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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.

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.

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.

Background Soft-tissue sarcomas (STS) are rare malignant tumors those are resistant to chemotherapy. We have previously reported the 3-year follow-up result on the efficacy of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-risk STS of the extremities (JCOG0304). In the present study, we analyzed the 10-year follow-up results of JCOG0304. Methods Patients with operable, high-risk STS (T2bN0M0, AJCC 6th edition) of the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy, which consisted of 60 mg/m 2 of DXR plus 10 g/m 2 of IFM over a 3-week interval. The primary study endpoint was progression-free survival (PFS) estimated by Kaplan-Meier methods. Prognostic factors were evaluated by univariable and multivariable Cox proportional hazards model. Results A total of 72 patients were enrolled between March 2004 and September 2008, with 70 of these patients being eligible. The median follow-up period was 10.0 years for all eligible patients. Local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. The 10-year PFS was 65.7% (95% CI: 53.4–75.5%) with no PFS events being detected during the last 5 years of follow-up. The 10-year overall survival was 78.1% (95% CI: 66.3–86.2%). Secondary malignancy was detected in 6 patients. The subgroup analysis demonstrated that there was significant difference in survival with regard to primary tumor size. Conclusions Only a few long-term results of clinical trials for perioperative chemotherapy treatment of STS have been reported. Our results demonstrate that the 10-year outcome of JCOG0304 for patients with operable, high-risk STS of the extremities was stable and remained favorable during the last 5 years of follow-up. Trial registration This trial was registered at the UMIN Clinical Trials Registry as C000000096 on August 30, 2005.

There are no reports evaluating sleep disturbance and skeletal muscle loss in response to the treatment of soft tissue sarcoma (STS) with chemotherapy. This study investigated the effects of combined doxorubicin (DXR) and ifosfamide (IFM) on sleep and skeletal muscle. This retrospective cohort study included 14 patients with high-grade STS. Participants underwent five 7-day hospitalizations during which they received chemotherapy for 5 consecutive days. Sleep analysis and muscle-volume evaluation were investigated using a wearable device during hospitalization and by bioelectrical impedance analysis at each chemotherapy course. Chemotherapy significantly impeded sleep, increased wake-time after sleep onset, and aggravated movement index during hospitalization. In long-term body composition assessment, chemotherapy induced muscle-mass loss and fat-mass gain. Combination of DXR and IFM for STS induces skeletal muscle loss and sleep disruption.

This study aimed to determine the maximum tolerated dose (MTD) of pegylated liposomal doxorubicin (PLD) combined with both ifosfamide (IFO) and supported by human granulocyte colony-stimulating factor (rhG-CSF) for treating advanced soft tissue sarcoma (STS). Twenty-three patients were enrolled in this trial with 3+3 dose-escalation from January 2020 to September 2022. PLD was initiated at 30 mg/m and incrementally escalated by 5 mg/m per step. MTD was the primary endpoint, and the safety profile served as the secondary endpoint. Two patients treated with PLD (55 mg/m ) experienced dose-limiting toxicities. Ultimately, the MTD of PLD was established as 50 mg/m (single cycle) in combination of IFO (3 g/m /day for days 1-3) and supported by rhG-CSF. Across all dose levels, common grade 3/4 adverse events included leukopenia (86.96%), neutropenia (82.61%), and lymphopenia (56.52%). Twelve of the 23 patients voluntarily chose to continue treatment with this regimen. The overall response rate was 33.33% (95% confidence interval: 9.92-65.11), and the disease control rate was 83.33% (95% confidence interval: 51.59-97.91). This study successfully determined the MTD of PLD in combination with IFO and rhG-CSF for advanced STS, offering a potentially valuable treatment option with a tolerable safety profile.

We recently proposed an equation to estimate the glomerular filtration rate (GFR) in children with cancer based on plasma cystatin C and serum creatinine levels together with body weight (the “CysPed equation”). The current clinical study reports a prospective evaluation of this equation in 18 children treated by nephrotoxic chemotherapy. The CysPed equation resulted in less bias and greater precision compared to two equations previously proposed equations by Schwartz, with or without plasma cystatin C. Moreover, the decrease in GFR due to chemotherapy was clearly identified by the CysPed equation. This equation may be used to monitor the renal function in childhood cancer units.

Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a rare disease characterized by a higher incidence of lymphatic invasion, metastasis, and recurrence compared to the squamous cell carcinoma and adenocarcinoma subtypes. Furthermore, it is prone to early distant metastasis and has a poor prognosis. Chemotherapy has an important role in the management of cervical SCNEC. The effective treatment schemes for early-stage SCNEC are local treatment with radical surgery and systemic chemotherapy. However no standard treatment regimen exists because of a rare disease. We reviewed previous reports to determine whether etoposide/platinum, which is used for histopathologically similar small cell carcinoma of the lung, is an appropriate initial chemotherapy regimen for SCNEC of the cervix. In this review the Cochrane library sources, ClinicalTrials.gov, Web of Silence, PubMed and search engine of Google scholar were searched for all interventional studies, reviews, case reports and meta-analyses published in 1997-2021. Etoposide/platinum (EP) is the most commonly used regimen and paclitaxel/carboplatin is the second most common, used as a part of multimodality therapy for SCNEC of the cervix in most studies. Cisplatin/vincristine/bleomycin, cisplatin/irinotecan, cisplatin/ifosfamide/etoposide were also reported in concurrence with EP; however no clinical trials are dedicated to SCNEC. Etoposide and platinum tend to have a better prognosis compared to other regimens used for other subtypes of cervical cancer. For recurrent cervical SCNEC, treatment options for patients are very limited. The application of molecular testing for targeted mutations may suggest potential future therapies that may be useful in this disease.

Prognosis of metastatic malignant peripheral nerve sheath tumor (MPNST) is poor and the role of chemotherapy is controversial. There has been no report of metastatic MPNST with a good prognosis without surgery for metastases. A 40-year-old man with neurofibromatosis type 1 (NF1)-related MPNST on his shoulder with multiple lung metastases visited our hospital. After two cycles of chemotherapy with ifosfamide, carboplatin and etoposide (ICE), the primary lesion and lung metastases had shrunk. The primary lesion was resected with negative margins. Subsequently, 'gradual subtraction' ICE was administered, wherein the dose was reduced and the treatment interval was increased. After 14 courses of ICE over a period of 2 years, the lung metastases disappeared; there has been no recurrence for over 12 years. ICE can be an excellent, inexpensive treatment for NF1-related MPNST. 'Gradual subtraction' chemotherapy allowed us to maintain long-term efficacy, induce tumor dormancy, and reduce side-effects.