Skip to main content
Log in

New agents in the treatment of primary brain tumors

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Summary

A review of single agent trials of cytotoxic agents in adults with high grade gliomas is presented. The rationale for testing these agents in patients with brain tumors was variable and is discussed. The criteria to evaluate responses were also variable ranging from subjective evaluation of clinical improvement with a stable radiographic assessment to the same objective response criteria utilized for solid tumors. Trials of agents specifically designed for brain tumors such as AZQ and spiromustine have been disappointing. There are encouraging results being seen in early trials of newer agents which await confirmation in larger trials but which hold promise for improving the disappointing results seen so far with chemotherapy in primary brain tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Gregor A, Rampling R, Aapro M, Malmstrom P, Whittle IR, Rye R, Stewart M, Sellar R, Demierre B, Ironside JW, Wahlby S, Smyth JF: Phase II study of tauromustine in malignant glioma. Eur J Cancer 28A(12): 1959–1962, 1992

    PubMed  Google Scholar 

  2. Macdonald DR, Cascino TL, Schold SC, Cairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8(7): 1277–1280, 1990

    PubMed  Google Scholar 

  3. Taylor SA, Upchurch C, Goodwin W, Brown T, Selby G, Vogel FS, Eyre H: Assessment of response to new agents for primary CNS malignancies. Proc Am Soc Clin Oncol 12: 502, 1993 (abstr/poster)

    Google Scholar 

  4. Taylor S, Belt RG, Joseph U, Haas CD, Hoogstraten B: Phase I evaluation of AT-125 single dose every three weeks. IND 2: 311–314, 1984

    Google Scholar 

  5. McGovern JD, Stewart JC, Elfring GL, Smith RB, Soares N, Wood JH, Poplack DG, Von Hoff DD: Plasma and cerebrospinal fluid pharmacokinetics of acivicin in Ommaya reservoir-bearing Rhesus monkeys. Cancer Treat Rep 65: 1333–1341, 1982

    Google Scholar 

  6. Jayaram NH, Cooney DA, Ryan JA, Neil GL, Dion RL, Bono VH: L-[5,5S]-amino-3 chloro-4,5-dihydro-5 isoxazole acetic acid (NSC 163501): a new amino acid antibiotic with the properties of an antagonist of L-glutamine. Cancer Chemother Rep 59: 481–491, 1975

    PubMed  Google Scholar 

  7. Dranoff G, Elion GB, Friedman HS, Campbell GL, Bigner DD: Influence of glutamine on the growth of human glioma and medulloblastoma in culture. Cancer Res 45(9): 4077–4081, 1985

    PubMed  Google Scholar 

  8. O'Dwyer PJ, Alonso MT, Leyland-Jones B: Acivicin: a new glutamine antagonist in clinical trials. J Clin Oncol 2(9): 1064–1071, 1984

    PubMed  Google Scholar 

  9. Taylor SA, Crowley J, Pollock TW, Eyre HJ, Jaeckle C, Hynes HE, Stephens RL: Objective antitumor activity of acivicin (AT-125) in patients with recurrent CNS malignancies: A Southwest Oncology Group Trial. J Clin Oncol 9: 1476–1479, 1991

    PubMed  Google Scholar 

  10. Bender JF, Grillo-Lopez AJ, Posada JG: Diaziquone (AZQ). IND 1: 071–084, 1983

    Google Scholar 

  11. Curt GA, Kelley JA, Kufta CV, Smith BH, Kornblith PL, Young RC, Collins JM: Phase II and pharmacokinetic study of aziridinylbenzoquinone [2,5-diaziridinyl-3,6-bis (carboxyethoxyamino)-1,4-benzoquinone diaziquone, NSC 182986] in high-grade gliomas. Cancer Res 43: 6102–6105, 1983

    PubMed  Google Scholar 

  12. Anonymous: Effect of AZQ (1,4-cyclohexadiene-1,4-diacarbamic acid-2,5-bis (1-aziridinyl)-3,6-dioxodiethylester) in recurring supratentorial malignant brain gliomas. A phase II study. EORTC Brain Tumour Cooperative Group. Eur J Cancer & Clin Oncol 21(1): 143–146, 1985

  13. Maral J, Poisson M, Pertuiset BF, Mashaly P, Weil M, Jacquillat CE, Grillo-Lopez AJ: Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma. J Neuro Oncol 3: 245–249, 1985

