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A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

ABSTRACT: Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6?years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2?years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB.

SUBMITTER: Lewis EC

PROVIDER: S-EPMC7586843 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

Lewis Elizabeth C EC Kraveka Jacqueline M JM Ferguson William W Eslin Don D Brown Valerie I VI Bergendahl Genevieve G Roberts William W Wada Randal K RK Oesterheld Javier J Mitchell Deanna D Foley Jessica J Zage Peter P Rawwas Jawhar J Rich Maria M Lorenzi Elizabeth E Broglio Kristine K Berry Donald D Saulnier Sholler Giselle L GL

International journal of cancer 20200524 11

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of ...[more]

PMID: 32391579

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Project description:BackgroundNeuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.Methods and findingsTwenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056).ConclusionsDFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.Trial registrationClinicaltrials.gov NCT#01059071.

Project description:BackgroundPatients who have completed Phase II cardiac rehabilitation have low rates of maintenance of exercise after program completion, despite the importance of sustaining regular exercise to prevent future cardiac events.PurposeThe efficacy of a home-based intervention to support exercise maintenance among patients who had completed Phase II cardiac rehabilitation versus contact control was evaluated.DesignAn RCT was used to evaluate the intervention. Data were collected in 2005-2010 and analyzed in 2010.Setting/participantsOne hundred thirty patients (mean age=63.6 years [SD=9.7], 20.8% female) were randomized to exercise counseling (Maintenance Counseling group, n=64) or contact control (Contact Control group, n=66).InterventionMaintenance Counseling group participants received a 6-month program of exercise counseling (based on the transtheoretical model and social cognitive theory) delivered via telephone, as well as print materials and feedback reports.Main outcome measuresAssessments of physical activity (7-Day Physical Activity Recall), motivational readiness for exercise, lipids, and physical functioning were conducted at baseline, 6 months, and 12 months. Objective accelerometer data were collected at the same time points. Fitness was assessed via maximal exercise stress tests at baseline and 6 months.ResultsThe Maintenance Counseling group reported significantly higher exercise participation than the Contact Control group at 12 months (difference of 80 minutes, 95% CI=22, 137). Group differences in exercise at 6 months were nonsignificant. The intervention significantly increased the probability of participants' exercising at or above physical activity guidelines and attenuated regression in motivational readiness versus the Contact Control Group at 6 and 12 months. Self-reported physical functioning was significantly higher in the Maintenance Counseling group at 12 months. No group differences were seen in fitness at 6 months or lipid measures at 6 and 12 months.ConclusionsA telephone-based intervention can help maintain exercise, prevent regression in motivational readiness for exercise, and improve physical functioning in this patient population.

Project description:PurposePlatinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established.DesignMATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints.ResultsFrom 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P = 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P = 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%).ConclusionsS-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

Dataset Information

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

Publications

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

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