Journal of Neuro-Oncology 10: 139-144, 1991. © 1991KluwerAcademic Publishers. Printedin the Netherlands. Clinical Study
Treatment of recurrent malignant supratentorial gliomas with carboplatin (CBDCA) M. Poisson, 1 Y. P6r60n, 1 J. Chiras 2 and J.Y. Delattre 1 1Department of Neurology, 2 Department of Neuroradiology, La Salp6tridre, Paris, France
Key words: recurrent malignant glioma, carboplatin Summary
Twenty patients with malignant supratentorial gliomas progressing after radiation therapy and chemotherapy with nitrosoureas received intravenous carboplatin, 450 mg/m 2. Courses of therapy were repeated every four weeks. Therapeutic evaluation was performed monthly using neurologic examination and CT scan of the brain. Of 19 patients evaluable for response, 2 (10%) responded to therapy and 6 (30%) had stable disease. The estimated median time to tumor progression for responding and stable patients was 6 months. Median duration of survival was 6 months for all patients. Of 20 patients evaluable for toxicity, none had renal or auditory toxicity. Side effects consisted of hematologic toxicity in 4 patients (20%): one patient had grade 4 toxicity requiring discontinuation of carboplatin and 3 patients had grade 2-3 toxicity. Abbreviation: HECNU - 1-(2-chloroethyl)-l-nitroso-3-(2-hydroxyethyl) urea
The treatment of malignant gliomas is disappointing. When surgery, radiation therapy and chemotherapy with a nitrosourea are used the median time to tumor progression is about 8 months [1]. At this stage, a few patients may benefit from reoperation. Reirradiation is highly neurotoxic and there is no benefit to expect when another nitrosourea is used. Therefore, the only alternative is often to try another class of chemotherapeutic drug. Platinum analogues are possible second line chemotherapeutic agents for recurrent malignant gliomas. Aida and Bodell [2] did not find cross resistance between chlornitrosoureas and cisplatinum on human malignant gliomas cell lines. Intraarterial infusions of cisplatin have been occasionally useful in patients with recurrent malignant gliomas, including patients previously treated with nitrosoureas [3]. Unfortunately, intraarterial cisplatin may induce severe neurological and ophthalmological complications [3]. Intravenous cisplatin has been success-
ful in various neoplasms including CNS malignancies [4] but the administration of this drug was associated with a variety of toxicites. Carboplatin (cis-diammine-1, 1-cyclobutane dicarboxylate platinum II) is a second generation cisplatin analogue that has shown less GI toxicity, neurotoxicity and renal toxicity than the parent compound [5]. Carboplatin is as effective as cisplatin in several human tumors [6, 7]. Furthermore, carboplatine crosses the blood-brain barrier to a greater extent than cisplatin [8]. We undertook a phase II study of carboplatine for recurrent malignant supratentorial gliomas.
Patients and methods
Twenty patients suffering from recurrent malignant supratentorial gliomas received intravenous infusions of carboplatin (Table 1). There were 12
140
men and 8 women aged 30 to 70 years (mean 49). Tumor histology was glioblastoma multiforme in 10 patients, anaplastic astrocytoma in.7 patients, anaplastic oligodendroglioma in 2 patients. In one patient, the diagnosis of malignant glioma was made by CT scan and angiography. Patients had been previously treated with surgery, radiation therapy and chemotherapy. Surgery was performed in 19/ 20 patients (1 had complete resection, 11 had partial resection and 7 had tumor biopsy). All patients had received radiation therapy: 19 patients had received a dose of 50 to 60 Gray using 1.8 Gy per fraction 5 times a week on a generous focal field (including the tumor and adjacent parenchyma) and 1 patient had received a course of whole brain radiation therapy delivering 30 Gy in 10 fractions over two weeks. All patients had received nitrosoureas: 8 patients had intraarterial (IA) H E C N U (mean cumulative dose of 525 mg), 10 patients had IA H E C N U and intravenous (IV) BCNU or CCNU per os (PO) (mean cumulative dose of 900 mg) and 2 patients had IV BCNU or PO CCNU (mean cumulative dose of 800 mg). Each patient had received a mean number of 4 courses of nitro-