    Google Scholar 

  14. Feun LG, Yung WKA, Leavens ME, Burgess MA, Obbens EA, Bedikan AY, Savaraz N, Stewart DJ, Benjamin RS, Fields WS, Bodey GP: A phase II trial of 2,5-diaziridinyl 3,6-bis (carboethoxy amino) 1,4-benzoquinone (AZQ, NSC 182986) in recurrent primary brain tumors. J Neuro Oncol 2: 13–17, 1984

    Google Scholar 

  15. Haid M, Khandekar JD, Christ M, Johnson CM, Miller SJ, Locker GY, Merrill JM, Reisel H, Hatfield A, Lanzotti V, Stiff P, Shaw G, Krauss S, Showel J, Blough R, Gordon L: Aziridinylbenzoquinone in recurrent, progressive glioma of the central nervous system. A phase II study by the Illinois Cancer Council. Ca 6: 1311–1315, 1985

    Google Scholar 

  16. Tapazoglou E, Kish J, Ensley J, Al-Sarraf M: Response rate and toxicity with aziridinyl-benzoquinone in patients with recurrent gliomas. A progress report. Am J Clin Oncol (CCT) 11(4): 474–478, 1988

    Google Scholar 

  17. Schold SC, Friedman HS, Bjornsson TD, Falletta JM: Treatment of patients with recurrent primary brain tumors with AZQ. Neurology 34: 615–619, 1984

    PubMed  Google Scholar 

  18. Eagan RT, Dinapoli RP, Cascino TL, Scheithauer B, O'Neill BP, O'Fallon JR: Comprehensive phase II evaluation of aziridinyl-benzoquinone (AZQ, Diaziquone) in recurrent human primary brain tumors. J Neuro Oncol 5: 309–314, 1987

    Google Scholar 

  19. Taylor SA, McCracken JD, Eyre HJ, O'Bryan RM, Neilan BA: Phase II trial of AZQ (NSC 182986) in patients with primary central nervous system malignancies (CNSM). A Southwest Oncology Group Study. J Neuro Oncol 3: 131–135, 1985

    Google Scholar 

  20. Chamberlain MC, Prados MD, Silver P, Levin VA: A phase I/II study of 24 hour intravenous AZQ in recurrent primary brain tumors. J Neuro Oncol 6: 319–323, 1988

    Google Scholar 

  21. Schold SC, Herndon JE, Burger PC, Halperin EC, Vick NA, Cairncross JG, Macdonald DR, Dropcho EJ, Morawetz R, Bigner DD, Mahaley MS: Randomized comparison of diaziquone and carmustine in the treatment of adults with anaplastic glioma. J Clin Oncol 11(1): 77–83, 1993

    PubMed  Google Scholar 

  22. Eyre HJ, Jaeckle K, Green SJ, Morantz R, Vogel FS: AZQ 24-hour infusion vs BCNU for adult high-grade gliomas: preliminary results of SWOG-8737. Proceedings 9th International Conference on Brain Tumor Research and Therapy 10/91

  23. Yung WKA, Mechtler L, Gleason MJ: Intravenous carboplatin for recurrent malignant glioma: a phase II study. J Clin Oncol 9: 860–864, 1991

    PubMed  Google Scholar 

  24. Poisson M, Pereon Y, Chiras J, Delattre JY: Treatment of recurrent malignant supratentorial gliomas with carboplatin (CBDCA). J Neuro Oncol 10: 139–144, 1991

    Google Scholar 

  25. Walker RW: Carboplatin (CBDCA) in the treatment of recurrent glioma. Neurology 38 (Suppl 1): 390–391, 1988

    Google Scholar 

  26. Stewart DJ, O'Bryan RM, Al-Sarraf M, Costanzi JJ, Oishi N: Phase II study of cisplatin in recurrent astrocytomas in adults: A Southwest Oncology Group Study. J Neuro Oncol 1: 145–147, 1983

    Google Scholar 

  27. Spence AM, Berger MS, Livingston RB, Ali-Osman F, Griffin B: Phase II evaluation of high-dose intravenous cisplatin for treatment of adult malignant gliomas recurrent after chloroethylnitrosourea. J Neuro Oncol 12: 187–191, 1992

    Google Scholar 

  28. Razis E, Mittelman A, Coombe N, Puccio C, Chun H, Ahmed T, Helkson L, Cook P, Arlin Z: Phase II clinical trial of didemnin B (DNB) in patients (Pts) with glioblastoma multiforme (GM). Proc Am Soc Clin Oncol 11: 432, 1992

