Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study.

PURPOSE Temozolomide (TMZ) and 13-cis-retinoic acid (cRA) have shown activity in prior single-agent trials of recurrent malignant gliomas (MG). This phase II trial evaluated efficacy and toxicity of combination temozolomide and cRA treatment in recurrent MG. PATIENTS AND METHODS Adults with recurrent supratentorial MG for whom surgery, radiation, and/or chemotherapy failed were eligible. Treatment included oral TMZ 150 or 200 mg/m2/d, days 1 through 5, and cRA 100 mg/m2/d, days 1 to 21, every 28 days. Primary end point was progression-free survival at 6 months (PFS 6); secondary end points included response, survival, and PFS12. RESULTS Eighty-eight eligible patients (glioblastoma multiforme [n = 40]; anaplastic gliomas [n = 48; astrocytoma, 28; oligodendroglioma, 14; mixed glioma, six]) received treatment. PFS 6 was 43% (95% confidence interval [CI], 33% to 54%) and PFS12 was 16% (95% CI, 10% to 26%). Median overall PFS was 19 weeks (95% CI, 16 to 27 weeks), and median overall survival (OS) was 47 weeks (95% CI, 36 to 58 weeks). OS was 46% (95% CI, 36% to 57%) at 52 weeks and 21% (95% CI, 13% to 31%) at 104 weeks. Of 84 assessable patients, there were two (3%) complete responses and eight (12%) partial responses (complete plus partial response, 15%). Among 499 treatment cycles, the most common grade 3/4 events included granulocytopenia (1.8%), thrombocytopenia (1.4%), and hypertriglyceridemia (1.2%). CONCLUSION TMZ and cRA were active, exceeding our 20% thresholds for PFS 6 success, assuming 20% improvement over our previously reported database (glioblastoma multiforme: expected, 30%; observed, 32%; anaplastic glioma: expected, 40%; observed, 50%).

[1]  A. Kyritsis,et al.  The treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin) , 1997, Journal of Neuro-Oncology.

[2]  W. Yung,et al.  All-trans-retinoic acid: a phase II radiation therapy oncology group study (RTOG 91-13) in patients with recurrent malignant astrocytoma , 1997, Journal of Neuro-Oncology.

[3]  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.

[4]  C. Monville,et al.  Retinoic acid increases proliferation rate of GL‐15 glioma cells, involving activation of STAT‐3 transcription factor , 2002, Journal of neuroscience research.

[5]  F. Recchia,et al.  Ifosfamide, cisplatin, and 13‐Cis retinoic acid for patients with advanced or recurrent squamous cell carcinoma of the head and neck , 2001, Cancer.

[6]  M. J. van den Bent,et al.  Temozolomide chemotherapy in recurrent oligodendroglioma , 2001, Neurology.

[7]  E. Frenkel,et al.  Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. , 2001, Cancer research.

[8]  C. Fages,et al.  Effects of a novel synthetic retinoid on malignant glioma in vitro: inhibition of cell proliferation, induction of apoptosis and differentiation. , 2001, European journal of cancer.

[9]  E. Brown,et al.  Agonists of the retinoic acid- and retinoid X-receptors inhibit hepatocyte growth factor secretion and expression in U87 human astrocytoma cells. , 2001, Brain research. Molecular brain research.

[10]  S. Schold,et al.  Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  N. Barth,et al.  Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma. , 2001, Neuro-oncology.

[12]  D. Osoba,et al.  A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse , 2000, British Journal of Cancer.

[13]  Y. Luo,et al.  All trans-retinoic acid suppresses in vitro growth and down-regulates LIF gene expression as well as telomerase activity of human medulloblastoma cells. , 2000, Anticancer research.

[14]  G. Sica,et al.  Cisplatin, vindesine, mitomycin-C and 13-cis retinoic acid in the treatment of advanced non small cell lung cancer. A phase II pilot study. , 2000, Anticancer research.

[15]  C. Fages,et al.  Effects of retinoic acid and tumor necrosis factor alpha on GL‐15 glioblastoma cells , 2000, Neuroreport.

[16]  P. Black,et al.  Retinoids inhibit human glioma cell proliferation and migration in primary cell cultures but not in established cell lines. , 2000, Neurosurgery.

[17]  L. Barré,et al.  Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of Rat. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[18]  M. Álvarez-Dolado,et al.  Retinoic acid and 1,25‐dihydroxyvitamin D3 inhibit tenascin‐C expression in rat glioma C6 cells , 1999, Journal of neuroscience research.

[19]  Susan M. Chang,et al.  Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  M J Gleason,et al.  Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  C. Daumas-Duport,et al.  Retinoic acid modulates RAR alpha and RAR beta receptors in human glioma cell lines. , 1999, Anticancer research.

[22]  D. Thomas,et al.  Sensitivity of short-term cultures derived from human malignant glioma to the anti-cancer drug temozolomide. , 1999, Anti-cancer drugs.

[23]  J. Jiricny,et al.  Involvement of the mismatch repair system in temozolomide-induced apoptosis. , 1998, Molecular pharmacology.

[24]  L. Frati,et al.  Advanced carcinoma of the pancreas: phase II study of combined chemotherapy, beta-interferon, and retinoids. , 1998, American journal of clinical oncology.

[25]  H. Mugishima,et al.  [Treatment results of intermittent and cyclic regimen with ATRA and chemotherapy in childhood acute promyelocytic leukemia. Children's Cancer and Leukemia Study Group]. , 1997, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[26]  C. Ackerley,et al.  Retinoic acid and the cyclin dependent kinase inhibitors synergistically alter proliferation and morphology of U343 astrocytoma cells , 1997, Oncogene.

[27]  W. Yung,et al.  Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[28]  M. Berger,et al.  Role of O6-methylguanine-DNA methyltransferase in resistance of human brain tumor cell lines to the clinically relevant methylating agents temozolomide and streptozotocin. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  M. Dolan,et al.  Activity of temozolomide in the treatment of central nervous system tumor xenografts. , 1995, Cancer research.

[30]  H. Fine,et al.  Meta‐analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults , 1993, Cancer.

[31]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  M. Stevens,et al.  Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA. , 1990, Anti-cancer drug design.

[33]  S P Langdon,et al.  Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. , 1987, Cancer research.