soureas and the median time to tumor progression following onset of nitrosoureas was 7.5 months. Tumor progression was documented by clinical examination showing neurological deterioration and by evidence of tumor progression on successive CT scan or magnetic resonance image scan (MRI). Mean Karnofsky index prior to carboplatin infusions ranged from 40 to 90 (mean, 60). Maximum diameter of the area of contrast enhancement on CT ranged from 20 to 100 mm. Eligibility requirements included WBC > 3 4 0 0 m m 3, platelets >130 000ram 3, hemoglobin > 10g/dl. In addition, serum creatinin, transaminases, and bilirubin levels had to be within normal limits. Carboplatin was administered IV at a dose of 450 mg per meter square (with a maximum dose of 1000mg) [9]. Courses of therapy were repeated every four weeks. The number of courses per patient ranged from 1 to 11 (mean, 4). Neurological and GI tolerance was judged on clinical examinations repeated every four weeks. Patients were also followed by blood counts, measurement of blood urea nitrogen, serum creatinin and SGOT repeated every 2 weeks. Therapeutic effects was
Table 1. Patients characteristics Total number of patients Sex (M/F) Mean age (range) Mean Karnofsky index at onset of carboplatin, (range) Histology of the tumor • Glioblastoma multiforme • Anaplastic astrocytoma • Anaplastic oligodendroglioma • Unknown Previous treatments • Surgery • Radiation therapy • Chemotherapy with nitrosoureas Intraarterial Intraarterial and systemic Systemic Largest diameter of contrast enhancement on CT (ram) at onset of carboplatin • 20-40 mm • >40mm Evaluable for toxicity Evaluable for response
20 12 M/8 F 49 years (30-70) 60 (40-90) Number of patients 10 7 2 1 19 20 20 8 2 10 5 15 20 19
141 judged using Karnofsky scale and CT examinations. Patients were considered responders when they improved clinically and on CT scan. A partial response consisted of a reduction of 25 to 90% of the mean diameter of contrast enhancement on CT, and a complete response was defined as a complete response or a reduction over 90% of the mean diameter of the contrast enhancement on CT scan. We accepted a 90% reduction of the tumor diameter as complete response because, in our experience, a small non progressive residual abnormal area is often observed at the tumor site. Stable disease was defined as a neurological stabilization for at least three months, without change in corticosteroid dosage, and when the mean diameter of contrast enhancement on CT did not change more than 25%. A neurological deterioration requiring an increase of at least 40 mg of methylprednisolone during 15 days or more was considered a treatment failure, even if there was no change of the tumor size on CT scan. Progression of the mean diameter of contrast enhancement over 25% on CT was another evidence of treatment failure.
tients developed peripheral neuropathy or auditory toxicity. Audiogram was normal in one patient who had received a cumulative dose of 7000 mg of carboplatine. Three patients who were also receiving sodium valproate developed increase of serum SGOT levels between 50 and 150% of the normal values. Blood toxicity over grade I occurred in four patients (20%) (Table 2). Blood toxicity was noted within two weeks after the first course in 3 patients. One patient developed a grade 4 pancytopenia requiring blood transfusions. Blood counts improved within two weeks but carboplatin was discontinued because the risk of subsequent toxicity was felt to be too high. Another patient developed a grade 3 thrombocytopenia improving within two weeks. The subsequent two courses were administered every 6 weeks with a 20% dose reduction without toxicity. The third patient had a grade II thrombocytopenia and leucopenia. Treatment was discontinued in this patient because of neurological deterioration. Finally, a transient grade 2 thrombopenia was noted after the third treatment in one patient.
Results
Therapeutic effects
Tolerance
19/20 patients could be evaluated for therapeutic response (Table 3). An objective response was noted in 2/19 patients (10%). One patient suffering from anaplastic astrocytoma had a complete response lasting 8+ months and one patient suffering from anaplastic oligodendroglioma had a partial response lasting 3+ months. Stabilization lasting 3 to 9+ months was observed in 6/19 patients (30%): 4 patients had glioblastoma and 2 an anaplastic
Tolerance was evaluated in 20 patients. Vomiting of short duration affected 6/20 patients (30%) usually beginning two hours after chemotherapy and lasting 6 to 8 hr. Intravenous fluid replacement was not required. Serum creatinine levels did not change and there was no trend toward increasing serum creatinine with repeated therapy. No pa-
Table 2. Hematologic toxicity Grade a Patients (N)
0 11
1 5
2 2
3 1
4 1
White blood cells 103 Platelets 103
> 4 > 100
3.0-3.9 75-99
2.0-2.9 50-74
1.0-1.9 25-49
< 1 < 25
a
Grade of toxicity according to W H O scale.
