Skip to main content
SpringerLink
Log in

A Prospective Blinded Study of the Predictive Value of an Extreme Drug Resistance Assay in Patients Receiving CPT-11 for Recurrent Glioma

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

Abstract

This adjunct to a prospective phase II blinded study of 48 patients with recurrent malignant glioma evaluated the predictive reliability of an extreme drug resistance (EDR) to identify clinical resistance to irinotecan (CPT-11), using fresh tumor biopsies obtained from recurrent patients immediately prior to their first dose of CPT-11 therapy. In vitro tumor response to SN38 (bioactive species of CPT-11 used in the EDR assay) determined prior to treatment was correlated with objective response, time to tumor progression (TTP) and survival following the administration of CPT-11. SN38 activity was tested in 19 of 29 tumors, with 15 of 18 assay results evaluable for correlation with clinical outcomes. In vitro drug resistance was classified as either extreme, intermediate (IDR), or low (LDR). TTP and survival were estimated by the Kaplan–Meier method, and compared using the Mantel–Haenszel log-rank and Fisher's exact test statistics. In vitro tumor response was bifurcated into either EDR (n = 4) or IDR/LDR (n = 11) categories for comparison with outcomes. Results correlated significantly with both TTP and survival. Median TTP for IDR/LDR cases was 3 months versus 6 weeks for EDR cases (log-rank test; p = 0.0288, hazards ratio = 3.06). A 13-week median survival for EDR cases was significantly shorter compared to 38 weeks for IDR/LDR cases (p = 0.029). Further, 100-day survival favored the IDR/LDR cases (Fisher's exact test; p = 0.008). At last follow-up, two of three survivors were patients who had tumors IDR/LDR to SN38. These prospective data support the notion that patients should avoid agents to which their tumor demonstrates EDR.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Silverberg E, Lubera JA: Cancer statistics. CA Cancer J Clin 39(1): 3-20, 254 and 399 (comments), 1989

    Google Scholar 

  2. Walker AE, Robins M, Weinfeld FD: Epidemiology of brain tumors: the national survey of intracranial neoplasms. Neurology 35: 219-226, 1985

    Google Scholar 

  3. Hochberg FH, Pruitt AA: Assumptions in the radiotherapy of glioblastoma. Neurology 30: 907-911, 1980

    Google Scholar 

  4. Friedman H, Cokgor I, Kerby T, Lawless A, Rich J, Stewart E, Rasheed K, Affronti M, Tourt-Uhlig S, Provenzale J, McLendon R, Colvin O, Bigner D, Malczyn J, Friedman A, Miller L: Phase I trial of CPT-11 plus BCNU in malignant glioma. Proc Am Soc Clin Oncol 18: 150a, A577, 1999

    Google Scholar 

  5. Colvin OM, Cokgor I, Ashley DM, Kerby T, Arbuck S, Malczyn J, Miller L, Cloughesy T, Houghton PJ, Rich J, Friedman AH, Friedman HS: Irinotecan treatment of adults with recurrent or progressive malignant glioma. Proc Am Soc Clin Oncol 17: 387a, A1493, 1998

    Google Scholar 

  6. Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughesy T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17: 1516-1525, 1999

    Google Scholar 

  7. Reid J, Buckner J, Schaaf L, Novotny P, Wright K, Kimmel D, Miller L: Pharmacokinetics of irinotecan (CPT-11) in recurrent glioma patients: results of an NCCTG phase II trial. Proc Am Soc Clin Oncol 18: 141a, A540, 1999

    Google Scholar 

  8. Filka E, Nelson G, Friedman H, Kabbinavar F, Miller L, Menco H, Cloughesy T: Intrapatient dose escalation of irinotecan in patients with recurrent malignant glioma receiving anticonvulsants. Proc Am Soc Clin Oncol 18: 144a, A552, 1999

    Google Scholar 

  9. Rothenberg ML, Kuhn JG, Burris HA III, Nelson J, Eckardt JR, Tristan-Morales M, Hilsenbeck SG, Weiss GR, Smith LS, Rodriguez GI et al.: Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11(11): 2194-2204, 1993

    Google Scholar 

  10. de Forni M, Bugat R, Chabot GG, Culine S, Extra JM, Gouyette A, Madelaine I, Marty ME, Mathieu-Boue A: Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients. Cancer Res 54(16): 4347-4354, 1994

    Google Scholar 

  11. Negoro S, Fukuoka M, Masuda N, Takada M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Niitani H, Taguchi T: Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small cell lung cancer. J Natl Cancer Inst 83: 1164-1168, 1991

    Google Scholar 

  12. Abigerges D, Armand JP, Chabot GG, Da Costa L, Fadel E, Cote C, Herait P, Gandia D: Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86: 446-449, 1994

    Google Scholar 

  13. Abigerges D, Chabot GG, Armand JP, Herait P, Gouyette A, Gandia D: Phase I and pharmacologic studies of the camptothecin analogue irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13: 210-221, 1995

    Google Scholar 

  14. Masuda N, Fukuoka M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Negoro S, Nishioka M, Nakagawa K, Takada M: CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10: 1225-1229, 1992

