|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Clinical Therapy Trails-Drug |
Department of Medicine, University of Wisconsin, Madison, WI 53792 (H.I.R., M.M.); University of California at San Francisco, San Francisco, CA 94143 (S.M.C., M.D.P., K.N.); University of Texas MD Anderson Cancer Center, Houston, TX 77030 (W.K.A.Y., K.H.); University of Pittsburgh, Pittsburgh, PA 15213 (D.S.); Department of Neurology, University of Michigan, MI 48109 (L.J., H.G.); University of Texas Southwestern at Dallas, Dallas, TX 75390 (K.F.); University of Texas at San Antonio, San Antonio, TX 78284 (J.G.K.); University of California at Los Angeles, Los Angeles, CA 90095 (T.C.)
2 Address correspondence and reprint requests to H. Ian Robins, Department of Medicine, University of Wisconsin Comprehensive Cancer Center K4/666, 600 Highland Ave., Madison, WI 53792.
Abstract
This phase II study in recurrent high-grade glioma evaluated the response rate, toxicities, and time to treatment failure of high-dose carboplatin modulated by a 24-h infusion of thymidine (75 g/m2). The trial was based on preclinical data and a prior phase I study (J. Clin. Oncol. 17, 2922-2931, 1999); a phase II recurrent high-grade glioma study was initiated in July of 1998. Thymidine was given over 24 h; carboplatin was given over 20 min at hour 20 of the thymidine infusion. The starting dose of carboplatin had a value of 7 for the area under the curve (AUC), with allowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity was observed. Treatment cycles were repeated every 4 weeks. Accrual as of September 1999 was 45 patients [4 were unevaluable]: 76% with glioblastoma multiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type, and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy (78%). As observed in the earlier phase I study (in which carboplatin pharmacokinetics were unaltered by thymidine or antiseizure medications), thymidine was myeloprotective, resulting in a minimal need for dose reduction for patients having a >2 grade toxicity (in only 4% of the courses of treatment). Of 101 total courses, the number of courses (at the AUCs) was 3 (5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 non-hematologic toxicities included headache (4%), altered consciousness (3%), fatigue (1%), and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM; 5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease (14.6%); and 30 progressive disease (73.2%). For GBM patients, median survival was 23 weeks (with a 95% confidence interval of 20 to 50 weeks), and progression-free survival was 8 weeks (with a 95% confidence interval of 7-16 weeks). These results in GBM were comparable to other phase II GBM trials and thus do not represent a therapeutic advance in the treatment of GBM. Taken collectively, however, results are consistent with continued investigation of thymidine in combination with chemotherapeutic agents for high-grade glioma and other malignant diseases. The significant myeloprotection afforded by thymidine may have particular relevance to polychemotherapeutic regimens.
References
Blumenreich, M.S., Woodcock, T.M., Andreeff, M., Hidemann, W.,
Chou, T.C., Vale, K., O'Hehir, M., Clarkson, B.D., and Yound, C.W.
(1984) Effect of very high-dose thymidine infusions on leukemia
and lymphoma patients. Cancer Res.
44,2203
-2207.
Cohen, J.D., and Robins, H.I. (1990) Thymidine enhancement of carboplatin cytotoxicity: In vivo studies in normal B6D2F1 mice. Cancer Lett. 55,39 -44.[CrossRef][Medline]
Cohen, J.D., Robins, H.I., Schmitt, C.L., and Tanner, M.A.
(1989) Interactions of thymidine, hyperthermia, and
cis-diammine-1, 1-cyclobutane dicarboxylate platinum (II) in human T cell
leukemia. Cancer Res.
49,5805
-5809.
Cohen, J.D., Robins, H.I., and Javid, M.J. (1990) Sensitization of C6 glioma to carboplatin cytotoxicity by hyperthermia and thymidine. J. Neurooncol. 9, 1-8.[CrossRef][Medline]
Fox, R.M. (1989) Changes in deoxynucleoside triphosphate pools induced by inhibitors and modulators of ribonucleotide reductase. In: Cory, J.G., and Cory, A.H. (Eds.), Inhibitors of Ribonucleoside Diphosphate Reductase Activity. New York: Pergamon Press. pp. 113-126.
Jordell, D.I., Egorin, M.J., Canetta, R.M., Langenberg, P.,
Goldbloom, E.P., Burroughs, J.N., Goodlow, J.L., Tan, S., and Wiltshaw, E.
(1992) Relationships between carboplatin exposure and tumor
response and toxicity in patients with ovarian cancer. J. Clin.
Oncol. 10,520
-528.
Kornblith, P.L., and Walker, M. (1988) Chemotherapy for malignant gliomas. J. Neurosurg. 68, 1-17.[Web of Science][Medline]
Kufe, D.W., Beardsley, P., Karp, D., Parker, L., Rosowsky, A.,
Canellos, G., and Frei, E., III. (1980a) High-dose thymidine
infusions in patients with leukemia and lymphoma.
Blood 55,580
-589.
