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Tumori, 94: 674-680, 2008
Carboplatin and oral cyclophosphamide
combination after temozolomide failure
in malignant gliomas
Emel Yaman, Suleyman Buyukberber, Aytug Uner, Ugur Coskun,
Deniz Yamac, Banu Ozturk, Ali Osman Kaya, Ramazan Yıldız,
Mustafa Benekli for the Anatolian Society of Medical Oncology (ASMO)
Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey
ABSTRACT
Background. Temozolomide is a novel cytotoxic agent for malignant gliomas. How-
ever, treatment failure occurs approximately in half of patients, and the optimal regi-
men in this setting has yet to be defined. In the present study, we assessed retrospec-
tively the efficacy and toxicity of the combination of carboplatin and oral cyclophos-
phamide in temozolomide-resistant patients.
Methods. We evaluated the medical records of 30 patients with malignant gliomas. Af-
ter failure of temozolomide therapy, patients were treated with a combination of car-
boplatin and oral cyclophosphamide. Treatment consisted of intravenous carbo-
platin AUC 6 (based on the Calvert Formula) on day 1 and oral cyclophosphamide 75
mg/m2 daily on days 1 to 14, followed by 14 days of rest, with the treatment repeated
every 4 weeks.
Results. All patients were evaluated for response and toxicity. The objective response
rate was 30%, including 9 partial responses. Median time to disease progression and
median overall survival was 7 months and 8 months, respectively. Clinically respon-
sive patients had statistically significant longer progression-free survival and overall
survival than unresponsive patients. Hematological side effects were commonly ob-
served toxicities, with neutropenia the most frequent.
Conclusions. Our data suggest that carboplatin and oral cyclophosphamide therapy
is a convenient regimen after failure of temozolomide therapy in patients with malig-
nant gliomas because of its activity, feasibility and tolerability. Further prospective
studies are needed in this setting.
Introduction
Treatment of malignant gliomas is palliative; results are usually dismal. Median sur-
vival is usually less than 1 year1,2. Until recently, radiotherapy following optimal re-
section was the standard therapy, due to the chemo-resistant nature of the tumor.
Key words: carboplatin, cyclophos-
Nowadays, temozolomide is the most promising agent in malignant gliomas, with a
phamide, malignant gliomas, temo-
2-year survival rate of 26% in glioblastoma multiforme and 35% in anaplastic astro- zolomide refractory.
cytoma3-6. Unfortunately, despite the hopeful results with temozolomide, no re-
sponse was observed in approximately half of the patients or progression occurred Correspondence to: Prof Dr Suleyman
only after a short time. The optimal management of these patients is somewhat un- Buyukberber, Gazi University Faculty
clear, and there is no accepted therapy. A wide variety of drugs including irinotecan of Medicine, Director of Medical On-
in combination with carmustine7, PCV (procarbazine, vincristine, CCNU)8, imatinib cology Department, Ankara, Turkey.
mesylate and hydroxyurea combination9-11, erlotinib12, gefitinib13 and bevacizumab Tel 00-90-312-2025830;
fax 00-90-312-2158710;
plus irinotecan14,15 are under evaluation in this respect.
e-mail buyukberber@gazi.edu.tr
Carboplatin and cyclophosphamide are both effective alkylating agents in the treat-
ment of malignant glioma16-22. Their combination showed some activity in patients Received November 11, 2007;
with unresectable tumors at the pre-irradiation setting in a phase II study21. accepted May 28, 2008.
CARBOPLATIN AND CYCLOPHOSPHAMIDE IN TEMOZOLOMIDE-REFRACTORY GLIOMAS 675
This is the first report on a carboplatin and oral cy- on MRI, and worsening of the neurological condition
clophosphamide regimen in temozolomide-refractory with corticosteroid doses remaining stable or increas-
malignant glioma patients. ing. Stable disease (SD) meant other conditions.
Treatment plan
Patients and methods
Treatment consisted of intravenous carboplatin AUC
6 (based on the Calvert formula) and cyclophos-
Patients
phamide, 75 mg/m2 daily on days 1 to 14, followed by 14
We retrospectively evaluated the medical records of days of rest, and repeated every 4 weeks.
