Trofosfamide 50mg tablets

Background: Rhabdomyosarcoma and other soft tissue sarcomas (STS) with high-risk features are still associated with an unsatisfactory outcome. We evaluated the efficacy of oral maintenance therapy added at the end of standard therapy in patients with high-risk rhabdomyosarcoma and STS. Methods: /day). The primary outcome was event-free survival (EFS) and the secondary outcome was overall survival (OS) in the intent-to treat population. This trial is registered at ClinicalTrials.gov, NCT00876031, and, EudraCT 2007-0001478-10. Findings: Between July 1st, 2009 and June 30th, 2019, 195 patients were randomly assigned to the M-arm (n = 96) or S-arm (n = 99). In the intent-to-treat population, with a median follow-up of 5.2 years (IQR 3.9-6.1) for surviving patients, the 3-year EFS in the M-arm was 66.9% (95% CI 58.1-77.2) versus 75.6% (67.6-84.6) in the S-arm (hazard ratio, (HR) 1.62, 95% CI 0.98-2.69, p = 0.06). 3-year OS was 82.8% (95% CI 75.4-90.8) in the M-arm versus 84.7% (95% CI 77.8-92.1) in the S-arm (HR 1.55, 95% CI 0.84-2.89, p = 0.17). Grade 3-4 adverse events were haematological in 66% of patients, febrile infections in 6%, gastrointestinal in 10%, and sensory neuropathy in 1%. Interpretation: The addition of 25 weeks of oral maintenance therapy with trofosfamide, etoposide and idarubicin after standard therapy does not improve EFS and OS in patients with high-risk rhabdomyosarcoma and other STS. Funding: Deutsche Kinderkrebsstiftung Grant No.DKS 2009.09, DKS 2012.06, DKS 2015.13, DKS 2018.10 and DKS 2021.04.

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Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of “maintaining” tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% (p = 0.056) and overall survival of 85.0% vs. 72.4% (p = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions.

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PURPOSE: As there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies. METHODS: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG). RESULTS: 139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8-92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55-77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSION: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG.

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Purpose: Peripheral T-cell lymphoma (PTCL) is a rare and heterogenous hematologic malignancy with poor prognosis especially in elderly and frail patients who are not eligible for intensive treatment. The resulting palliative setting necessitates tolerable but effective schedules for outpatient treatment. TEPIP is a locally developed, all-oral low-dose regimen comprising trofosfamide, etoposide, procarbazine, idarubicin, and prednisolone. Methods: In this observational retrospective, single-center study, the safety and efficacy of TEPIP was evaluated in 12 patients (pts.) with PTCL treated at the University Medical Center Regensburg between 2010 and 2022. The endpoints were overall response rate (ORR) and overall survival (OS), and adverse events were individually reported according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Results: The enrolled cohort was characterized by advanced age (median 70 years), extensive disease (100% Ann Arbor ≥stage 3), and poor prognosis (75% high/high-intermediate international prognostic index). The most common subtype was angioimmunoblastic T-cell lymphoma (8/12), and 11/12 patients had relapsed or refractory disease at TEPIP onset with a median of 1.5 prior treatment regimens. After a median of 2.5 TEPIP cycles (total of 83 cycles), the ORR was 42% (complete remission 25%), and the OS reached a median of 185 days. Any grade of adverse event (AE) occurred in 8/12 patients, with four patients showing AE ≥CTCAE grade 3 (33%), and the AEs were mainly non-hematological. Conclusion: TEPIP demonstrated competitive efficacy with a tolerable safety profile in a highly palliative cohort of patients with difficult-to-treat PTCL. The all-oral application, which makes outpatient treatment possible, is particularly noteworthy.

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Abstract Background Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients. Methods We collected clinicopathological data from adult progressive glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control. Results A total of n = 22 progressive glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 vs 2.3 months, HR: 1.961, 95% CI: 0.9724–3.9560, P = .0274) and median overall survival (9.0 vs 5.7 months, HR: 4.687, 95% CI: 2.034–10.800, P = .0003) were significantly prolonged compared to the control cohort (n = 17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n = 16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n = 15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n = 11/15, 73%). Conclusions This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients. The observed survival outcomes might suggest potential beneficial effects. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective trial.

