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Superiority of PCNU over AZQ in the treatment of primary brain tumors: results of a prospective randomized trial (81-20) by the brain tumor study group

Summary

Purpose

A two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment ofde novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies.

Methods

During 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75–100 mg/m2 intravenously (IV) every 8 weeks or AZQ 15 mg/m2 IV once a week for 4 weeks, every 6–8 weeks. All patients who had not received ‘full dose’ radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review.

Results

Median survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p=0.01) and the VSG (p=0.02). Lifetable analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p=0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups.

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References

  1. 1.

    Shapiro WR, Green SB, Burger PCet al.: A randomized comparison of intra-arterial versus intravenous BCNU, with or without intravenous-5-fluorouracil, for newly diagnosed patients with malignant glioma. J Neurosurg 76(5): 772–781, 1992

  2. 2.

    Wood JR, Green SB, Shapiro WR: The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol 6(2): 338–343, 1988

  3. 3.

    Walker MD, Alexander E Jr, Hunt WEet al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J Neurosurg 49: 333–343, 1978

  4. 4.

    Walker MD, Strike TA, Sheline GE: An analysis of doseeffect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5: 1725–1731, 1979

  5. 5.

    Walker MD, Green SB, Byar DPet al.: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant gliomas after surgery. N Engl J Med 303(23): 1323–1329, 1980

  6. 6.

    Green SB, Byar DB, Strike TAet al.: Randomized phase II comparison of PCNU and AZQ for the treatment of primary brain tumors (Study 8120). Proc Am Soc Clin Oncol 4: 143, 1985 (abstr)

  7. 7.

    Montgomery JA, Mayo JG, Hansch C: Quantitative structure-activity relations in anticancer agents. Activity of selected nitrosoureas against a solid tumor, the Lewis lung carcinoma. J Med Chem 17: 477–480, 1974

  8. 8.

    Rahman Aet al.: Pharmacologic disposition of 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea (PCNU) in mice. Proc Am Assoc Cancer Res 22: 296, 1981 (abstr)

  9. 9.

    Rahman A, Luc PV, Schein PSet al.: Pharmacological disposition of 1-(2-chloroethyl-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea in mice. Cancer Res 44(1): 149–153, 1984

  10. 10.

    Clinical Brochure — PCNU (NSC 95466). National Cancer Institute, Division of Cancer Treatment, Cancer Treatment Evaluation Program, Investigational Drug Branch. July, 1978

  11. 11.

    Annual Report to the Food and Drug Administration — PCNU (NSC 95466), IND14598. National Cancer Institute, Division of Cancer Treatment, Cancer Treatment Evaluation Program, Investigational Drug Branch. October, 1980

  12. 12.

    Kahn AH, Driscoll JS: Potential central nervous system antitumor agents. Aziridinyl-benzoquinones 1. J Med Chem 19: 313–317, 1976

  13. 13.

    Chou F, Kahn AH, Driscoll JS: Potential central nervous system antitumor agents. Aziridinyl-benzoquinones 2, J Med Chem 19: 1302–1308, 1976

  14. 14.

    Egorin JM, Bellis EH, Salcman Met al.: The pharmacology of diaziquone given in intravenous or intracarotid infusion to normal and intracranial tumor-bearing puppies. J Neurosurg 60(5): 1005–1013, 1984

  15. 15.

    Clinical Brochure — AZQ (NSC 182986). National Cancer Institute, Division of Cancer Treatment, Cancer Treatment Evaluation Program, Investigational Drug Branch. August, 1979

  16. 16.

    Friedman HS, Bigner SH, Schold SCet al.: The use of experimental models of human medulloblastoma in the design of rational therapy. In: Walker MD, Thomas DOT (eds) Biology of Brain Tumor. Boston, Martinus Nijhoff, 1986, pp 405–409

  17. 17.

    Taylor SA, McCracken JD, Eyre HJet al.: Phase II study of aziridinylbenqozuinone (AZQ) in patients with central nervous system malignancies: A Southwest Oncology Group study. J Neurooncol 3(2): 131–135, 1985

  18. 18.

    Frytak S, Eagan RT, Ames MMet al.: Phase I study of diaziquone. Cancer Treat Rep 68(7–8): 975–978, 1984

  19. 19.

    Minutes of the Phase I Working Group Meeting. National Cancer Institute, Division of Cancer Treatment, Cancer Treatment Evaluation Program, Investigational Drug Branch. December 2, 1980

  20. 20.

    Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemo Rep 50: 163–170, 1966

  21. 21.

    Cox DR: Regression models and life tables. J R Stat Soc (B) 34: 187–202, 1972

  22. 22.

    Dinapoli RP, Brown L, Buckner Jet al.: Phase III comparative evaluation of PCNU and BCNU combined with radiation therapy (RT) for high-grade glioma: a collaborative trial of the North Central Treatment Group and Mayo Clinic. Neurology 41 (Suppl 1): 382, 1991 (abstr)

  23. 23.