30 patients with high-grade malignant gliomas who re-
ceived intravenous carboplatin and oral cyclophos- Toxicity and dosage modifications
phamide combination between May 2005 and March
Patients were closely monitored throughout the
2007.
chemotherapy cycles for toxicity, especially hematolog-
Patients with high-grade malignant gliomas that had
ical. Hematological and non-hematological toxicity was
a recurrence after curative radiotherapy and prior temo-
graded according to National Cancer Institute Common
zolomide resistance were eligible for the study. Temo-
Toxicity Criteria scale25. In case of any grade 3-4 hema-
zolomide failure was defined as clinical or radiological
tological or reversible grade 3 non-hematological toxic-
progression within 6 months of completion of temo-
ities (except nausea or vomiting), drug doses were re-
zolomide treatment. All patients had to have
duced by 25% for subsequent cycles. Treatment was in-
histopathologically proven high-grade malignant
terrupted if any grade 4 non-hematologic toxicity or af-
glioma based on The 2000 World Health Organization
ter dose reduction recurrent grade 3-4 hematological or
(WHO) scheme23 and measurable intracranial disease
grade 3 non-hematological toxicity was observed. Treat-
by contrast-enhanced magnetic resonance imaging
ment was delayed for up to 2 weeks if any symptomatic
(MRI) of the cranium. If radiation necrosis was suspect-
toxicity persisted, or in cases of grade 3-4 leukopenia
ed, spectroscopic MRI was performed to exclude radia-
tion necrosis. Other inclusion criteria were: age 18-75 and thrombocytopenia. Colony-stimulating factors
years, Karnofsky performance status (KPS) >50, life ex- were allowed only for patients with grade 4 neutropenia
pectancy longer than 3 months, and a 4-week interval or patients with a febrile neutropenia attack. Erythro-
after the last chemotherapy cycle. Patients with prior cyte transfusions were used in patients with grade 4
malignancies other than basal cell carcinoma or cervi- anemia or symptomatic patients with grade 3 anemia.
cal carcinoma in situ, psychiatric disorder and uncon-
Statistical analysis
trolled infections were excluded. Additionally, pregnant
or lactating women were not allowed to participate in Progression-free survival (PFS) was defined as the pe-
the study. riod from the start of the chemotherapy to the first ob-
Patients were required to have adequate bone morrow servation of disease progression or death from any
(white blood cell count >3 x 109/l, platelets >100 x 109/l, cause. Overall survival (OS) was defined as the period
hemoglobulin >10g/dl), liver (total billirubin <2 mg/dl, from the first day of treatment until the date of last fol-
aspartate aminotransferase or alanine aminotrans- low-up or death. Based on the intention-to-treat princi-
ferase <3 x the upper limit of normal) and renal (blood ple, data on all enrolled patients were used in the statis-
urea nitrogen <30 mg/dl, creatinine <1.5 x the upper tical analysis. PFS at 6 months was calculated. PFS and
limit of normal) functions. Anti-epileptics and corticos- OS were estimated by the Kaplan-Meier method. Sur-
teroids were allowed to control neurological signs and vival curves were compared with the logrank test. P val-
symptoms. ues of less than 0.05 were accepted as significant.
Primary objectives of the study were to evaluate the
Response evaluation efficacy and toxicity of the carboplatin and oral cy-
Responses to treatment were evaluated after every 3 clophosphamide regimen as second-line therapy based
cycles by contrast-enhanced MRI of the cranium, ac- on response to therapy, PFS, PFS at 6 months, OS, and
cording to WHO criteria24. Responses were defined as: OS at 1 year).
complete response, disappearance of all enhancing and
non-enhancing tumor on MRI, improved neurological
status without corticosteroid usage); partial response, Results
reduction of more than 50% of the lesion size on the two
largest tumor diameters, stable or improved neurologi- Patients
cal status with the corticosteroid doses being stable or A total of 30 patients were evaluated retrospectively.
decreasing; progressive disease, an increase of more All patients were adequate for response and toxicity.
than 25% in tumor size, the appearance of new tumor Twenty-two (73.3%) were male and 8 (26.7%) were fe-
676 E YAMAN, S BUYUKBERBER, A UNER ET AL
male. Median age was 46 years (range, 22-65). Charac- 1.2
teristics of the patients are shown in Table 1.
A total of 129 cycles of chemotherapy was adminis-
tered, with a median of 4 cycles per patient (range, 2-8). 1.0
The duration of chemotherapy ranged from 2 to 8
months (median, 6).
Estimated probability
.8
Efficacy and survival
The objective response rate (ORR) was 30%. Partial re- .6
sponse was achieved in 9 (30%) patients, and 11 (36.7%)
patients had disease stabilization for more than 3
months. Two (6.7%) partial responses were observed in .4
prior temozolomide-refractory patients. No complete
response was noted. The patients were followed for a
.2
median of 8 months (range, 3-22). Survival data was last
updated in November 2007(Figures 1-2). Median PFS
was 7 months (95% CI, 4.5-9.5). Patients with a clinical 0.0
response (objective response and stabile disease) had 0 10 20 30
significantly longer PFS than unresponsive patients (10
vs 3 months) (P <0.001) (Figure 3). Six-month and 1-year PFS (months)
PFS rates were 51% and 20%, respectively. However, no
Figure 1 - Progression-free survival (PFS).
