Treatment with topotecan plus cyclophosphamide in children with first relapse of neuroblastoma

Ashraf, Kaleem; Shaikh, Furqan; Gibson, Paul; Baruchel, Sylvain; Irwin, Meredith S.

doi:10.1002/pbc.24587

Cited by 30 publications

(32 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…47,48 The initial phase II study used a 5-day schedule of 250 mg/m 2 /d cyclophosphamide and 0.75 mg/m 2 /d topotecan repeated every 21 days and achieved objective responses (OR) in 6 of 13 (46%) NB patients. 50 Within the Children's Oncology Group, TopoCy has now been incorporated into the upfront induction regimen. Results demonstrated a trend toward superiority for the TopoCy combination, although this reached statistical significance only for progression-free survival; there was no difference in OS between the treatment arms.…”

Section: Topotecan Combinationsmentioning

confidence: 99%

Current and Future Strategies for Relapsed Neuroblastoma

Morgenstern

Baruchel

Irwin

2013

Journal of Pediatric Hematology/Oncology

Self Cite

View full text Add to dashboard Cite

More than half of the patients with high-risk neuroblastoma (NB) will relapse despite intensive multimodal therapy, with an additional 10% to 20% refractory to induction chemotherapy. Management of these patients is challenging, given disease heterogeneity, resistance, and organ toxicity including poor hematological reserve. This review will discuss the current treatment options and consider novel therapies on the horizon. Cytotoxic chemotherapy regimens for relapse and refractory NB typically center on the use of the camptothecins, topotecan and irinotecan, in combination with agents such as cyclophosphamide and temozolomide, with objective responses but poor long-term survival. I-meta-iodobenzylguanidine therapy is also effective for relapsed patients with meta-iodobenzylguanidine-avid disease, with objective responses in a third of cases. Immunotherapy with anti-GD2 has recently been incorporated into upfront therapy, but its role in the relapse setting remains uncertain, especially for patients with bulky disease. Future cell-based immunotherapies and other approaches may be able to overcome this limitation. Finally, many novel molecularly targeted agents are in development, some of which show specific promise for NB. Successful incorporation of these agents will require combinations with conventional cytotoxic chemotherapies, as well as the development of predictive biomarkers, to ultimately personalize approaches to patients with "targetable" molecular abnormalities.

show abstract

Section: Topotecan Combinationsmentioning

confidence: 99%

Current and Future Strategies for Relapsed Neuroblastoma

Morgenstern

Baruchel

Irwin

2013

Journal of Pediatric Hematology/Oncology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The combination of cyclophosphamide plus topotecan has been active in rhabdomyosarcoma, neuroblastoma, and Ewing sarcoma patients with recurrent or refractory disease who have not received topotecan previously (18)(19)(20). The combination of topotecan, cyclophosphamide, and etoposide is tolerable and effective in relapsed and newly diagnosed neuroblastoma in phase II clinical trials and upfront phase III clinical trials (18,21). Single-agent topotecan has also been found to be antiangiogenic in preclinical models of pediatric cancers (22,23).…”

Section: Introductionmentioning

confidence: 99%

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Zhang

Marrano

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Tumor cells residing in tumor hypoxic zones are a major cause of drug resistance and tumor relapse. In this study, we investigated the efficacy of evofosfamide, a hypoxia-activated prodrug, and its combination with topotecan in neuroblastoma and rhabdomyosarcoma preclinical models.Experimental Design: Neuroblastoma and rhabdomyosarcoma cells were tested in vitro to assess the effect of evofosfamide on cell proliferation, both as a single agent and in combination with topotecan. In vivo antitumor activity was evaluated in different xenograft models. Animal survival was studied with the neuroblastoma metastatic tumor model.Results: All tested cell lines showed response to evofosfamide under normoxic conditions, but when exposed to hypoxia overnight, a 2-to 65-fold decrease of IC 50 was observed. Adding topotecan to the evofosfamide treatment significantly increased cytotoxicity in vitro. In neuroblastoma xenograft models, single-agent evofosfamide treatment delayed tumor growth. Complete tumor regression was observed in the combined topotecan/evofosfamide treatment group after 2-week treatment. Combined treatment also improved survival in a neuroblastoma metastatic model, compared to singleagent treatments. In rhabdomyosarcoma xenograft models, combined treatment was more effective than single agents. We also showed that evofosfamide mostly targeted tumor cells within hypoxic regions while topotecan was more effective to tumor cells in normoxic regions. Combined treatment induced tumor cell apoptosis in both normoxic and hypoxic regions.Conclusions: Evofosfamide shows antitumor effects in neuroblastoma and rhabdomyosarcoma xenografts. Compared with single-agent, evofosfamide/topotecan, combined therapy improves tumor response, delays tumor relapse, and enhances animal survival in preclinical tumor models. Clin Cancer Res; 22(11); 2697-708. Ó2015 AACR.

show abstract

“…Early relapses had a more rapid, unfavorable course, with ~80% of mortalities occurring within 2 years, whereas the survival time was longer for late relapses. At present, children are offered a wide variety of salvage regimens following relapse (29)(30)(31). Multiple salvage therapy has been reported in a previous study to extend the median survival time between 2.2 and 3.2 months for patients with MYCN amplification and between 0.7 and 5.8 months for patients with early relapse subsequent to stem cell transplantation, but the long-term disease-free survival following recurrent disease remains extremely poor (32).…”

Section: Discussionmentioning

confidence: 99%