1 / 21

Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons

The effects of glutamine on vincristine-induced neuropathy in pediatric patients with cancer - a pilot study . Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons Morgan Stanley Children’s Hospital of New York- Presbyterian New York University School of Medicine.

taurus
Download Presentation

Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The effects of glutamine on vincristine-induced neuropathy in pediatric patients with cancer- a pilot study Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons Morgan Stanley Children’s Hospital of New York- Presbyterian New York University School of Medicine

  2. Vincristine in Cancer Therapy • Vinca-alkaloid derived from the periwinkle plant • Integral part of many pediatric protocols • ALL, Hodgkin’s disease, non-Hodgkins lymphoma, rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, Wilms tumor • Mechanism of vincristine (VCR) • Binds to tubulin disrupts microtubule function  mitotic arrest & cell death • Interfere with many biochemical processes: amino acid uptake, inhibition of protein, DNA, & RNA synthesis, disrupts lipid & glucose metabolism

  3. Vincristine-Induced Neuropathy • Neurotoxicity is the dose-limiting toxicity of VCR therapy • Manifests as a sensory and/or motor neuropathy • Presentation of neuropathy in children • Paresthesias, numbness, loss of proprioception, gait disturbances • More difficult to detect • May be subtle • Believed to be related to cumulative dose in adults

  4. Glutamine • Neutral non-essential amino acid, frequent use as a nutritional supplement • Glutamine depletion over time in cancer patients • May have a promising role in prophylaxis against VCR-induced neuropathy • Proposed mechanisms of neuroprotectant effect • Related to circulating nerve growth factor (NGF) levels; glutamine’s ability to upregulate NGF mRNA • Glutamine enhances microtubule formation and/or stability • Low toxicity

  5. Study Objectives Eligibility Criteria • Evaluate effect of glutamine on VCR-mediated antitumor efficacy in vitro • Describe the incidence of VCR-induced peripheral neuropathy in pediatric oncology patients • Investigate the efficacy of glutamine in ameliorating VCR-induced peripheral neuropathy • To investigate the effect of glutamine on serum nerve growth factor and glutamine levels • Inclusion • Ages 5 to 21 years • Ability to complete baseline assessment • Diagnosis of leukemia or solid tumors and expected to receive ≥ 15 mg/m2 of VCR over 30 weeks • Exclusion • Primary CNS tumors or CNS metastases • Recurrent disease • Grade II, III or IV neurological status by the NCI CTC 3.0 on clinical exam • Already received > 8mg/m2 of VCR during therapy at the time of consent

  6. Study Instruments Symbol Digits Test Purdue Pegboard Test Hand Dynamometer Grip Strength

  7. Study Design • Neurological Assessments • Clinical exam • Purdue Pegboard Test • Symbol Digits Test • Grip Strength Test • Blood Collection • Serum NGF • Serum glutamine • Baseline, Day 0, 21, & 42 Baseline • Double-blind, randomized, placebo-controlled trial Neurological Status evaluated every 3 weeks • Randomization Criteria • Clinically progressive neurological findings • Increase in one toxicity grade by the NCI CTC 3.0 on clinical exam • or • Clinically progressive neuropsychological findings • ≥ 1/2 SD from patient’s own baseline score on any of the instruments that measure fine and gross motor function Meet criteria  Randomization Glutamine Placebo Day 0 Day 0 Day 21 - discontinue supplement Day 21 Day 21 Glutamine dose6 g/m2 (max of 10 g/dose) BID Day 42 Day 42

  8. In vitro testing David J. Kroll, Ph.D. Senior Research PharmacologistResearch Triangle Park, NC • Physiologic levels of glutamine: 500 – 600 µM • CCRF-CEM human T-cell leukemia cells • The effects of 0.5, 2, 5, and 10 mM of glutamine on • cell cycle distribution • cellular growth rate • sensitivity to vincristine cytotoxicity • sensitivity to L-asparaginasecytotoxicity

  9. Results – In vitro testing

  10. Results – In vitro testing • No effect of glutamine on cell cycle distribution

  11. Results – In vitro testing • No effect of glutamine on vincristine sensitivity in CCRF-CEM cells

  12. Results – In vitro testing

  13. Clinical Trial Demographics • 23 patients, 3 removed, 2 on observation • Ages 5 – 19 years • Mean 9.9, Median 8.5 • 10 males, 8 females • Diagnosis • ALL – 16 • Rhabdomyosarcoma – 2 • Ewings sarcoma – 2 • Wilms tumor – 2 • Hodgkin’s Disease – 2

  14. Results – Randomization • Criteria for randomization met in first 18 of 18 patients • Criteria met by • Clinical exam – 5 patients • Neuropsych. Testing – 6 patients • Both – 7 patients • VCR-related neuropathy is prevalent in children with overt progression by clinical exam in 67% • May be greater if in fact neuropsych. testing is picking up signs at an earlier stage

  15. Results – Neuropsych. Testing • Potential practice effect with Symbol Digits test

  16. Results – Cumulative VCR • Cumulative dose of approximately 6 mg/m2 required for detection of signs by clinical exam or neuropsych. testing in all but one patient • No difference in number of days to randomization between patients with ALL compared to other diseases • It is the cumulative dose as opposed to dose-intensity (mg/m2/28-day interval) that determines randomization • Among six patients that received 6 mg/m2 ± 0.5, dose intensity varied from 2.5 to 5.8 mg/m2/28-day interval

  17. Results – Serum glutamine levels • No significant difference found between glutamine levels at baseline and at time of randomization (Z=-0.31, p=0.76) • Significant correlation between baseline and the change in glutamine (rho=-0.531, p=0.034)

  18. Results – Serum glutamine levels • No significant differences between ALL and other diseases

  19. Results – Glutamine & time to randomization • Significant difference in the number of days to randomization between patients who had a decrease and increase in glutamine (Z= -2.119, p=0.034) • Decrease – mean 80.9 days, SD=36.96 • Increase – mean 49.0 days, SD= 19.71

  20. Findings • No current evidence to suggest any adverse effect of glutamine on CCRF-CEM leukemia • cell growth, • cell cycle distribution, or • sensitivity to vincristine even at 20 times normal circulating concentrations • First 18 of 18 patients met criteria for randomization • 12 patients randomized due to progression of score on clinical exam • Cumulative dose of approximately 6 mg/m2 required for detection of signs by clinical exam or neuropsych. testing • No differences in in glutamine levels between baseline and randomization • No difference between patients with ALL and other diseases • Trends in glutamine levels may help predict who develops neuropathy

  21. Acknowledgments • Study group – E. Ladas RD MS, D. Hughes BA, S. Sands PsyD, D. Kroll PhD, L. Vahdat MD, O. BessmertnyPharmD, M. Weiner MD, K. Kelly MD, J. Glade Bender MD • GCRC, Irving Center for Clinical Research at Columbia University • Society for Integrative Oncology

More Related