Phase II study of concurrent continuous Temozolomide (TMZ) and Tamoxifen (TMX) for recurrent malignant astrocytic gliomas
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Journal of Neuro-Oncology 70: 91–95, 2004.
2004 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical Study
Phase II study of concurrent continuous Temozolomide (TMZ) and
Tamoxifen (TMX) for recurrent malignant astrocytic gliomas
Alexander M. Spence, Richard A. Peterson, Jeffrey D. Scharnhorst, Daniel L. Silbergeld and
Robert C. Rostomily
Departments of Neurology and Neurological Surgery, University of Washington School of Medicine, Seattle,
WA, USA
Key words: anaplastic astrocytoma, glioblastoma multiforme, phase II, Tamoxifen, Temozolomide
Summary
Purpose and background: The aim of this study was to assess the frequency of response and toxicity in adults
with recurrent anaplastic astrocytoma (AA) or glioblastoma multiforme (GM) treated with concurrent
continuous TMZ and TMX.
Methods: In addition to histology, eligibility included age >18 years, Karnovsky score ‡60, normal
laboratory parameters, no radiotherapy (RT) for 4 weeks, measurable disease and normal EKG. The chief
exclusions were: previous TMZ, TMX or dacarbazine (DTIC); nitrosourea within 6 weeks; history of deep
venous thrombosis or pulmonary emboli. All patients (pts) had received prior RT. TMZ was given at
75 mg/M2/day for 6 weeks, repeated every 10 weeks, maximum 5 cycles. Four pts received 60 mg/M2/day
for 6 weeks due to extensive prior chemotherapy exposure. TMX was started at 40 mg twice daily (b.i.d.)
for 1 week and then was increased in three successive weeks to 60, then 80, then 100 mg b.i.d. Response was
assessed before every cycle with MRI ± gadolinium (Gd).
Results: Sixteen pts enrolled: GM 10, AA 6; female 6, male 10; median age 48 (21–58); prior chemo-
therapy 7. There was one partial response and one stable disease. Eleven pts progressed by the end of cycle
1; three pts failed due to toxicity before completing cycle 1. Median time to treatment failure was 10 weeks.
The main toxicities were: transaminitis, pancytopenia, 1st division herpes zoster, deep vein thrombosis and
fatigue. The study was closed due to the low response rate and frequency of toxicity.
Introduction M2/day repeated every 28 days. The most frequent
toxicities were gastrointestinal, namely, nausea
Temozolomide was developed and tested in the and vomiting, and hematologic. There were 17
early 1990s by Newlands and coworkers who glioma patients, a mix of low and high grade, from
established the schedule of 150–200 mg/M2/day which seven demonstrated objective responses and
for 5 days repeated every 28 days [1–3]. The chief six maintained stable disease. These results have
mechanisms of action include alkylation of N-7 encouraged additional trials with this schedule
guanine and depletion of alkyl transferase [4–7]. [12,16,18].
The drug has now been widely tested for treatment Experience with high-dose TMX alone
of gliomas of several types in both phase II and for recurrent high grade gliomas suggests a 20–
phase III settings [8–15]. Additional phase I work 40% response plus stabilization rate [19,20].
reported in 1996–1998 established the feasibility Distinct from TMZ, the mechanism of action
and safety of continuous TMZ at 75 mg/M2/day of high-dose TMX in gliomas is thought to be
for 6 weeks [6,16,17]. This schedule permits a mainly protein kinase C inhibition and inter-
2.1-fold greater drug exposure per 4 weeks in ference with downstream signal transduction
comparison with the 5 day schedule of 200 mg/ [21–26].92
The goals of the present study were to assess the increase in the same measurements with stable or
frequency of response and toxicity of the combi- worsening neurological examination or appear-
nation of TMZ and TMX at high doses since both ance of new lesion(s). Stable disease (SD) was any
of these agents have shown activity against other response.
malignant gliomas and demonstrate non-overlap-
ping mechanisms of action and toxicity.
Results
Methods Sixteen patients enrolled in the study (Table 1).
