DNA Mismatch Repair and 0 6 -Alkylguanine-DNA Alkyltransferase Analysis and Response to Temodal in Newly Diagnosed Malignant Glioma By Henry S. Friedman, Roger E. McLendon, Tracy Kerby, Margaret Dugan, Sandra H. Bigner, Andrew J. Henry, David M. Ashley, Jeff Krischer, Shelley Lovell, Karima Rasheed, Fred Marchev, Andrew J. Seman, Ilkcan Cokgor, Jeremy Rich, Elizabeth Stewart, O. Michael Calvin, James M. Provenzale, Darell D. Bigner, Michael M. Haglund, Allan H. Friedman, and Paul L. Modrich Purpose: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and 06-alkylguanine-DNA alkyltransferase (AGT). Patients and Methods: Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m 2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. Results: Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients devel-
hoped progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. Conclusion: These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal. J Clin Oncol 16:3851-3857. 1998 by American Society of Clinical Oncology.
TEMODAL (Schering-Plough Research Institute, Kenilworth, NJ) is an imidazole tetrazinone with a mechanism of action similar to that of dacarbazine, specifically through metabolic conversion to a common active intermediate, the methylating agent 5-(3-methyl)- 1-triazeu-1-yl)imidazole-4-carboxamide (MTIC). 1 Dacarbazine is extremely active in rodent sarcoma models but has been a disappointment in human clinical trials, in large part because of the relatively inefficient metabolic dealkylation that is required to form the active metabolite MTIC. Temodal, by virtue of oral administration and spontaneous conversion to MTIC under physiologic conditions, represents a more rational approach for methylation as an antineoplastic strategy.' Preliminary phase I and II trials in Britain initially showed the activity of Temodal in patients with recurrent high-grade glioma.23 A subsequent multiinstitutional trial has shown a high response rate produced by Temodal in patients with recurrent anaplastic astrocytoma (AA).4 These earlier trials, coupled with the marked activity of Temodal against a panel of CNS tumor xenografts in athymic nude mice,5 provided the foundation for a trial that evaluated Temodal in the treatment of patients with newly diagnosed malignant glioma. Furthermore, our demonstrations that 06-alkylguanine-DNA
alkyltransferase (AGT) activity or an acquired deficiency of DNA mismatch repair can produce resistance to methylating agents, such as procarbazine or Temodal, in human glioblastoma multiforme (GBM) xenografts 6 led us to investigate DNA mismatch repair status with response to Temodal in AGT status in newly diagnosed malignant gliomas. We now report the response rate to Temodal in patients with newly diagnosed malignant glioma and a low-level status of DNA mismatch repair AGT and high-level AGT status in nonresponders.
From the Departments of Surgery, Medicine, Radiology, Pathology, Pediatrics, and Biochemistry and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC; H. Lee Moffitt Cancer Center; and Schering-Plough Research Institute, Kenilworth, NJ. Submitted April 8, 1998; acceptedAugust 18, 1998. Supported in part by grants no. NS20023, NS30245, and CA57725 from the National CancerInstitute, Bethesda, MD. Address reprint requests to Henry S. Friedman, MD, Division of Pediatric Neuro-Oncology, DUMC-3624, Durham, NC 27710; Email
[email protected]. ©1998 by American Society of ClinicalOncology. 0732-183X/98/1612-0013$3.00/0
Journal of Clinical Oncology, Vol 16, No 12 (December), 1998: pp 3851-3857 Information downloaded from jco.ascopubs.org and provided by at Universidade de São Paulo on July 16, 2011 from Copyright © 1998 American Society of Clinical Oncology. All rights reserved. 143.107.79.203
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FRIEDMAN ET AL
PATIENTS AND METHODS Objectives The objective of the trial was to determine the efficacy of Temodal, defined as response rate, in the treatment of patients with newly diagnosed, supratentorial GBM or AA before radiation therapy.
