that chemotherapy significantly improved overall survival (OS) ( P  = 0.011), a finding corroborated after propensity score matching ( P  = 0.036). Specifically, the 5-year, 10-year, and 15-year overall survival(OS) of patients who received chemotherapy were 52.11%, 35.25%, and 25.29%, respectively. In contrast, the corresponding survival rates of patients who did not receive chemotherapy or whose chemotherapy status was unknown were 48.21%, 39.29%, and 25.00%, respectively. Subgroup analyses revealed enhanced chemotherapy efficacy in males (HR = 0.48, P  = 0.01), high grade tumors (HR = 0.54, P  = 0.015), and high income patients (HR = 0.35, P  = 0.001), while ​stage stratified analysis showed that the overall survival benefit of chemotherapy was limited to patients with stage I–II disease (P for interaction = 0.008). Further interaction analysis revealed that the survival benefit of chemotherapy in patients with stage III–IV disease was significantly attenuated compared to those with stage I–II disease (HR = 0.06, P  = 0.049), indicating a pronounced stage dependent effect. Multivariate Cox regression identified age, tumour stage and radiotherapy as independent prognostic factors. The constructed nomogram integrating these factors with marital status and chemotherapy achieved C-indices of 0.674 (training set) and 0.691 (validation set). Notably, it exhibited strong discriminative ability with AUC values of 0.672, 0.658, and 0.657 for predicting 5-, 10-, and 15-year OS in the training set, and even higher values of 0.741, 0.712, and 0.745 in the validation set. This tool provides individualized 5-, 10-, and 15-year OS predictions, addressing critical gaps in CBO specific prognostic assessment and supporting personalized therapeutic decision making.

The multi-disciplinary approach involving imaging, multi-agent chemotherapy, meticulous surgical procedures, and careful postoperative care has facilitated an increase in the use of limb-sparing surgery for pediatric osteosarcoma. Osteosarcoma usually occurs around the metaphysis of the distal femur or proximal tibia and needs wide excision with the adjacent joint and replacement by a megaprosthesis. The recent advancement in imaging modalities and surgical techniques supports joint-preservation surgery (JPS), involving the preservation of the adjacent epiphysis, for select patients following careful assessment of the tumor margins and precise tumor excision. An advantage of this surgery is that it maintains the adjacent joint and preserves the growth of the residual epiphysis, which provides excellent limb function. Various reconstruction options are available, including allograft, tumor-devitalized autograft, vascularized fibula graft, distraction osteogenesis, and custom-made implants. However, several complications are inevitable with these options, such as loosening, non-union at the host-graft junction, infection, fracture, implant loosening, breakage, deformity, limb-length discrepancy related to the reconstruction methods, or patient growth in pediatric osteosarcoma. Surgeons should fully understand the advantages and disadvantages of this procedure. In this review, we discuss the concept of JPS, types of reconstruction methods, and current treatment outcomes. It is our opinion that the further analysis by multi-institutional setting is necessary to clarify long-term outcomes and establish global guidelines on the indications and surgical procedure for JPS.

Background This meta-analysis compared survival and function in patients with limb osteosarcoma treated with limb-salvage surgery (LSS) versus amputation or rotationplasty. Methods Medline, Cochrane, EMBASE, and Google Scholar were searched until November 30, 2015 for studies reporting Musculoskeletal Tumor Society (MSTS) scores and survival rates in osteosarcoma patients. Differences between patients undergoing LSS versus ablative surgery were analyzed based on MSTS scores and postoperative survival rates. Results Of 1330 patients in the studies analyzed, 934 underwent LSS, and 662 were treated with amputation. A random-effects model was applied due to heterogeneity among studies ( Q statistic = 1.829, I 2  = 0 %, p  = 0.767). No difference was found in post-operative local recurrence rate between amputees and patients receiving LSS. The 5-year survival rate was significantly lower with amputation compared with LSS (OR 0.628; 95 % CI 0.431–0.913, p  = 0.015). The 2-year survival rate was not different between amputation and LSS. In addition, amputees had lower MSTS scores than those undergoing LSS (difference in means = −4.46 %, 95 % CI 6.49–2.45 %, p  < 0.001). Conclusions LSS results in higher 5-year survival rates and better functional outcomes as indicated by MSTS scores in patients with limb osteosarcomas.