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Relapsed or refractory osteosarcoma carries a poor prognosis after standard chemotherapy. We conducted a multicenter, randomized, phase II trial (NCT05277480) to compare apatinib plus ifosfamide/etoposide (IE) with IE alone in patients who had progressed following at least one prior line of chemotherapy. Patients were randomized 2:1 to receive apatinib (500 mg orally once daily) plus IE (ifosfamide 1.8 g/m²/day and etoposide 100 mg/m²/day, days 1–3 every 3 weeks) or IE alone (same doses, days 1–5 every 3 weeks). The primary endpoint was progression-free survival (PFS). Between April 14, 2022, and August 22, 2023, 81 patients were enrolled (53 in apatinib plus IE group and 28 in IE group). After a median follow-up of 19.9 months, the median PFS was 5.5 months (95% confidence interval [CI]: 3.9, 6.4) with apatinib plus IE compared with 3.4 months (95% CI: 1.4, 4.6) with IE (hazard ratio, 0.60; 95% CI: 0.37, 0.98; P  = 0.0402). The trial met its pre-specified primary endpoint. These results suggest that apatinib plus IE may improve PFS in relapsed or refractory osteosarcoma, but as a randomized phase II study, the findings are exploratory and require confirmation in phase III trials. In patients with metastatic osteosarcoma who have progressed on first-line chemotherapy, the prognosis is poor. Here, the authors report a phase II randomized clinical trial comparing the combination of apatinib (multi tyrosine kinase inhibitor) and chemotherapy (ifosfamide and etoposide) against chemotherapy alone in patients with relapsed or refractory metastatic osteosarcoma.

Objectives Synthetic data may proxy clinical data. At the absence of direct clinical data, this study aimed to compare Irinotecan and Ifosfamide (II) with Topotecan in synthetic, recurrent small cell lung cancer (SCLC) patients within a simulated clinical trial. Materials and methods Two simulation stages were conducted. Initially, 200 recurrent SCLC cases were simulated to replicate a previous phase 3 trial, testing the utility of Cox proportional hazards model and simulation methodology together, where patients were randomized to receive Cyclophosphamide, Adriamycin, Vincristine (CAV) or Topotecan. In the second stage, 600 recurrent SCLC patients were simulated and randomized to compare Topotecan versus II in terms of overall survival (OAS), using Reinforcement Learning (RL) and Cox proportional hazards model. Results CAV versus Topotecan comparison showed no statistical difference in overall survival (hazard ratio (HR): 0.89, 95% CI: 0.67–1.18, P  = 0.418), aligning with the original clinical trial. For the Topotecan versus II comparison, the RL framework significantly favored the II arm (mean reward points: 193.43 versus − 251.82, permutation P  < 0.0001). Likewise, II arm exhibited superior median OAS compared to Topotecan arm (11.12 versus 6.30 months). HR was 0.44 (95% CI: 0.38–0.52) with P  < 0.0001, in favor of II. Conclusion Artificial trial results for CAV versus Topotecan matched the original trial, confirming indifference of OAS. Additionally, II yielded superior overall survival compared to Topotecan in recurrent SCLC patients. These demonstrate the potential of RL and simulation in conjunction with Cox modelling for similar studies. However, definitive conclusions necessitate a randomized clinical trial between II and Topotecan in this patient cohort.

Ewing's sarcoma, a highly malignant tumor of children, adolescents, and young adults, often responds to local excision plus a now-standard four-drug regimen of chemotherapy. This study shows that standard chemotherapy alternating with courses of ifosfamide plus etoposide significantly improves survival in patients with nonmetastatic disease at the time of diagnosis, but not in those with metastatic disease. Ewing's sarcoma is a highly malignant tumor of bone that occurs in children, adolescents, and young adults. When treated with local control measures only (surgery or radiation therapy), the disease has an extremely high fatality rate. 1 The use of adjuvant chemotherapy, which began in the early 1970s, resulted in a marked improvement in the outcome. Since the first Intergroup Ewing's Sarcoma Study demonstrated improved outcomes with the inclusion of doxorubicin, nearly every chemotherapy protocol for Ewing's sarcoma has been based on four drugs: doxorubicin, cyclophosphamide, vincristine, and dactinomycin. 2 – 4 In the early 1980s, treatment with ifosfamide, with or without etoposide, . . .