    Google Scholar 

  29. Levin VA, Chamberlain MC, Prados MD, Choucair AK, Berger MS, Silver P, Seaqer M, Gutin P, Davis RL, Wilson CB: Phase I–II study of eflornithine and mitoguazone combined in the treatment of recurrent primary brain tumors. Cancer Treat Rep 71: 459–464, 1987

    PubMed  Google Scholar 

  30. Levin VA, Prados MD, Yung WKA, Gleason MJ, Ictech S, Malec M: Treatment of recurrent gliomas with eflornithine. J Nat Canc Inst 84(18): 1432–1437, 1993

    Google Scholar 

  31. Taylor SA, Crowley J, Townsend J, Vogel FS, Eyre H, Braun JJ, Goodwin JJ: Phase II evaluation of echinomycin (NSC-526417) in patients with central nervous system malignancies: A Southwest Oncology Group Study. J Neuro Oncol 15: 181–184, 1993

    Google Scholar 

  32. Hutton JJ, Von Hoff DD, Kuhn J, Phillips J, Hersh M, Clark G: Phase I clinical investigation of 9-beta-D arabinofuranosyl-2-fluoroadenine-5′-monophosphate (NSC312887), a new purine antimetabolite. Cancer Res 44: 4183–4186, 1984

    PubMed  Google Scholar 

  33. Schold SC, Friedman HS, Bigner DD: A human glioma (HGL)-athymic mouse (AM) system for evaluation of novel brain tumor chemotherapeutic agents. Neurology 34: 377, 1984

    Google Scholar 

  34. Spriggs DR, Stopa E, Mayer RJ, Schorne W, Kufe DW: Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: Phase I and neuropathological study. Cancer Res 46: 5953–5958, 1986

    PubMed  Google Scholar 

  35. Cascino TL, Brown LD, Morton RF, Everson LK, Marschke RF, Dinapoli RP, O'Fallon JR: Evaluation of fludarabine phosphate in patients with recurrent glioma. Am J Clin Oncol (CCT) 11(5): 586–588, 1988

    Google Scholar 

  36. Taylor SA, Crowley J, Vogel FS, Townsend JJ, Eyre HJ, Jaeckle KA, Hynes HE, Guy JT: Phase II evaluation of fludarabine phosphate in patients with central nervous system tumors: A Southwest Oncology Group Trial. IND 9(2): 195–197, 1991

    Google Scholar 

  37. Feun LG, Savaraj N, Landy H, Levin H, Lampidis T: Phase II study of homoharringtonine in patients with recurrent primary malignant central nervous system tumors. J Neuro Oncol 9: 159–163, 1990

    Google Scholar 

  38. Savaraj N, Feun LG, Lu K, Leavens M, Moser R, Fields WS, Loo TL: Central nervous system (CNS) penetration of homoharringtonine (HHT). J Neuro Oncol 5: 77–81, 1987

    Google Scholar 

  39. Elliott TE, Buckner JC, Cascino TL, Levitt R, O'Fallon JR, Scheithauer BW: Phase II study of ifosfamide with mesna in adult patients with recurrent diffuse astrocytoma. J Neuro Oncol 10: 27–30, 1991

    Google Scholar 

  40. Carapella CM, Paggi MG, Cattani F, Ciottoli GB, Floridi A, Jandolo B, Raus L, Riccio A, Caputo A: The potential role of lonidamine (LND) in the treatment of malignant glioma: Phase II study. J Neuro Oncol 7: 103–108, 1989

    Google Scholar 

  41. Carapella CM, Paggi MG, Calvosa F, Cattani F, Jandolo B, Mastrostefano R, Raus L, Riccio A: Lonidamine in the combined treatment of malignant gliomas. A randomized study. J Neuro Surg Sci 34(3–4): 261–264, 1990

    Google Scholar 

  42. Schiffer D, Sales S, Soffietti R: Lonidamine in malignant brain tumors. Seminars in Oncology 18(2) Suppl 4: 38–41, 1991

    Google Scholar 

  43. Stewart DJ, Hugenholtz H, DaSilva VF, Benoit BG, Richard MT, Verma T, Earhart R, Robillard L: Phase II study of weekly intravenous menogaril in the treatment of recurrent astrocytomas in adults. J Neuro Oncol 13: 183–188, 1992