Table 1 - Patient characteristics
Characteristic No. (%) Anaplastic Glioblastoma 1.2
astrocytoma multiforme
No. of patients (%) 30 (100) 7 (23.3) 23 (76.7)
1.0
KPS
Median 80 75 80
80-100 17 (56.7) 5 (29.4) 12 (70.6)
Estimated probability
50-70 13 (43.3) 2 (15.4) 11 (84.7) .8
Gender
Male 22 (73.3) 7 (31.8) 15 (68.2)
Female 8 (26.7) 0 (0) 8 (100) .6
Age (yr)
<50 19 (63.3) 4 (21) 15 (79)
>50 11 (36.7) 3 (27.3) 8 (72.7) .4
Time from the end
of radiotherapy
to enrollment (mo) .2
Median 6 11.5 6
Range 3-30 4-30 3-12
0.0
Best response to prior
0 10 20 30
temozolomide therapy
Partial response 6 (20) 0 (0) 6 (100)
Stabile disease 8 (26.7) 0 (0) 8 (100) Overall survival (months)
Progressive disease 16 (53.3) 7 (30.8) 9 (69.2)
Time to progression Figure 2 - Overall survival (OS).
after prior
temozolomide
therapy
3-6 months 18 (60) 3 (16.7) 15 (83.3)
<3 months 12 (40) 4 (33.3) 8 (66.7) correlation was found between PFS and age, KPS,
Second surgical
histopathological diagnosis (grade III or IV), prior
intervention before temozolomide response, or prior response duration
treatment (data not shown).
Yes 2 (10) 1 (50) 1 (50) Median OS was 8 months (95% CI, 5.75-10.25) (Figure
No 28 (90) 6 (21.4) 22 (78.6)
2). In clinically responsive patients, OS was significantly
KPS, Karnofsky performance status. longer than in the unresponsive patients (12 vs 5
CARBOPLATIN AND CYCLOPHOSPHAMIDE IN TEMOZOLOMIDE-REFRACTORY GLIOMAS 677
1.2 Toxicity
The carboplatin and oral cyclophosphamide combi-
1.0 nation was usually well tolerated. Adverse events are
summarized in Table 2. Hematological toxicity (all
.8
grades) was reported by 24 (80%) patients. Most toxici-
Estimated probability
ties were moderate. Ten (33.3%) patients experienced
P <0.001 grade 3-4 neutropenia; one of them was complicated
.6 with neutropenic fever (3.3%). Six (20%) of them re-
quired prophylactic colony-stimulating factor. Only 2
.4 (6.7%) patients had grade 3 thrombocytopenia; no
Response
grade 4 thrombocytopenia was observed. Grade 4 ane-
.2 mia is observed in 1 patient (3.3%) who required ery-
throcyte transfusion; subsequently, a dose reduction of
Yes carboplatin by 25% was done in the patient. In 8 pa-
0.0
tients, chemotherapy cycles were delayed by a median
of 2 weeks (range, 2-4) due to grade 4 neutropenia (in 5
-.2 No
patients) or grade 3 thrombocytopenia (in 3 patients).
2 4 6 8 10 12 14 16 18 20 Grade 3-4 nausea and vomiting were reported in 6 (20%)
P FS (m onths) patients. Four patients (13.3%) had mild neuropathy. In
one patient, chemotherapy was interrupted because of
Figure 3 - Progression-free survival among responders and nonre- prolonged myelosupression. There was no chemothera-
sponders (P <0.001). py-related death.
Discussion
months) (P <0.001) (Figure 4). The survival rate at 6
months and at 1 year was 63% and 29%, respectively. No Treatment of malignant glioma is a common chal-
statistically significant correlation was observed be- lenge among physicians. Cellular resistance mecha-
tween OS and KPS, histopathological diagnosis (grade nisms, altered pharmacokinetics of cytotoxic agents
III or IV), age, prior temozolomide response or prior re- due to concomitant anti-convulsant drug usage26-28,
sponse duration (data not shown). and low penetration rates of systemic chemotherapeu-
tic drugs into cerebrospinal fluid and brain may lead to
chemotherapy resistance. Malignant glioma treatment
has changed dramatically in recent years with the intro-
duction of temozolomide. Even though results of temo-
1.2 zolomide treatment have been better than any other
regimen, with better tolerability, it gives an objective re-
1.0 sponse in only 10% of patients and disease stabilization
in another 53% of patients29. After temozolomide fail-
Estimated probability
ure, the optimal strategy to increase survival has not yet
.8
been determined. Neither re-resection strategies30-32
P <0.001 nor stereotactic surgery methods33-34 are effective in this
.6 population. New administration schedules of temozolo-
mide35-36 and second-line chemotherapy regimens have
.4
Response
.2
No Table 2 - Common toxicity
0.0
Toxicity No. of patients (%)
-.2 Yes All grades Grade 3-4
0 10 20 30
Neutropenia 24 (80) 10 (41.7)
Overall survival (months) Thrombocytopenia 5 (16.7) 2 (40)
Anemia 3 (10) 2 (66.7)
Figure 4 - Overall survival among responders and nonresponders Nausea/vomiting 14 (46.7) 6 (42.8)
Neuropathy 4 (13.3) 0 (0)
(P <0.001).