142 astrocytoma. The median duration of response + stabilization was 6 months. Estimated median duration of survival for the entire group was 6 months: 7 patients died of progressive disease (2 to 6 months after carboplatin onset) while 12 patients are living 3 to 12 months after the onset of carboplatin.
175 mg/m 2 were given intravenously followed by a three weeks rest, for a single course. Two patients (10%) (one with anaplastic astrocytoma and one with glioblastoma multiforme) had a partial response of 4 and 9+ months duration, respectively. Seven patients (36%) had stable disease (4 patients with glioblastoma multiforme, 2 with brainstem gliomas, one with ependymoma) for 3 to 11+ months. Our patients are somewhat different from those of Walker et al., since we treated only adults with supratentorial malignant gliomas who had received previous radiation therapy and who had failed chemotherapy with a nitrosourea. Furthermore, carboplatin was administered at a dose of 450 mg/m 2 every 4 weeks. However, our results are almost similar to those of Walker et al. [11] since 2 of our patients had a response of 3+ and 8+ months and 6 patients (30%) had stable disease to 3 to 9+ months duration. Therefore, both protocols of carboplatin administration have similar therapeutic effects. We could not identify predictive
Discussion
There are few reports on the use of carboplatin for glial tumors. Carboplatin was administered to children with a variety of recurrent brain tumors at a dose of 100 to 175 mg per meter square IV repeated every week for 4 weeks and followed by a 3 weeks rest [10]. An objective response was observed in 6/14 patients suffering from medulloblastomas but neither response nor stabilization was found in 4 recurrent malignant gliomas. Walker et al. [11] used carboplatin in 19 adults with recurrent supraor infra-tentorial gliomas. Four weekly doses of
Table 3. Characteristics of patients who responded or stabilized with carboplatin
Patients Age
Effects of carboplatin Sex
Tumor (1)
Cumulative dose of nitrosoureas (mg)
KI (2)
N (3)
KI (4)
Response (5) CR
63
F
GBM
61
M
GBM
44
M
GBM
57
M
GBM
44
F
AA
40
F
AA
35
M
AA
30
F
OA
HECNU IA 5OO HECNU IA 500 BCNU IV 950 HECNU IA + BCNU IV 800 HECNU IA 45O HECNU IA + CCNU 900 HECNU IA 500 HECNU IA 500
PR
Duration of stabilization
Duration of survival
S
70
11
70
+
9+
9+
40
5
50
+
3
6
80
3
80
+
4+
4+
50
4
50
+
4+
4+
80
7
80
+
6
7+
40
10
50
+
9
12+
60
5
80
8+
8+
50
3
60
3+
3+
+ +
(1) Tumor histology: GBM: glioblastoma multiforme, AA: anaplastic astrocytoma, 'OA: anaplastic oligodendroglioma. (2) KI: Karnofsky Index at onset of carboplatin. (3) N: Number of carboplatin courses. (4) Karnofsky index after carboplatin. (5) Response CR: complete response, PR: partial response, S: stabilization.