    Brown L, Buckner J, Dinapoli Ret al.: Comparative toxicities of PCNU versus BCNU as adjuvant chemotherapy for patients with high-grade glioma. Proc Am Soc Clin Oncol 9: A360, 1990 (abstr)

  24. 24.

    Allen JC, Hancock C, Walker Ret al.: PCNU and recurrent childhood brain tumors. J Neurooncol 5(3): 241–244, 1987

  25. 25.

    Ragab AH, Burger P, Badnitsky Set al.: PCNU in the treatment of recurrent medulloblastoma and ependymoma. A POG study. J Neurooncol 3(4): 341–342, 1986

  26. 26.

    Feun LG, Maor M, Stewart DJet al.: Pilot study of PCNU and cranial radiation therapy in the treatment of patients with malignant gliomas. Oncology 47(5): 389–392, 1990

  27. 27.

    Eagan RT, Dinapoli RP, Cascino TLet al.: Comprehensive phase II evaluation of aziridinylbenzoquinone (AZQ, Diaziquone) in recurrent human primary brain tumors. J Neurooncol 5(4): 309–314, 1987

  28. 28.

    Castleberry RP, Ragab AH, Steuber CPet al.: Aziridinyl-benzoquinone (AZQ) in the treatment of recurrent pediatric brain and other malignant solid tumors. A Pediatric Oncology Group phase II study. Invest New Drugs 8(4): 401–406, 1990

  29. 29.

    Castleberry RP, Ragab AH, Steuber CPet al.: A phase II study of aziridinylbenzoquinone (AZQ) in recurrent pediatric brain and other solid tumors. Proc Am Soc Clin Oncol 6: A858, 1987 (abstr)

  30. 30.

    Ettinger LJ, Ru N, Krailo Met al.: A phase II study of diaziquone in children with recurrent or progressive primary brain tumors: a report from the Childrens Cancer Study Group. J Neurooncol 9(1): 69–76, 1990

  31. 31.

    Tapazoglou E, Lee M, Simpson Jet al.: Concurrent aziridinylbenzoquinone (AZQ) chemotherapy and radiotherapy (RT) in patients with malignant gliomas: RTOG study. Proc Am Soc Clin Oncol 7: A329, 1988 (abstr)

  32. 32.

    Chamberlain MC, Prados MD, Silver Pet al.:A phase I/II study of 24 hours intravenous AZQ in recurrent primary brain tumors. J Neurooncol 6(4): 319–323, 1988

  33. 33.

    Haid M, Khandekar JD, Merrill JMet al.: Phase II aziridinylbenzoquinone (AZQ) therapy of recurrent or progressive glioma (ROPG) of the central nervous system (CNS): final report. Proc Am Soc Clin Oncol 6: A266, 1987 (abstr)

  34. 34.

    Feun LG, Yung WK, Leavens MEet al.: A phase II trial of 2,5-diaziridinyl 3,6-bis(carboethoxyamino)1,4-benzoquinone (AZQ), NSC 182986) in recurrent primary brain tumors. J Neurooncol 2(1): 13–17, 1984

  35. 35.

    Tapazoglou E, Kish J, Ensleyet al.: Response rate and toxicity with aziridinylbenzoquinone in patients with recurrent gliomas. A progress report. Am J Clin Oncol 11(4): 474–478, 1988

  36. 36.

    Yung WKA, Harris MI, Bruner JMet al.: Intravenous BCNU and AZQ in patients with recurrent malignant gliomas. J Neurooncol 7 (3): 237–240, 1989

  37. 37.

    Decker DA, Al-Sarraf M, Kresge Cet al.: Phase II study of aziridinylbenzoquinone (AZQ: NSC-182986) in the treatment of malignant gliomas recurrent after radiation. Preliminary report. J Neurooncol 3(1): 19–21, 1985

  38. 38.

    Schold SC Jr, Friedman HS, Bjornsson TDet al.: Treatment of patients with recurrent primary brain tumors with AZQ. Neurology 34(5): 615–619, 1984

  39. 39.

    Green SB, Shapiro WR, Burger PCet al.: Randomized comparison of intraarterial (IA) cisplatin and intravenous (IV) PCNU for the treatment of primary brain tumors (BTCG Study 8420A). Proc Am Soc Clin Oncol 8: 86, 1989

  40. 40.

    Schold SC Jr, Herndon JE, Burger PCet al.: Randomized comparison of diaziquone and carmustine in the treatment of adults with anaplastic glioma. J Clin Oncol 11(1): 77–83, 1993

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Author information

Correspondence to Mark G. Malkin.

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Deceased

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Malkin, M.G., Green, S.B., Byar, D.P. et al. Superiority of PCNU over AZQ in the treatment of primary brain tumors: results of a prospective randomized trial (81-20) by the brain tumor study group. J Neuro-Oncol 22, 55–65 (1994). https://doi.org/10.1007/BF01058355

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Key words

  • brain tumors
  • radiation therapy
  • PCNU
  • AZQ