Background The value of chemotherapy in soft tissue sarcoma (STS) remains controversial. Several expert teams consider that chemotherapy provides a survival advantage and should be proposed in high-risk (HR) patients. However, the lack of accuracy in identifying HR patients with conventional risk factors (large, deep, FNCLCC grade 3, extremity STS) is an issue that cannot be neglected. For example, while the FNCLCC grading system is a powerful tool, it has several limitations. CINSARC, a 67-gene signature, has proved to be an additional independent factor for predicting metastatic spread and outperforms histological grade. Regardless of FNCLCC grade, CINSARC stratifies patients into two separate prognostic groups: one with an excellent prognosis (low-risk (LR) CINSARC) and the other with a worse outcome (HR-CINSARC) in terms of metastatic relapse. Here we evaluate the role of chemotherapy in grade 1–2 STS patients with HR-CINSARC and assess the prognostic value of CINSARC in patients treated with standard of care. Methods CHIC is a parallel, randomized, open-label, multicenter study evaluating the effect on metastasis-free survival of adding perioperative chemotherapy to standard of care in patients with grade ½ STS sarcoma defined as HR by CINSARC. In this target selection design, 600 patients will be screened with CINSARC to randomize 250 HR-CINSARC patients between standard of care and standard of care plus chemotherapy (4 cycles of 3 weeks of intravenous chemotherapy with doxorubicin in combination with dacarbazine or ifosfamide according to histologic subtype). LR-CINSARC patients will be treated by standard of care according to the investigator. The primary endpoint is metastasis-free survival. Secondary endpoints include overall survival, disease-free survival and safety. Furthermore, the prognostic value of CINSARC will be evaluated by comparing LR-CINSARC patients to HR-CINSARC patients randomized in standard of care. Discussion CHIC is a prospective randomized phase III trial designed to comprehensively evaluate the benefit of chemotherapy in HR-CINSARC patients and to prospectively validate the prognostic value of CINSARC in grade ½ STS sarcoma patients. Trial registration ClinicalTrials.gov identifier: NCT04307277 Date of registration: 13 March 2020

SummaryBackground Sorafenib is a potent targeted-therapy that blockades angiogenesis and has demonstrated activity against some sarcoma subtypes. Preclinical studies suggested that treatment with sorafenib plus cytotoxic agents could result in additive efficacy. Methods Patients with advanced soft tissue sarcoma, with or without anthracycline pretreatment were included. Patients received oral sorafenib 400 mg twice daily starting on Day +2, ifosfamide 2.0 g/m2 iv infusion lasting 4 h on days 1, 2 and 3 with concurrent mesna 400 mg/m2 every three weeks until disease progression or unacceptable toxicity or up to a maximum of 6 cycles of ifosfamide (sorafenib could be continued until progressive disease or unacceptable toxicity). Primary objective was progression-free rate (PFR) at 3 and 6 months; secondary objectives were overall response rate (ORR), Progression-free survival (PFS), Overall survival (OS) and safety. This article reports the phase II part of a phase I/II clinical trial. Results Thirty-five patients were enrolled. PFR at 3 and 6 months was 66% (95% CI 48–81) and 37% (95% CI 22–55). Six patients (17%) achieved partial response and 17 (49%) stable disease. Median PFS was 4.8 months (CI 95% 1.94–6.36) and overall survival 16.2 months (95% CI 8.75-NA). Conclusion Treatment with sorafenib plus ifosfamide achieved a significant clinical benefit with an acceptable safety profile in patients with advanced soft tissue sarcoma resistant to anthracyclines, which warrants a more detailed study in randomized clinical trials.