678 E YAMAN, S BUYUKBERBER, A UNER ET AL
been studied7,9-11,14. Here, we have presented our expe- clophosphamide combination. The regimen yielded a
rience with carboplatin and oral cyclophosphamide clinical benefit in 19.5% of patients without any surgical
combination after temozolomide failure in terms of ef- resection.
ficacy and safety in malignant gliomas. We observed a clinical benefit of 66.7% (ORR + SD) af-
The data about chemoresistant patients with malig- ter the carboplatin and oral cyclophosphamide combi-
nant gliomas are conflicting due to the heterogeneity of nation as second-line therapy in malignant gliomas.
previous treatment schedules. Most available studies Our response rates are similar to literature data attained
included patients who received cytotoxic drugs other with combination regimens in phase II studies7,9,10,14.
than temozolomide. After nitrosourea failure, temo- Moreover, with a median follow-up of 8 months (range,
zolomide yielded an objective response rate of 5.4-19% 3-22), median PFS and median OS were 7 and 8 months,
with a median PFS of 11.7-12.4 weeks3,37. Our results, respectively.
with an objective response rate of 30% and disease sta- Age and KPS of patients have been shown to be im-
bilization rate of 36.7%, are comparable with those of portant prognostic factors in malignant glioma pa-
temozolomide regimens at first relapse. Moreover, our tients41-43. However, we found no correlation between
study demonstrated a median PFS of 7 months and 6- age or KPS and PFS or OS. Additionally, tumor grade was
month and 1-year PFS of 51% and 20%, respectively. The another determinant of patient survival, but we found
favorable results of the current study can be explained no difference in terms of PFS and OS. This may be due
by 2 theories. Firstly, the current regimen included a to the small number of patients: only 7 patients at grade
platinum agent which has relatively high cerebrospinal III histology and 23 patients at grade IV.
fluid penetration rates. In addition, in recent years, cis- The toxicity reported by Viñolas et al21 with the carbo-
platin has been added to temozolomide to increase the platin and cyclophosphamide regimen was high; all pa-
response rates and PFS38-40. Secondly, although alter- tients experienced myelosupression at least in the sec-
ations in pharmacokinetics of some chemotherapeutics ond cycle. Interestingly, in their patients, the median
due to concomitant anti-epileptic usage have been re- KPS was 90 before the treatment and median age was 49
ported26-28, no data is present about the interaction be- years. In contrast, the current combination was general-
tween anti-epileptics and carboplatin or cyclophos- ly well tolerated, with only 5% of patients requiring dose
phamide. reduction. Bone marrow toxicity was moderate, and
There is limited data in the literature concerning ther- 25% of patients required supportive therapy, although
apy after temozolomide failure. Brandes et al.7 reported the KPS of our patients was slightly lower – a median of
that irinotecan and BCNU combination resulted in a 70 with a similar median age. The difference in toxicity
clinical benefit rate of 71.4% (ORR + SD) in patients with profile between the two studies may be related to the in-
temozolomide failure. Median PFS and median OS were creased dose of carboplatin: 200 mg/m2 during 3 days
17 weeks and 11.7 months, respectively. However, one by Viñolas et al. and AUC 6 according to the Calvert For-
patient (2.4%) required dose reduction and 2 patients mula in our study.
(4.8%) required interruption of chemotherapy due to Although this is a retrospective study, response rates
toxicity. Similarly, imatinib and hydroxyurea as a sec- and survival data are very similar to those observed in
ond-line choice after temozolomide failure yielded a other studies performed in temozolomide-refractory
clinical benefit in 57% of patients10,11 with a median PFS patients. Moreover, the current regimen was generally
of 10 weeks and median OS of 19 weeks. Viñolas et al.21 well tolerated. In conclusion, the carboplatin and oral
showed that a single-agent cyclophosphamide regimen cyclophosphamide regimen may be a choice when
had a clinical benefit rate of 45%, with 2 months and 4 temozolomide resistance is the problem. More random-
months median PFS and median OS, respectively. An ized data are needed in this regard.
unfavorable effect of this regimen was the high toxicity
rates: grade 3 and 4 toxicity was noted in 28% and 3% of
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