There were 10 GM and 6 AA; 6 female, 10 male.
Adult patients over 18 years with recurrences of The median age was 48 years with a range of
either AA or GM following RT were sought for the 21–58. All patients had received prior RT. In three
study. Measurable disease on MRI T1 with Gd was patients the RT included fast neutrons [27,28].
required. The Karnovsky performance score Seven patients had received prior chemotherapy.
requirement was ‡60. Adequate hematologic One patient completed 5 cycles (PR) and one
parameters, liver function and renal function along completed 1 cycle plus a week (SD) before dying
with normal electrocardiogram were required. No suddenly at home. Nine completed 1 cycle but
RT for 4 weeks was allowed. One prior chemo- progressed. Two progressed before completing
therapy was allowed including carmustine (BCNU) 10 weeks of cycle 1 but had completed the 6 weeks
wafers, if progression was confirmed by positron of TMZ. Three came off study before completing 1
emission tomography with [18F]fluorodeoxyglu- cycle and did not complete 6 weeks of TMZ in
cose. Patients were excluded if they had received cycle 1 due to toxicity. Median time to treatment
previous chemotherapy with TMZ, TMX or DTIC failure was 10 weeks (Figure 1). Median survival
or had received a nitrosourea within 6 weeks. Hi- from time of initiation of protocol treatment was
story of deep venous thrombosis or pulmonary 26 weeks. The main toxicities were: transaminitis
embolism were additional exclusions. The proce- grade (gr) III, 2 pts; pancytopenia gr IV, 1 pt; 1st
dures followed were in accordance with ethical division herpes zoster gr III, 1 pt; deep vein
standards of the University of Washington Human
Subjects Committee. Informed consent was ob-
tained from the patient or a responsible relative. Table 1. Patient data (n = 16)
Temozolomide was prescribed at 75 mg/M2/day
for 6 weeks, repeated every 10 weeks with a max- Age (years) Median 48 range 21–58
imum of 5 cycles. For patients that had received No. %
extensive prior chemotherapy the starting dose
was 60 mg/M2/day for 6 weeks. Sex
Tamoxifen was administered at 40 mg b.i.d. for Male 10 63
1 week, then escalated to 60 mg b.i.d. for 1 week, Female 6 37
then 80 mg b.i.d. for 1 week, then 100 mg b.i.d. Histology
for the maintenance continuous dose. GM 10 63
Patients were evaluated for response after every AA 6 37
cycle of therapy by clinical and radiographic cri- Karnovsky score
teria. Complete response (CR) was disappearance 70 6 38
of all disease on CT or MRI (with contrast) with 80 2 13
stable or improving neurological examination 90 7 44
without any increase in steroid dose persisting for 100 1 6
at least 10 weeks (one cycle length). Partial re- Prior Radiotherapy 16 100
sponse (PR) was a 50% or greater reduction in the
Prior Chemotherapy 7 44
sums of the products of the cross-sectional diam-
eters of the lesion(s) persisting for at least 10 weeks Cycle 1 dose TMZ
with the same clinical and steroid requirements. 75 mg/M2/day 12 75
60 mg/M2/day 4 25
Progressive disease (PD) was greater than 25%93
Survival After TMZ/TMX
Time to Treatment Failure
1 1
Median 10 Median 26
.8 .8
.6 .6
.4 .4
.2 .2
0 0
0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90
Time (weeks) Time (weeks)
Figure 1. Kaplan–Meier plots of the time to treatment failure (left) and survival after onset of treatment with TMZ and TMX (right).
thrombosis gr IV, 2 pts; and fatigue gr III, 1 pt. based regimen that included PCB in 21 or carbo-
Thus, from 16 patients there was 1 PR, 1 SD, 11 platin plus teniposide. There were 2 CR, 13 PR
PD and 3 who failed in cycle 1 due to toxicity. and 17 SD but time to progression and median
survival time were not increased.