    Google Scholar 

  15. Ohno R, Okada K, Masaoka T, Kuramoto A, Arima T, Yoshida Y, Ariyoshi H, Ichimaru M, Sakai Y, Oguro M et al.: An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol 8: 1907-1912, 1990

    Google Scholar 

  16. Tsuda H, Takatsuki K, Ohno R, Masaoka T, Okada K, Shirakawa S, Ohashi Y, Ota K: Treatment of adult T-cell leukemia-lymphoma with irinotecan hydrochloride (CPT-11). CPT-11 study group on hematological malignancy. Br J Oncol 70(4): 771-774, 1994

    Google Scholar 

  17. Ptiot HC: US pivotal studies of irinotecan in colorectal carcinoma. Oncology 12(8 Suppl. 6): 48-53, 1998

    Google Scholar 

  18. Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA III, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14: 1128-1135, 1996

    Google Scholar 

  19. Pitot HC, Wender DB, O'Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE: Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15: 2910-2919, 1997

    Google Scholar 

  20. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ: Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54: 3723-3725, 1994

    Google Scholar 

  21. Takimoto CH, Arbuck S: The camptothecins. In: Chabner BA and Longo DL (eds) Cancer Chemotherapy and Biotherapy. 2nd edn., Lippincott-Raven Publishers, Philadelphia, 1996, pp. 463-484

    Google Scholar 

  22. Hsiang YH, Liu LF: Identification of mammalian DNA topo-I as an intracellular target for the anticancer drug camptothecin. Cancer Res 48: 1722-1726, 1988

    Google Scholar 

  23. Voigt W, Matsui S, Yin MB, Burhans WC, Minderman H, Rustum YM: Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis. Anticancer Res 18: 3499-3505, 1998

    Google Scholar 

  24. Sun M, Duann P, Lin CT, Zhang H, Liu LF: Rapid chromatin structural alteration induced by topoisomerase I-mediated DNA damage. Ann NY Acad Sci 922: 340-342, 2000

    Google Scholar 

  25. Mehta RS, Cloughesy T, Parker R, Fruehauf JP: Predictive value of extreme drug resistance assay in patients receiving CPT-11 for recurrent glioma: a prospective trial. Proc Am Soc Clin Oncol 18: 219a, A843, 1999

    Google Scholar 

  26. Kern DM, Weisenthal LM: Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. J Natl Cancer Inst 82: 582-588, 1990

    Google Scholar 

  27. Mehta R, Bornstein R, Yu I-R, Parker RJ, McLaren CE, Nguyen KP, Li K-T, Fruehauf JP: Breast cancer survival and in vitro tumor response in the extreme drug resistance assay. Breast Cancer Res Treat 66: 225-237, 2001

    Google Scholar 

  28. Holloway RW, Mehta RS, Finkler NJ, Li K-T, McLaren CE, Parker RJ, Fruehauf JP: Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients. Gynecol Oncol 87: 8-16, 2002

    Google Scholar 

  29. Mechetner E, Kyshtoobayeva A, Zonis S, Kim H, Stroup R, Garcia R, Parker RJ, Fruehauf JP: Levels of multidrug resistance (MDR1) p-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin. Clin Cancer Res 4: 389-398, 1998

    Google Scholar 

  30. Kern DH, Drogemuller CR, Kennedy MC, Hildebrand-Zanki SU, Tanigawa N, Sondak VK: Development of miniaturized, improved nucleic acid-precursor incorporation assay for chemosensitivity testing of human solid tumors. Cancer Res 45: 5436-5441, 1985

    Google Scholar 

  31. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assn 53: 457-481, 1958

    Google Scholar 

  32. Parker RJ, Kyshtoobayeva A, Mehta R, Brem H, Brem S, Vanier V, Barger G, Fruehauf JP: In vitro drug response and prognostic marker profiles in primary brain tumors. Proc Am Assn Cancer Res 41: 257, A1637, 2000

    Google Scholar 

  33. Kaneda N, Nagata H, Furuta T, Yokokura T: Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 50: 1715-1720, 1990

    Google Scholar 

  34. Fruehauf JP, Bosanquet AG: In vitro determination of drug response: a discussion of clinical applications. PPO Update 7: 1-17, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oncotech, Inc., Tustin, CA, USA

    Ricardo J. Parker, John P. Fruehauf & Rita Mehta

  2. Department of Medicine, Division of Hematology/Oncology, University of California, Irvine, CA, USA

    John P. Fruehauf & Rita Mehta

  3. Henry E. Singleton Brain Cancer Research Program, School of Medicine, University of California, Los Angeles, CA, USA

    Emese Filka & Timothy Cloughesy

Authors
  1. Ricardo J. Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John P. Fruehauf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rita Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emese Filka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Timothy Cloughesy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parker, R.J., Fruehauf, J.P., Mehta, R. et al. A Prospective Blinded Study of the Predictive Value of an Extreme Drug Resistance Assay in Patients Receiving CPT-11 for Recurrent Glioma. J Neurooncol 66, 365–375 (2004). https://doi.org/10.1023/B:NEON.0000014549.77646.f6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:NEON.0000014549.77646.f6

Search

Navigation