Abstract
The Radiation Therapy Oncology Group enrolled 30 patientswith recurrent malignant astrocytomas onto a phase IIstudy (RTOG 91-13). Patients were treated with all-trans-retinoicacid at a starting dose of 120 mg/m2per day orally continuously until disease progression. Fourteenpatients had glioblastoma, 14 had anaplastic astrocytoma, and2 had other histologies; 53% were under 50years of age. All patients had failed radiationtherapy and/or at least one chemotherapy regimen. Allpatients had a Karnofsky performance status score ofat least 70, but only 37% had aKPS of 90-100. Forty percent had a neurologicfunction status of grade 1 (able to work).A minimum of 4 weeks of all-trans-retinoic aciddefined adequate treatment. Twenty-five patients received adequate therapy.Most common toxicities were dry skin, cheilitis, anemia,and headache; 3 patients had grade 3 headacherequiring suspension of all-trans-retinoic acid. No grade 3hematologic toxicity was observed. Of 25 adequately treatedpatients, 3 showed objective regression of tumor onmagnetic resonance imaging and computed tomography scans, 3patients remained stable, and 19 patients had diseaseprogression. The median time to tumor progression was3.8 months and the median survival time was5.7 months.This study suggests that this dose of singleagent all-trans-retinoic acid has modest clinical activity againstrecurrent malignant gliomas with tolerable side effects. Aresponse rate of 12% and a stabilization rateof 12% are lower than expected. Future studieswith higher dosage or in combination with biologicalresponse modifiers or chemotherapy may be warranted.
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Walker MD, Alexander G Jr, Hunt WE, Leventhal CM, Mahaley MS Jr, Mealey J, Norrell HA: Evaluation of mithramycin in the treatment of anaplastic gliomas. J Neurosurg 44: 655–667, 1976
Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahalley MS, Mealey J, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49; 333–343, 1978
Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP: Meta-analysis of radiotherapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71: 2585–2597, 1993
Lippman SM, Kessler JF, Meyskens FL Jr: Retinoids as preventive and therapeutic anticancer agents (Part II). Cancer Treat Rep 17: 493–515, 1987
Kessler JF, Jones SE, Levine N, Lynch PJ, Booth AR, Meyskens FL Jr: Isotretinoin and cutaneous helper T-cell lymphoma (mycosis fungoides). Arch Dermatol 123: 201–204, 1987
Lippman SM, Meyskens FL: Results of the use of vitamin A and retinoids in cutaneous malignancies. Pharmac Ther 40: 107–122, 1989
Lippman SM, Meyskens FL: Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. Ann Intern Med 107: 499–501, 1987
Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, Fofonoff S, Byers R, Atkinson EN, Vaughan C, Toth BB, Kramer A, Dimery IW, Skipper P, Strong S: 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 315: 1501–1505, 1986
Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318: 1633–1637, 1988
Lippman SM, Kessler JF, Al-Sarraf M, Alberts DS, Itri LM, Mattox D, Van Hoff DO: Treatment of advanced squamous cell carcinoma of the head and neck with isotretinoin: A phase II randomized trial. Invest New Drugs 6: 51–56, 1988
Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72: 567–572, 1988
Chomienne C, Ballerini P, Balitrand N, Amar M, Bernard JF, Boivin P, Daniel MT, Berger R, Castaigne S, Degos L: Retinoic acid therapy for promyelocytic leukemia. Lancet 746–747, 1989
Castaigne S, Chomienne C, Ballerini P, Huang ME, Daniel MT, Berger R, Miclea JM, Degos L: All-trans-retinoic acid: A novel differentiation therapy for acute promyelocytic leukemia (Abstract) Blood 117a, 1989
Yung WK, Lotan R, Lee P, Lotan D, Steck P: Modulation of growth and epidermal growth factor receptor activity by retinoic acid in human glioma cells. Cancer Research 49: 1014–1019, 1989
Olson JA; Adverse effects of large doses of vitamin A and retinoids. Semin Oncol 10: 290–293, 1983
Levin VA, Wilson DB, Crafts D, Norman D, Hoffer P, Spire JP: Criteria for evaluating malignant brain tumor patients undergoing chemotherapy. J Neurosurg 47: 329–335, 1977
Norman D, Enzmann D, Levin VA, Wilson CB, Newton TH: Computerized tomographic scanning in the evaluation of malignant gliomas under therapy. Radiol 121: 85–88, 1976