In the report of Chang et al. 18 pts with recur-
Discussion rent gliomas of all grades were treated with TMX
at 240 mg/M2/day plus alpha interferon [32]. Be-
The dose and schedule of continuous TMZ of cause of side effects of moderate to severe revers-
75 mg/M2/day was determined in Phase I work ible dizziness and unsteady gait, the dose of TMX
and the response and stable disease rates were was reduced to 120 mg/M2/day. Despite this dose
encouraging [6,16,17]. Since this schedule permits reduction, the severity of these neurological tox-
a 2.1-fold greater drug exposure per 4 weeks in icities lead the authors to close the investigation.
comparison to the standard 5-day schedule of In 16 evaluable pts there was 1 minor response, 3
200 mg/M2/day repeated every 28 days, it was se- SD and 12 PD.
lected for testing in combination with high dose One small study of recurrent gliomas combined
continuous TMX. However, Khan et al. reported TMZ and TMX, but the pts had been previously
a phase II study of 35 patients with recurrent treated with TMX. Therefore, these results are not
malignant gliomas treated with TMZ alone at comparable to ours [33].
75 mg/M2/day for 42 days in cycles of 70 days From this brief review, it is apparent that there
[18]. There were PRs in 2 patients with AA and are no studies directly comparable to the present
marginal responses in 3 patients with GM. Median one. Our study was too small to determine whether
progression free survival and overall survival were the two drugs, TMZ and TMX, at some level,
2.5 and 8.7 months, respectively. These authors interfere with each other’s mechanism of action.
felt that the results did not support an improved Nor did it determine whether TMZ at the con-
rate of response or survival. ventional dose and schedule in combination with
Prior experience with high-dose TMX alone for TMX might have done better or worse. In com-
recurrent high grade gliomas, on the other hand, parison to the major studies that initially evaluated
suggests a 20–40% response plus stabilization rate TMZ, the results of the present study suggest no
[19,20,29,30]. Other investigators have combined trend of improvement and discourage additional
high-dose TMX with other agents for recurrent efforts with the doses and schedules reported here
malignant astrocytic gliomas, e.g., procarbazine [14,15].
(PCB) [31] or alpha interferon [32].
The study of Brandes et al. included 53 pts
treated with PCB at 100 mg/M2/day plus TMX Acknowledgement
100 mg/day in repeated 30-day courses, with a 30-
day interval between courses [31]. All cases had This study was supported by Schering Plough
received prior chemotherapy with a nitrosourea- Corporation.94
References concomitant radiation plus temozolomide followed by
adjuvant temozolomide. J Clin Oncol 20: 1375–1382, 2002
1. Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith 13. van den Bent MJ, Chinot O, Boogerd W, Bravo Marques
DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, J, Taphoorn MJ, Kros JM, van der Rijt CC, Vecht CJ, De
Brampton MH, Gibson AC: Phase I trial of temozolomide Beule N, Baron B: Second-line chemotherapy with tem-
(CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65: ozolomide in recurrent oligodendroglioma after PCV
287–291, 1992 (procarbazine, lomustine and vincristine) chemotherapy:
2. Newlands ES, O’Reilly SM, Glaser MG, Bower M, Evans EORTC Brain Tumor Group phase II study 26972. Ann
H, Brock C, Brampton MH, Colquhoun I, Lewis P, Rice- Oncol 14: 599–602, 2003
Edwards JM, Illingworth RD, Richards PG: The Charing 14. Yung WK, Albright RE, Olson J, Fredericks R, Fink K,