Eligibility Patient eligibility included the following: (1) histologically confirmed, newly diagnosed supratentorial GBM or AA; (2) patients may or may not have had a surgical resection; however, patients must be treated within 28 days, inclusive of the date of surgery or biopsy, whichever is the later date; (3) age of 18 years or older; (4) evidence of at least one bidimensional measurable enhancing lesion, documented on gadolinium magnetic resonance imaging (MRI) within 72 hours after surgical resection or greater than 14 days after surgery. The patients had to be on a nonincreasing dose of corticosteroids for at least 7 days before the baseline scan for all scans except the postoperative scan performed within 72 hours of surgery. (5) Karnofsky performance status of 70% or greater; (6) absolute neutrophil count (ANC) greater than 1,500 cells/pL and platelet count greater than 125,000 cells/ipL; (7) serum creatinine, blood urea nitrogen, and bilirubin levels less than 1.5 times the upper limit of laboratory normal and serum AST level less than 2.5 times the upper limit of normal; (8) patients who received corticosteroids must have received a stable dose for 1 week before the administration of Temodal; (9) signed informed consent approved by the institutional review board before patient entry; and (10) if sexually active, women were required to use contraceptive measures for the duration of the treatment. Exclusion criteria included the following: (1) pregnancy; (2) prior radiation therapy, interstitial brachytherapy, or radiosurgery to the brain or the need for immediate radiation therapy; (3) prior chemotherapy; (4) surgical resection within 2 weeks before study-drug administration; (5) frequent vomiting or a medical condition that could interfere with oral medication intake; (6) previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in situ of the cervix and basal or squamous cell carcinoma of the skin; and (7) known HIV positivity or AIDS-related illness.
DrugAdministration and Dose Modifications Temodal was supplied by Schering-Plough Research Institute as a machine-filled, white, opaque, preservative-free, two-piece hard gelatin capsule available in 250-, 100-, 20-, and 5-mg strengths. Temodal was administered orally on an empty stomach with approximately 100% bioavailability. The dose was rounded to the nearest 5 mg. Patients in a fasting state received Temodal orally once daily for 5 consecutive days (days 1 through 5) at a starting dose of 200 mg/m 2 daily. Treatment cycles were repeated every 28 days after the first daily dose of Temodal from the previous cycle (Table 1). Water was allowed during the fasting period (minimum of 1 hour before the administration of each dose of Temodal). Patients continued fasting 2 hours after the administration of each Temodal dose. Temodal was administered with approximately 8 ounces of water over as short a time as possible. Patients were instructed to swallow, without chewing, whole capsules in rapid succession. If vomiting occurred during the course of treatment, no re-dosing of the patient was allowed before the next scheduled dose. In the absence of disease progression or unacceptable toxicity, patients continued to receive treatment with Temodal for up to a maximum of four cycles before radiotherapy. Growth factors were not used to induce elevations in neutrophil counts for the purposes of
administration of Temodal on the schedule dosing interval or to allow treatment with Temodal at a higher dose. If Temodal was not administered on the scheduled day of dosing, the complete blood count was repeated weekly for up to and including 3 weeks until the ANC was greater than 1,500/pL and the platelet count was greater than 100,000/pL. If these hematologic criteria were met, chemotherapy was administered according to dose adjustments as follows: no dose modification for an ANC nadir of 1,000/pL or greater or platelet nadir of 50,000/pL or greater and a 50-mg/m 2 decrease in dosage for ANC nadir less than 1,000/pL or platelet nadir less than 50,000/pL. If the ANC remained less than 1,500/pL or platelet count less than 100,000/pL at 3 weeks, the patient no longer received Temodal and was immediately referred for radiation therapy. Patients who required dose reductions to a dose level of less than 100 mg/m 2 daily no longer received Temodal. For clinical toxicity criteria grades 3 and 4 nonhematologic toxicity, the dosage for the subsequent cycle was reduced by two dose levels (but no less than 100 mg/m2 daily). If these events recurred, the patient was withdrawn from the study. If no further common toxicity criteria grades 3 or 4 nonhematologic toxicity occurred on subsequent repeat dosing, then the total dose administered for the next cycle was the same as the dosage administered during the previous cycle.
Evaluations Patients underwent physical and neurologic examinations, hematology tests and chemistries, and MRI scans before every 4-week cycle. Hematologic parameters were evaluated on day 21.
