A phase II trial of a multi‐agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer

Robison, Nathan; Campigotto, Federico; Susan, N.; Manley, Peter; Turner, Christopher D.; Zimmerman, Mary Ann; Chordas, Christine; Werger, Annette M.; Allen, Jeffrey C.; Goldman, Stewart; Rubin, Joshua B.; Isakoff, Michael S.; Pan, Wilbur; Khatib, Ziad; Comito, Melanie; Bendel, Anne; Pietrantonio, Jay B.; Kondrat, Laura; Hubbs, Shannon M.; Neuberg, Donna; Kieran, Mark W.

doi:10.1002/pbc.24794

Cited by 133 publications

(141 citation statements)

References 30 publications

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“…Promising results were recently reported for a metronomic chemotherapy protocol in the treatment of recurrent embryonal brain tumors (46). It took more than ten years to empirically and incrementally develop the sophisticated 8-drug combination regimen based on the results of previous pre-clinical and clinical studies (47–49). By involving clinicians, biologists and modelers throughout the entire process, our workflow has the potential to significantly reduce the time required to develop optimal metronomic protocols.…”

Section: Discussionmentioning

confidence: 99%

Formalizing an Integrative, Multidisciplinary Cancer Therapy Discovery Workflow

McGuire¹,

Enderling

Wallace

et al. 2013

Cancer Research

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Although many clinicians and researchers work to understand cancer, there has been limited success to effectively combine forces and collaborate over time, distance, data and budget constraints. Here we present a workflow template for multidisciplinary cancer therapy that was developed during the 2nd Annual Workshop on Cancer Systems Biology sponsored by Tufts University, Boston, MA in July 2012. The template was applied to the development of a metronomic therapy backbone for neuroblastoma. Three primary groups were identified: clinicians, biologists, and scientists (mathematicians, computer scientists, physicists and engineers). The workflow described their integrative interactions; parallel or sequential processes; data sources and computational tools at different stages as well as the iterative nature of therapeutic development from clinical observations to in vitro, in vivo, and clinical trials. We found that theoreticians in dialog with experimentalists could develop calibrated and parameterized predictive models that inform and formalize sets of testable hypotheses, thus speeding up discovery and validation while reducing laboratory resources and costs. The developed template outlines an interdisciplinary collaboration workflow designed to systematically investigate the mechanistic underpinnings of a new therapy and validate that therapy to advance development and clinical acceptance.

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Section: Discussionmentioning

confidence: 99%

Formalizing an Integrative, Multidisciplinary Cancer Therapy Discovery Workflow

McGuire¹,

Enderling

Wallace

et al. 2013

Cancer Research

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“…Antiangiogenic agents such as bevacizumab have also failed to control recurrent ependymomas [ 21 ]. Metronomic therapy has shown some benefi t in selected cases [ 22 ]. Recent drug screen in preclinical models have shown that 5-FU may be an option [ 23 ].…”

Section: Relapse Strategymentioning

confidence: 98%

Oncological Management of Ependymomas

Grill

Iglesias

2015

Posterior Fossa Tumors in Children

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Despite its frequency (third most common brain tumor in children), publications about ependymomas per year are three times less frequent than for medulloblastomas (120 vs. 330). The knowledge and the sophistication of the protocols are lagging behind those of medulloblastomas. Accordingly, this has limited the progress made for these tumors. The improvement of neurosurgery is probably the driving force improving the outcome of children affected with this disease in the last 20 years. The three main questions that remain for ependymomas are the following: (i) Which biomarkers are useful to understand the oncogenesis and prognosis? (ii) Is there a role for chemotherapy? (iii) What is the appropriate strategy at the time of relapse?The management of ependymomas is currently mainly based on surgery and radiotherapy because of the relative ineffi cacy of chemotherapy. At each step of the management, these two treatments have to be considered for an optimal care. Presently oncological management for all intracranial ependymomas is homogenous despite the recent fi ndings that ependymoma biology may largely differ by location. First-Line Treatment: SurgeryThe initial surgical management is aiming at complete removal of the tumor, if necessary in more than one step because it remains the principal risk factor for survival. Indeed, in case of incomplete resection, one should not proceed to irradiation. Risk of relapse is fi ve times higher in case of incomplete resection even after fulldose radiation therapy [ 1 ]. In the Saint-Jude series, presently the best results published so far, 5-year event-free survival is only 41 % (95 % CI = 18-64 %) in case of near-total or subtotal resection versus 81.5 % (95 CI = 73-90 %) in case of gross-total resection, p < 0.0001. Any attempt should therefore be made to obtain a macroscopically complete resection. In between two surgeries, there is no defi nitive indication for chemotherapy since most of the regimens tested have not shown many responses [ 2 ]. Pre-irradiation chemotherapy may compensate for an incomplete resection as it has been shown with a recently published phase II using a standard chemotherapy regimen based on cisplatin in patients with incompletely resected; in this report, patients with incompletely resected ependymomas treated with pre-irradiation chemotherapy had similar although slightly lower EFS than those with completely resected ependymomas treated with irradiation only [ 3 ]. In addition, some anecdotal reports have shown that second surgery may be facilitated by a course or two of

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“…This study will evaluate the use of biweekly IV bevacizumab in combination with five oral drugs (thalidomide, celecoxib, fenofibrate, and alternating cycles of daily low-dose oral etoposide and cyclophosphamide), augmented with alternating courses of intrathecal etoposide and liposomal cytarabine. The primary objective of the MEMMAT trial was to evaluate the efficacy of this multidrug anti-angiogenic approach in this heavily pre-treated patient population [115]. Additionally, safety and tolerability data was also further assessed.…”

Section: Symposiamentioning

confidence: 99%

Next generation metronomic chemotherapy—report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6–8 May 2016, Mumbai

Pantziarka¹,

Hutchinson²,

André³

et al. 2016

ecancer

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The 5th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6th – 8th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

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A phase II trial of a multi‐agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer

Cited by 133 publications

References 30 publications

Formalizing an Integrative, Multidisciplinary Cancer Therapy Discovery Workflow

Formalizing an Integrative, Multidisciplinary Cancer Therapy Discovery Workflow

Oncological Management of Ependymomas

Next generation metronomic chemotherapy—report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6–8 May 2016, Mumbai

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