Cross Hospital experience with temozolomide in patients Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W,
with gliomas. Eur J Cancer 32A: 2236–2241, 1996 Glantz M, Greenberg H, Selker RG, Vick NA, Rampling
3. Stevens MF, Newlands ES: From triazines and triazenes to R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D,
temozolomide. Eur J Cancer 29A: 1045–1047, 1993 Zaknoen S, Levin VA: A phase II study of temozolomide
4. Baer JC, Freeman AA, Newlands ES, Watson AJ, Rafferty vs. procarbazine in patients with glioblastoma multiforme
JA, Margison GP: Depletion of O6-alkylguanine-DNA at first relapse. Br J Cancer 83: 588–593, 2000
alkyltransferase correlates with potentiation of temozolo- 15. Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada
mide and CCNU toxicity in human tumour cells. Br J M, Friedman HS, Albright R, Olson J, Chang SM, O’Neill
Cancer 67: 1299–1302, 1993 AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen
5. Lee SM, Thatcher N, Crowther D, Margison GP: Inac- S, Levin VA: Multicenter phase II trial of temozolomide in
tivation of O6-alkylguanine-DNA alkyltransferase in hu- patients with anaplastic astrocytoma or anaplastic oligo-
man peripheral blood mononuclear cells by temozolomide. astrocytoma at first relapse. Temodal Brain Tumor
Br J Cancer 69: 452–456, 1994 Group. J Clin Oncol 17: 2762–2771, 1999
6. Newlands ES, Stevens MFG, Wedge SR, Wheelhouse RT, 16. Brock CS, Newlands ES, Wedge SR, Bower M, Evans H,
Brock C: Temozolomide: a review of its discovery, Colquhoun I, Roddie M, Glaser M, Brampton MH, Rustin
chemical properties, pre-clinical development and clinical GJ: Phase I trial of temozolomide using an extended
trials. Cancer Treatment Rev 23: 35–61, 1997 continuous oral schedule. Cancer Res 58: 4363–4367, 1998
7. Mitchell RB, Dolan ME: Effect of temozolomide and 17. Newlands ES, Rustin GJS, Evans H, Wedge SR, Bramp-
dacarbazine on O6-alkylguanine-DNA alkyltransferase ton MH: Phase I trial of oral temozolomide administered
activity and sensitivity of human tumor cells and xeno- over 6 and 7 weeks. In: Proc Ninth NCI-EORTC Sympo-
grafts to 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Che- sium on New Drugs in Cancer Therapy. 1996, p 345
mother Pharmacol 32: 59–63, 1993 18. Khan RB, Raizer JJ, Malkin MG, Bazylewicz KA, Abrey
8. Brada M, Hoang-Xuan K, Rampling R, Dietrich PY, LE: A phase II study of extended low-dose temozolomide
Dirix LY, Macdonald D, Heimans JJ, Zonnenberg BA, in recurrent malignant gliomas. Neuro-Oncology 4: 39–43,
Bravo-Marques JM, Henriksson R, Stupp R, Yue N, 2002
Bruner J, Dugan M, Rao S, Zaknoen S: Multicenter phase 19. Couldwell WT, Weiss MH, DeGiorgio CM, Weiner LP,
II trial of temozolomide in patients with glioblastoma Hinton DR, Ehresmann GR, Conti PS, Apuzzo ML:
multiforme at first relapse. Ann Oncol 12: 259–266, 2001 Clinical and radiographic response in a minority of
9. Cefalo G, Ruggiero A, Abate ME, Massimino M, patients with recurrent malignant gliomas treated
Zucchetti P, Mascarin M, Garre ML, Spreafico F, with high-dose tamoxifen. Neurosurgery 32: 485–489, 1993
Mastrangelo S, Clerico S, Ridola V, Mazzarella G, Di 20. Vertosick FTJ, Selker RG, Pollack IF, Arena V: The
Ricco C, Donfrancesco A, Perilongo G, Lazzareschi I, treatment of intracranial malignant gliomas using orally
Sandri S, Riccardi R: High response rate to temozolomide administered tamoxifen therapy: preliminary results in a
in heavily pretreated children and young adults with series of ‘failed’ patients. Neurosurgery 30: 897–902, 1992
medulloblastoma. Neuro-Oncology 4(Suppl 1): S18, 2002 21. Ahn SJ, Yoon MS, Hyuk S, Han W, Yoon YD, Han JS,