Biochemical markers of bone turnover reflecting the intensity of all bone remodeling processes in skeleton are important for fast and non-invasive assessment of bone formation and resorption processes. They can be used in terms of both physiological and pathological states. The aim of this study was to investigate if bone metabolism markers can be clinically useful for monitoring of treatment in children and adolescents with osteosarcoma. The study consisted of 55 patients (median age 15 years) with osteosarcoma and 60 healthy age matched counterparts. Serum bone turnover markers (bone alkaline phosphatase – BALP, osteocalcin – OC and C-terminal telopeptide of type I collagen – CTX) were analyzed by immunoenzymatic methods in patients at time of diagnosis, during treatment and after therapy. We observed that before treatment the concentration of OC in patients with osteosarcoma was significantly lower (p<0.05) compared to that obtained in healthy children, however, BALP and CTX were at a similar level. During chemotherapy the values of bone formation and resorption markers significantly decreased by about 20–30%. After therapy we observed different concentrations of all bone turnover markers in patients with favorable and unfavorable prognosis. Median values of OC and BALP were over twofold higher in patients with progression as compared to patients with remission of disease (p<0.01 and p<0.001, respectively). Patients with poor prognosis had also higher serum concentration of bone resorption marker in comparison to patients with remission (p<0.01). Presented results suggest that bone turnover markers identify changes in bone metabolism in patients with osteosarcoma during anticancer therapy. These markers due to the non-invasive methods and their specificity might be useful in monitoring of clinical treatment of osteosarcoma patients.

Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). Mesna is the drug of choice for prevention of HC. In this study, we analyzed cystoscopic and histological changes present in bladders of patients using IFS with mesna prophylaxis. Thirty-three patients selected for IFS plus three doses of mesna chemotherapy regime were assigned at random to two groups: Group I or reference group consisted of 18 patients yet untreated. Group II consisted of 15 patients in whom urinalysis and cystoscopy plus vesical biopsy were performed only 24 h after receiving the last dose of IFS. The cystoscopic and histological findings were used as parameters for evaluating the results. For the former the criterion adopted was macroscopic vesical changes in accordance with Gray's criteria. Histological analyses were performed by evaluation method especially adapted to this study. Even under treatment with three doses of mesna, 66.7% of patients presented cystoscopic alterations and 100% showed bladder mucosa microscopic alterations such as edema, exocytosis, and hemorrhage. The standard protocol used for prevention of IFS-induced HC with three doses of mesna does not completely prevent bladder damage. The histopathological criteria used in this study for observation of inflammatory events allowed staging the intensity of IFS-induced urothelial and mucosal injury.

Background The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. Patients and methods The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. Results The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3–4 non-haematological toxicities. Conclusions 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

BackgroundMultidrug chemotherapy for Ewing sarcoma can lead to severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, “Does primary prophylaxis with G-CSF benefit chemotherapy for Ewing sarcoma?” and CQ #2, “Does G-CSF-based intensified chemotherapy improve Ewing sarcoma treatment outcomes?”.MethodsA comprehensive literature search was conducted in PubMed, Cochrane Library, and Ichushi web databases, including English and Japanese articles published from 1990 to 2019. Two reviewers assessed the extracted papers and analyzed overall survival (OS), febrile neutropenia (FN) incidence, infection-related mortality, quality of life (QOL), and pain.ResultsTwenty-five English and five Japanese articles were identified for CQ #1. After screening, a cohort study of vincristine, ifosfamide, doxorubicin, and etoposide chemotherapy with 851 patients was selected. Incidence of FN was 60.8% with G-CSF and 65.8% without; statistical tests were not conducted. Data on OS, infection-related mortality, QOL, or pain was unavailable. Consequently, CQ #1 was redefined as a future research question. As for CQ #2, we found two English and five Japanese papers, of which one high-quality randomized controlled trial on G-CSF use in intensified chemotherapy was included. This trial showed trends toward lower mortality and a significant increase in event-free survival for 2-week interval regimen with the G-CSF primary prophylactic use compared with 3-week interval.ConclusionThis review indicated that G-CSF’s efficacy as primary prophylaxis in Ewing sarcoma, except in children, is uncertain despite its common use. This review tentatively endorses intensified chemotherapy with G-CSF primary prophylaxis for Ewing sarcoma.