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BACKGROUND: The prognosis of patients with advanced soft tissue sarcoma (STS) remains dismal. Trofosfamide (TRO) has been proposed as a well-tolerated oral maintenance therapy. This retrospective analysis aims to determine the value of this therapy. METHODS: Fifty-nine patients with advanced STS who received TRO maintenance therapy between 2016 and 2022 were reviewed and analysed regarding clinical parameters and outcomes. RESULTS: The median age was 48 years; the most common histological subtype was synovial sarcoma (n = 22, 37%), and 71% of patients (n = 42) presented with metastatic disease. No radiological evidence of disease (NED) before the start of maintenance was reported in 36% of patients (n = 21). The median follow-up was 38.2 months with a median maintenance duration of 9.0 months. The median event-free survival (EFS) and overall survival (OS) were 9.5 and 33.2 months, respectively. In metastatic patients achieving NED before the initiation of TRO, the median EFS was 29.4 months, while the median OS was not reached. In metastatic patients with anthracycline + ifosfamide (AI) as first-line induction therapy without prior metastasis-directed local therapy, the median EFS and OS from the start of AI were 13.9 and 26.8 months, respectively. Multivariate analysis of the overall cohort demonstrated that NED before the start of maintenance was significantly associated with a prolonged EFS (p = 0.024, hazard ratio [HR] = 0.26), and G2 histology correlated with longer OS (p = 0.030, HR = 0.16, reference: G3). INTERPRETATION: Oral maintenance therapy with TRO appears to improve outcomes in patients with advanced STS. Metastatic patients who achieve NED through prior metastasectomy may particularly benefit from TRO maintenance.

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Rescue therapies for relapsed/refractory (r/r) metastatic neoplasias present significant unmet needs. Tumor tissue editing regimen for 13 r/r tumor types, carcinomas, sarcomas and hematologic neoplasias, included in 15 phase I/II trials, nuclear/cytokine receptor agonists, pioglitazone, plus/minus dexamethasone or all-trans retinoic acid or interferon-α to counterbalance tumor tissue homeostasis and reprogramming of cancer hallmarks, stress response inhibitors, COX-2 inhibitor, everolimus, lenalidomide, or clarithromycin, and a stress response inducer, low-dose metronomic chemotherapy with treosulfan, trofosfamide, capecitabine, or azacitidine. CR in three, cCR in another five r/r neoplasias, as the best response occurred after transcriptional reprogramming of cancer hallmarks, inflammation control or differentiation induction. Receptor agonist combinations for cCR induction can be identical among quite different tumor types and diversified within the same tumor histology. Data reveal ubiquitous, differential transcriptional access to non-oncogene addiction (NOA) networks that cope with cancer hallmarks/stress responses and three levels of therapeutic NOA targeting. (1) Agonists of nuclear/cytokine receptor NOAs critically target tumor identity and viability, while (2) transcriptional reprogramming of NOA networks that contribute to tumor tissue addiction, thereby genome-agnostically counteracting oncogene addictions. (3) Targeting edited NOAs may improve long-term outcome with CR/cCR (everolimus, IMiD). Transcriptionally accessible NOA targets offer high specificity, modest toxicity profile, low cost of therapy and outpatient treatment, independent of comorbidities. Adaptive targeting of the transcriptomic landscapes of tumor cell compartments breaks tumor tissue addiction and overcomes M-CRAC, post-therapy metastasis, cancer cell recolonization, acquired resistance and genetic heterogeneity. Thus, editing approaches provide a template for controlling metastatic r/r tumors. In the future, diagnostics of NOA networks and transcription factors involved in tumor tissue addiction may be as valuable for therapy selection as histological/molecular genetic tumor typing for the establishment of personalized hematology/oncology.

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