10. Gilbert MR, Friedman HS, Kuttesch JF, Prados MD, Noh DY: Phospholipase C-protein kinase C mediated
Olson JJ, Reaman GH, Zaknoen SL: A phase II study of phospholipase D activation pathway is involved in tamox-
temozolomide in patients with newly diagnosed supra- ifen induced apoptosis. J Cell Biochem 89: 520–528,
tentorial malignant glioma before radiation therapy. 2003
Neuro-Oncology 4: 261–267, 2002 22. Baltuch GH, Couldwell WT, Villemure J-G, Yong VW:
11. Soffietti R, Costanza A, Ducati A, Laguzzi E, Nobile M, Protein kinase C inhibitors suppress cell growth in
Ruda R: Response of recurrent/progressive ependymomas established and low-passage glioma cell lines. A compar-
to temozolomide. Neuro-Oncology 5: 398–399, 2003 ison between staurosporine and tamoxifen. Neurosurgery
12. Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, 33: 495–501, 1993
Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, 23. Couldwell WT, Hinton DR, He S, Chen TC, Sebat I,
Miralbell R, Porchet F, Regli L, de Tribolet N, Mirima- Weiss MH, Law RE: Protein kinase C inhibitors induce
noff RO, Leyvraz S: Promising survival for patients with apoptosis in human malignant glioma cell lines. FEBS Lett
newly diagnosed glioblastoma multiforme treated with 345: 43–46, 199495
24. Couldwell WT, Uhm JH, Antel JP, Yong VW: Enhanced grade glioma: a report of clinical stabilization and tumour
protein kinase C activity correlates with the growth rate of regression. Can J Neurol Sci 20: 168–170, 1993
malignant gliomas in vitro. Neurosurgery 29: 880–886, 30. Chamberlain MC, Kormanik PA: Salvage chemotherapy
1991 with tamoxifen for recurrent anaplastic astrocytomas.
25. Horgan K, Cooke E, Hallett MB, Mansel RE: Inhibition Arch Neurol 56: 703–708, 1999
of protein kinase C mediated signal transduction by 31. Brandes AA, Ermani M, Turazzi S, Scelzi E, Berti F,
tamoxifen. Importance for antitumour activity. Biochem Amista P, Rotilio A, Licata C, Fiorentino MV: Procarba-
Pharmacol 35: 4463–4465, 1986 zine and high-dose tamoxifen as a second-line regimen in
26. Vertosick FTJ: The role of protein kinase C in the growth recurrent high-grade gliomas: a phase II study. J Clin
of human gliomas: implications for therapy. Cancer Oncol 17: 645–650, 1999
Journal 5: 328–331, 1992 32. Chang SM, Barker FG, Huhn SL, Nicholas MK, Page M,
27. Diaz AZ, Rajendran J, Spence AM, Krohn KA, Laramore Rabbitt J, Prados MD: High dose oral tamoxifen and
GE: Early toxicity and 18F-fluoromisonidazole positron subcutaneous interferon alpha-2a for recurrent glioma. J
emission tomography results in a prospective phase II trial Neuro-Oncol 37: 169–176, 1998
of fast neutron radiotherapy to decrease the hypoxic 33. Caroli M, Locatelli M, Campanella R, Beretta F, Farina
volume in glioblastoma multiforme followed by a photon G, Scanni A, Arienta C: Adjuvant chemotherapy after
radiotherapy boost (Abs 167). Neuro-Oncology 4: 353, surgery of high grade gliomas: the role of tamoxifen and
2002 temozolomide (Abs 353). Neuro-Oncology 3: 355–356,
28. Stelzer KJ, Tralins K, Mankoff DA, Silbergeld DL, 2001
Laramore GE, Spence AM: Fast neutron irradiation
based on fluoro-deoxyglucose positron emission tomogra-
phy (FDG-PET) and MRI localization for treatment of
glioblastoma multiforme (Abs 207). Neuro-Oncology 2: Address for offprints: Alexander M. Spence, M.D., Department
296, 2000 of Neurology, 356465, University of Washington, Seattle, WA
29. Baltuch G, Shenouda G, Langleben A, Villemure J-G: 98195, USA; Tel.: +1+206-543-2340; Fax: +1-206-685-8100;
High dose tamoxifen in the treatment of recurrent high E-mail: aspence@u.washington.eduYou can also read