Caplan RJ, Pajak TF, Cox JD: Analysis of the probability and risk of cause-specific failure. Int J Radiat Oncol Biol Phys 29: 1183–1186, 1994
Smith MA, Adamson PC, Balis FM, Feusner J, Aronson L, Murphy RF, Horowitz ME, Reaman G, Mannond GD, Fenton RM, Cannaghan GD, Hittleman WN, Poplack DG: Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer. J Clin Oncol 10: 1666–1673, 1992
Lee JS, Newman RA, Lippman SM, Huber MH, Minor J, Raber MN, Krakoff IH, Hong WK: Phase I evaluation of all-trans-retinoic acid in adults with solid tumors. J Clin Oncol 11: 959–966, 1993
Kahn MJ, Luginbuhl W, Gaines L, Bratschi J, Bavaria J, Kaiser L, Treat J: Leukocytosis associated with all-trans-retinoic acid therapy in metastatic non-small cell lung cancer. J Natl Cancer Inst 84: 1669–1671, 1992
Frankel SR, Eardley A, Lauwers G: The ‘retinoic acid syndrome’ in acute promyelocytic leukemia. Ann Intern Med 117: 292–296, 1992
Koike T, Tatewaki WH, Aoki A, Yoshimoto H, Yagaisawa K, Hashimoto S, Furukawa T, Sastoh H, Takahashi M, Li-bo Y, Ying W, Shibata A: Brief report: Severe symptoms of hyperhistaminemia after the treatment of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 327: 385–387, 1992
Koch HF: Biochemical treatment of precancerous oral lesions: The effectiveness of various analogues of retinoic acid. J Maxillofac Surg 6: 59–63, 1978
Band PR, Besner JG, Leclaire R, Girad C, Biorio G, Deshamps M, Gelinas M, Larochelle D: Phase I study on 13-cisretinoic acid toxicity. Cancer Treat Rep 66: 1759–1761, 1982
Yung WK, Simaga M, Levin VA: 13-cis-retinoic acid: A new and potentially effective agent for recurrent malignant astrocytomas. (Abstract) Proc Am Assoc Cancer Res 12: A497, 1993
Atiba J, Jamil S, Meyskens FL Jr, Cho J, Armentrout S, Berkson P, Wong S-F, Neal J: Transretinoic acid (tRA) in the treatment of malignant gliomas (MG): A phase II study (Abstract) Proc Am Soc Clin Oncol 13: A501, 1994
Westarp ME, Westarp MP, Bollag W: Effect of six retinoids and retinoic acid catabolic inhibitor liarozole on two glioblastoma cell lines, and first experience in malignant brain tumor patients. (Abstract) Fourth International Congress on Anti-cancer Chemotherapy, February 2–5, 1993, Paris, France, 116
Hoffman W, Rodemann HP, Schiller U: Retinoid and Interferon–an Induced Modulation of Proliferation and Differentiation in Human Tumor Cell Lines. (Abstract) Second International Cancer Chemo Prevention Conference, April 28–30, 1993, Berlin, Germany, 99
Kalin JR, Wells MJ, Hill DL: Effects of phenobarbital, 3-methylcholanthrene, and retinoid pretreatment on disposition of orally administered retinoids in mice. Drug Metab Dispos 12: 63–67, 1984
Siegenthaler G, Saurate JH: Plasma and skin carriers for natural and synthetic retinoids. Arch Dermatol 123: 1690a–1692a, 1987
Hirschel Scholz S, Siegenthaler G, Saurat JH: Ligand-specific and non-specific in vivomodulation of human epidermal cellular retinoid acid binding protein (CRABP). Eur J Clin Invest 19: 220–227, 1989
Hirschel Scholz S, Siegenthaler G, Saurat JH: Isotretinoin differs from other synthetic retinoids in its modulation of human cellular retinoid acid binding protein (CRABP). Br J Dermatol 120: 639–644, 1989
Villablanca JG, Khan AA, Avramis VI, Seeger RC, Hatthay KK, Ramsay NKC, Reynolds CP: Phase I trial of 13 cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol 13: 894–900, 1995
Reynolds CP, Schlinder P, Jones D, Gentile J, Proffitt R, Einhorn P: Comparison of 13-cis-retinoic acid to trans-retinoic acid using human neuroblastoma cell lines. In: Evans A, Biedler JL, Brodeur G et al. (eds) Advances in Neuroblastoma Research 4. New York, NY, Wiley, 1994; 237–244
Muindi J, Frankel SR, Miller W Jr, Jukubowski A, Scheinberg DA, Young CW, Dmitrovsky E, Warrell RP Jr: Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid ‘resistance’ in patients with acute promyelocytic leukemia. Blood 79: 299–303, 1992
Smith MA, Parkinson DR, Cheson BD, Friedman MA: Retinoids in cancer therapy. J Clin Oncol 10: 839–864, 1992
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Phuphanich, S., Scott, C., Fischbach, A.J. et al. All-trans-retinoic acid: a phase II radiation therapy oncology group study (RTOG 91-13) in patients with recurrent malignant astrocytoma. J Neurooncol 34, 193–200 (1997). https://doi.org/10.1023/A:1005765915288
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DOI: https://doi.org/10.1023/A:1005765915288