    Google Scholar 

  44. Feun LG, Yung WKA, Stewart DJ, Savaraij N, Bodey GP: Phase II trial of mitoguazone in malignant primary brain tumors. Cancer Treat Rep 69(3): 329–330, 1985

    PubMed  Google Scholar 

  45. Goodwin JW, Crowley J, Tranum B, Vance R, Slavik M, Balcerzak S, Hacker D: Phase II trial of spirogermanium in central nervous system tumors: A Southwest Oncology Group Study. Cancer Treat Rep 71(1): 99–100, 1987

    PubMed  Google Scholar 

  46. Peng G, Marques VE, Driscoll JS: Potential central nervous system antitumor agents. Hydantoin derivatives. J Med Chem 18: 846–849, 1975

    PubMed  Google Scholar 

  47. Rosenblum I, Stein AA: Preferential distribution of diphenylhydantoin in primary human brain tumors. Biochem Pharmacol 12: 1453–1454, 1963

    PubMed  Google Scholar 

  48. Brown TD, Ettinger DS, Donehower RC: A phase I trial of spirohydantoin mustard (NSC 172112) in patients with advanced cancer. J Clin Oncol 4(8): 1270–1276, 1986

    PubMed  Google Scholar 

  49. Heideman RL, Kelley JA, Packer RJ, Reaman GH, Roth JS, Balis F, Ettinger LJ, Doherty KM, Jeffries SL, Poplack DG: A pediatric phase I and pharmacokinetic study of spirohydantoin mustard. Cancer Res 48: 2292–2295, 1988

    PubMed  Google Scholar 

  50. Pazdur R, Redman BG, Corbett T, Phillips M, Baker L: Phase I trial of spiromustine (NSC 172112) and evaluation of toxicity and schedule in a murine model. Canc Res 47: 4213–4217, 1987

    Google Scholar 

  51. Prados M, Rodriguez L, Seager M, Silver P, Levin V: Phase II study of spirohydantoin mustard for the treatment of recurrent malignant gliomas. Cancer Treat Rep 71(11): 1105–1106, 1987

    PubMed  Google Scholar 

  52. Vive-Peterson J, Bork E, Moller H, Hansen HH: A phase I clinical evaluation of 1-(2 chloroethyl-)-3-2-(dimethylamino-sulfonyl)-ethyl/-1-nitrosourea (TCNU). Eur J Canc Clin Oncol 23: 1837–1843, 1987

    Google Scholar 

  53. Whittle IR, Macpherson JS, Smyth JF, Miller JD: The disposition of TCNU in malignant glioma. Clinical and pharmacokinetic studies. J Neurosurg 72: 721–725, 1990

    PubMed  Google Scholar 

  54. O'Reilly SM, Newlands ES, Glaser MG, Brompton M, Rice Edwards JM, Illingworth RD, Richards PG, Kennard C, Colquhoun IR, Lewis P, Stevens MFG: Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumors. Eur J Cancer 29A (7): 940–942, 1993

    PubMed  Google Scholar 

  55. Stevens MFG, Newlands ES: From triazines and triazenes to temozolomide. Eur J Cancer 29A(7): 1045–1047, 1993

    PubMed  Google Scholar 

  56. Newlands ES, Blackledge GRP, Slack JA, Rustin GTS, Smith DB, Stuart NSA, Quarterman CP, Hoffman R, Stevens MFG, Brampton MH, Gibson AC: Phase I trial of temozolomide (CCRG81045: M & B 39831: NSC 362856). Br J Canc 65: 287–291, 1992

    Google Scholar 

  57. Stewart DJ, Eisenhauer E, Macdonald DR, Cairncross JG, Langleben A: Phase II study of tiazofurin in gliomas in adults. J Neuro Oncol 15: 175–179, 1993

    Google Scholar 

  58. Tirelli U, D'Incalci M, Canetta R, Tumulo S, Franchin G, Veronesi A, Galligioni E, Trovo MG, Rossi C, Grigoletto E: Etoposide (VP-16-213) in malignant brain tumors: a phase II study. J Clin Oncol 2(5): 432–437, 1984

    PubMed  Google Scholar 

  59. Chamberlain MC: Recurrent brainstem gliomas treated with oral VP-16. J Neuro Oncol 15: 133–139, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taylor, S.A. New agents in the treatment of primary brain tumors. J Neuro-Oncol 20, 141–153 (1994). https://doi.org/10.1007/BF01052724

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01052724

Key words

Navigation