Kufe, D.W., Egan, E.M., Rosowsky, A., Ensminger, W., and Frei, E., III. (1980b) Thymidine arrest and synchrony of cellular growth in vivo. Cancer Treat. Rep. 64,1307 -1317.[Medline]
O'Dwyer, P.J., King, S.A., Hoth, D.F., and Leyland-Jones, B.
(1987) Role of thymidinein biomedicalmodulation: A review.
Cancer Res. 47,3911
-3919.
Poisson, M., Pereon, Y., Chiras, J., and Delattre, J.Y. (1991) Treatment of recurrent malignant supratentorial gliomas with carboplatin (CBDCA). J. Neurooncol. 10,139 -144.[Medline]
Prados, M.D., Warnick, R.E., Mack, E.E., Chandler, K.L., Rabbitt, J., Page, M., and Malec, M. (1996) Intravenous carboplatin for recurrent gliomas: A dose escalating phase II trial. Am. J. Clin. Oncol. 19,609 -612.[CrossRef][Medline]
Raymond, E., Izbicka, E., Soda, H., Gerson, S.L., Dugan, M., and Von Hoff, D.D. (1997) Activity of temozolamide against human tumor colony-forming units. Clin. Cancer Res. 3,1769 -1774.[Abstract]
Robins, H.I., Tutsch, K., Katschinski, D.M., Mehta, M., Jacobson,
E., Olsen, M., Cohen, J.D., Tiggelaar, C.L., Arzoomanian, R.Z., Alberti, D.,
Feierabend, C., and Wilding, G. (1999) A Phase I trial of
intravenous thymidine and carboplatin in patients with advanced cancer.
J. Clin. Oncol. 17,2922
-2931.
Robins, H.I., Prados, M.D., Rao, D.R., Chang, S., Yung, A., Hess, K., Schiff, D., Greenberg, H., Fink, K., Nicolas, K., Kuhn, J., and Mehta, M. (2000) A phase II trial of thymidine and carboplatin for recurrent malignant glioma: A North American Brain Tumor Consortium (NABTC) study. In: ASCO (Ed.), Thirty-sixth Annual Meeting of the American Society of Clinical Oncology, May 20-24, 2000, New Orleans, Louisiana: Program/Proceedings, Vol. 19. Alexandra, Va.: ASCO p. 166a. (abstract)
Schultz, M.Z., Sandler, A.B., Durivage, H.J., and Cooper, D.L. (1996) A phase I study of BCNU plus thymidine in patients with refractory cancer. Cancer Invest. 14,218 -224.[Medline]
Tentori, L., Orlando, L., Lacal, P.M., Benincasa, E., Faraoni, I.,
Bonmassar, E., D'Atri, S., and Graziani, G. (1997) Inhibition of
O6-alkylguanine DNA-alkyltransferase or poly(ADP-ribose) polymerase
increases susceptibility of leukemic cells to apoptosis induced by
temozolomide. Mol. Pharmacol.
52,249
-258.
Warnick, R.E., Prados, M.D., Mack, E.E., Chandler, K.L., Doz, F., Rabbitt, J.E., and Malec, M.K. (1994) A phase II study of intravenous carboplatin for the treatment of recurrent gliomas. J. Neurooncol. 19,69 -74.[CrossRef][Medline]
Wedge, S.R., Porteous, J.K., and Newlands, E.S. (1996) 3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. Br. J. Cancer 74,1030 -1036.[Web of Science][Medline]
Wong, E.T., Hess, K.R., Gleason, M.J., Jaeckle, K.A., Kyritsis,
M.D., Prados, M.D., Levin, V.A., and Yung, W.K.A. (1999) Outcomes
and prognostic factors in recurrent glioma patients enrolled onto phase II
clinical trials. J. Clin. Oncol.
17,2572
-2578.
Yung, W.K.A., Mechtler, L., and Gleason, M.J. (1991) Intravenous carboplatin for recurrent malignant glioma: A phase II study. J. Clin. Oncol. 9,860 -864.[Abstract]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. M. Chang, K. R. Lamborn, J. G. Kuhn, W.K. A. Yung, M. R. Gilbert, P. Y. Wen, H. A. Fine, M. P. Mehta, L. M. DeAngelis, F. S. Lieberman, et al. Neurooncology clinical trial design for targeted therapies: Lessons learned from the North American Brain Tumor Consortium Neuro-oncol, August 1, 2008; 10(4): 631 - 642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Grossman, A. O'Neill, M. Grunnet, M. Mehta, J. L. Pearlman, H. Wagner, M. Gilbert, H. B. Newton, and R. Hellman Phase III Study Comparing Three Cycles of Infusional Carmustine and Cisplatin Followed by Radiation Therapy With Radiation Therapy and Concurrent Carmustine in Patients With Newly Diagnosed Supratentorial Glioblastoma Multiforme: Eastern Cooperative Oncology Group Trial 2394 J. Clin. Oncol., April 15, 2003; 21(8): 1485 - 1491. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
