Therapeutic Efficacy of DTI-015 using Diffusion Magnetic Resonance Imaging as an Early Surrogate Marker

To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model, tumors were treated with direct intratumoral administration of DTI-015, a solution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats, and three treatment groups were established: DTI-015, EtOH, and sham. Two groups of rats received intratumoral injection of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 μl under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1, 24, 48, and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast, rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours, which further increased over time, followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage, development of a cystic region, and enhanced animal survival. Finally, not only were ADC measurements predictive of differences between treatment groups, but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy.

[1]  A. Woodcock,et al.  Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. , 1990, The New England journal of medicine.

[2]  S. Hassenbusch,et al.  Stereotactic injection of DTI-015 into recurrent malignant gliomas: phase I/II trial. , 2003, Neoplasia.

[3]  K. Hoang-Xuan,et al.  Primary brain tumours in adults , 2003, The Lancet.

[4]  P F Morrison,et al.  Convection-enhanced delivery of macromolecules in the brain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  L. Stewart,et al.  Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials , 2002, The Lancet.

[6]  Wei Li,et al.  Fast magnetic resonance diffusion‐weighted imaging of acute human stroke , 1992, Neurology.

[7]  R. Tomsak,et al.  Ocular and orbital toxicity following intracarotid injection of BCNU (carmustine) and cisplatinum for malignant gliomas. , 1985, Ophthalmology.

[8]  H. Cravioto,et al.  DTI-015 produces cures in T9 gliosarcoma. , 2003, Neoplasia.

[9]  R. Tamargo,et al.  The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers. , 1992, Journal of neurosurgery.

[10]  Manfred Westphal,et al.  A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. , 2003, Neuro-oncology.

[11]  J P Johnson,et al.  Intracerebral clysis in a rat glioma model. , 2000, Neurosurgery.

[12]  W. Mark Saltzman,et al.  Chemotherapeutic Drugs Released from Polymers: Distribution of 1,3-bis(2-chloroethyl)-l-nitrosourea in the Rat Brain , 1996, Pharmaceutical Research.

[13]  S. Hassenbusch,et al.  Levels of N7-(2-hydroxyethyl)guanine as a molecular dosimeter of drug delivery to human brain tumors. , 2001, Neuro-oncology.

[14]  Stephan E Maier,et al.  Early detection of response to radiation therapy in patients with brain malignancies using conventional and high b-value diffusion-weighted magnetic resonance imaging. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  T L Chenevert,et al.  Monitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[16]  R. Gillies,et al.  Early increases in breast tumor xenograft water mobility in response to paclitaxel therapy detected by non-invasive diffusion magnetic resonance imaging. , 1999, Neoplasia.

[17]  B. O'driscoll,et al.  Late BCNU lung: A light and ultrastructural study on the delayed effect of BCNU on the lung parenchyma , 1991, The Journal of pathology.

[18]  S E Maier,et al.  Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging. , 2001, Cancer research.

[19]  J. M. Taylor,et al.  Diffusion magnetic resonance imaging: an early surrogate marker of therapeutic efficacy in brain tumors. , 2000, Journal of the National Cancer Institute.

[20]  Benedick A Fraass,et al.  Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  A. Rehemtulla,et al.  Diffusion MRI detects early events in the response of a glioma model to the yeast cytosine deaminase gene therapy strategy , 2000, Gene Therapy.

[22]  T L Chenevert,et al.  Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[23]  B. Kleinschmidt-DeMasters,et al.  Intracarotid BCNU leukoencephalopathy , 1986, Cancer.

[24]  D. V. Hoff,et al.  Cancer chemotherapy handbook , 1980 .

[25]  V. Levin,et al.  Formation of DNA adducts and tumor growth delay following intratumoral administration of DTI-015 , 2003, Journal of Neuro-Oncology.

[26]  Rolf F. Barth,et al.  Rat brain tumor models in experimental neuro-oncology:The 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 Gliomas , 2004, Journal of Neuro-Oncology.

[27]  T. Chenevert,et al.  Contributions of cell kill and posttreatment tumor growth rates to the repopulation of intracerebral 9L tumors after chemotherapy: an MRI study. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. Green,et al.  A randomized comparison of intra-arterial versus intravenous BCNU, with or without intravenous 5-fluorouracil, for newly diagnosed patients with malignant glioma. , 1992, Journal of neurosurgery.

[29]  D. Whiting,et al.  Intra-arterial chemotherapy for brain tumors. , 1990, Cleveland Clinic journal of medicine.

[30]  G. R. Thompson,et al.  The hepatotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosurea (BCNU) in rats. , 1969, The Journal of pharmacology and experimental therapeutics.