Tumor Response Criteria Complete response (CR) was defined as the disappearance of all measurable enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids except for physiologic doses that may be required after prolonged therapy, and neurologically stable or improved. Partial response (PR) was defined as lesions that were either all measurable or all nonmeasurable, a 50% reduction or greater (< 100%) in the sum of the products of the largest perpendicular diameters of contrast enhancement for all measurable lesions or definitely better for all nonmeasurable lesions on consecutive MRI scans, steroid dose stable for 7 days before each scan at the same dose administered at the time of the previous scan or at a reduced dose, and neurologically stable or improved. No new lesions could arise. For patients with multifocal disease that included both measurable and nonmeasurable lesions, PR was defined as follows: evidence of residual enhancing tumor in which all measurable lesions met the overall radiologic response criteria of either CR or PR and no nonmeasurable lesions rated as definitely worse on the overall radiologic response scale on consecutive MRI scans at least 1 month apart, steroid dose stable for 7 days before each scan at the same dose administered at the time of the previous scan or at a reduced dose, and neurologically stable or improved. No new lesions could arise. Progressive disease (PD) was defined as a 25% or greater increase in the size of the product of the largest perpendicular diameters of contrast enhancement for any measurable lesions or definitely worse for any nonmeasurable lesions or any new tumor on MRI scans, and steroid dose stable for 7 days before each scan at the same dose administered at the time of the previous scan or at an increased dose, with or without neurologic progression. Stable disease (SD) was defined as all other situations.
Information downloaded from jco.ascopubs.org and provided by at Universidade de São Paulo on July 16, 2011 from Copyright © 1998 American Society of Clinical Oncology. All rights reserved. 143.107.79.203
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TEMODAL IN MALIGNANT GLIOMAS
Table 1. Patient Demographics and Trial Results Patient No.
Age (years)
Sex
Histology
Surgery
No. of Cycles of Temodal
Response toTemodal
MSH2
Staining MLH1
AGT
100 100 100 100 100
10-20 1-5 1-5 0 5-10 0 5-10 0
301 302 303 304 305
63 57 67 60 30
F M F M M
GBM GBM GBM GBM GBM
STR STR STR BX STR
1 4 2 1 4
PD PR PR/PD PR CR
100 100 100 100 100
306 307 308
56 61 35
M F M
GBM GBM GBM
BX BX; STR STR
4 3 4
PR CR/PD PR
100 100 90
90 100 70
309 310
55 70
F M
GBM GBM
STR STR
4 4
PR/PD PD
100 100
100 100
311
63
M
GBM
STR
4
SD
100
100
312 313 314 315
48 66 42 53
M M F F
GBM GBM GBM GBM
STR BX STR STR
1 1 4 4
PD PD SD CR*
100 100 10 100
100 100 20 100
316
60
M
GBM
STR
3
PD
90
90
317 318 319 320
55 68 67 52
F M M F
GBM GBM GBM GBM
BX BX BX STR
4 6 4 4
PR PR PR PR
100 100 95 90
100 100 95 90
321 322 323
71 54 56
F M F
GBM GBM GBM
STR BX BX
3 1 4
PR/PD PD PR
80 100 100
50 95 100
324 325 326
55 50 54
M M M
GBM GBM GBM
STR STR BX; STR
4 2 4
SD PD PR
100 100 100
100 100 100
327 328 329
56 69 29
M M F
GBM GBM GBM
BX BX STR; STR
1 1 4
PD PD SD
100 100 60
100 100 80
330 331
44 54
M M
GBM GBM
STR STR
1 4
PD PR
100 100
100 100
332
40
F
GBM
STR
2
PD
100
100
333 1
43 39
M F
GBM AA
STR STR
2 4
PD SD
100 100
100 10
2
34
M
AA
STR
4
SD
100
70
3 4 5
47 32 36
M F M
AA AA AA
BX STR BX
4 1 2
PR/PD PD PD
100 60 10
90 100 100
Subsequent Therapies PD thru XRT XRT-CPT-11 x 1 (PD) XRT (PD) XRT (sepsis) XRT-Mab-CCNU x 2-VP16-tamoxifen (PD) XRT (fell) XRT(PD)-CPT-11 x 2(PD) XRT-CCNU
Status Died Died Died Died Alive without progressive tumor Died Died Alive without progressive tumor Alive with progressive tumor Died
XRT (PD)-radiosurgery XRT (PR)-CCNU x 3 (PD)VP-16 x 2 (SD) 5-10 XRT(PD)-CPT-1 x 1 (PD)Alive with progressive tumor Topo/BCNU x 1 (PD)tamoxifen