143 factors of response or stabilization to carboplatin such as sex, age, Karnofsky index, size and histology of the tumor, or previous response to nitrosoureas. Recently, Follezou et al. [12] treated 33 patients with recurrent malignant gliomas with intraarterial carboplatin at a dose of 400 mg/m 2 every 4 weeks. 19 patients could be evaluated for response. 5 of them (26%) had partial response for 3 to 10 months and 5 patients had stable disease for 2 to 7 months. Unfortunately, the nature of previous treatments is not detailed in their study and two patients had severe neurological complications. Carboplatin has less side effects than cisplatin. A1fen et al. [10] as well as Walker et al. [11] emphazised the good renal, neurological and GI tolerance. In this study, vomiting of short duration was observed in about one third of the patients, but it was readily controlled with antiemetics. Clinically, we did not observe neurological and auditory toxicity. The only serious toxicity was hematologic. Allen et al. [10] reported that 9/28 (32%) patients had a thrombopenia (less than 50 000) which was associated in two cases with a severe leucopenia. One patient with severe thrombocytopenia (20 000) died from intratumoral hemorrhage. Walker et al. [11] reported that 7/19 patients developed grade II-III hematological toxicity requiring blood transfusions in one case. Three of these patients had previously received nitrosoureas. In this study, 4 patients (20%) had a grade II or more hematologic toxicity. Hematologic toxicity occurred after the first treatment in three patients and after the third treatment in one patient. No patient died as a consequence of hematologic toxicity. Platelets and RBC transfusions were necessary in one patient who did not receive further treatment because the toxic risk was judged to be too high. In another patient with hematologic toxicity, treatment was discontinued because of tumor progression. In the two other patients, carboplatin was continued at a reduced dose (80% of the initial dose) and injections were repeated every 6 weeks instead of 4. One of these patients died from recurrent tumor while the other had stable disease. The previous doses of nitrosoureas were similar in patients who developed hematologic toxicity with carboplatin and in patients who did not. However, the single
patient who developed grade 4 hematological toxicity with carboplatin had previously presented a grade III hematologic toxicity with nitrosoureas. She had received a total dose of 950 mg of nitrosoureas. The three other patients had received 450 mg of intraarterial HECNU, 285 mg of BCNU IV, and 850 mg of IA H E C N U + CCNU PO, respectively without hematologic toxicity over grade 1. In summary, when patients previously treated with radiation therapy and nitrosoureas develop recurrent tumor, the administration of carboplatin induce tumor regression in 10% of the patients and stabilization in 30% indicating definite, although limited activity as second line therapy. Hematological toxicity occur in 20%, generally after the first course. Lower doses of carboplatin are probably indicated for patients who had previous grade II or more hematologic toxicity with nitrosoureas.
References 1. E.O.R.T.C. B rain tumor group: Effect of CCNU on survival rate of objective remission and duration of free interval in patients with malignant brain glioma- final evaluation. Enr J Cancer 14: 851-856, 1978 2. Aida T, Bodell WJ: Cellular resistance to chloroethylnitrosoureas, nitrogen mustard and cis-diamrninedichloroplatinum II) in human gial-derived cell lines. Cancer Res 47: 1361-1366, 1987 3. Feun LG, WaUace S, Stewart DJ, Chuang VP, Yung WKA, Leavens ME, Burgess MA, Savaraj N, Benjamin RS, Young SE, Tang RA, Handel S, Mavligit G, Fields WS: Intracarotid infusion of cis-diamminedichloroplatinum in the treatment of recurrent malignant brain tumors. Cancer 54: 794-799, 1984 4. Walker RW, Allen JC: Treatment of recurrent primary intracranial childhood tumors with cis-diamminedichloroplatinum. Ann Neurol 14: 371, 1983 5. Canetta R, Rozencweig, Carter SK: Carboplatin: the clinical spectrum to date. Cancer Treat Rev 12: 125-136, 1985 6. Takahaski H, Sasaki Y, Saijo N, Sakurai M, Nakano H, Nagakawa K, Hoshi A, Jett JR, Hong NS: In vitro colony inhibition of carboplatin against stomach and lung cancer cell lines in comparison with cisplatin. Cancer Chemother Pharmacol 19: 197-200, 1987 7. Rose WC, Schurig JE: Preclinical antitumor and toxicologic profile of carboplatin. Cancer Treat Rev 12: 1-19, 1985 8. Boven E, Van der Vijgh WJF, Nauta MM, Schliiper HMM, Pinedo HM: Comparative activity and distribution studies of five platinum analogues in nude mice bearing human ovarian carcinome xenografts. Cancer Res 45: 86-90, 1985
144 9. Koeller JM, Trump DL, Tutsch KD, Earhart RH, Davis TE, Tormey DC" Phase I clinical trial and pharmacokinetics of carboplatin (NSC 241240) by single monthly 30-minute infusion. Cancer 57: 222-225, 1986 10. Allen JC, Walker R, Lucks E, Jennings M, Barfoot S, Tan C: Carboplatin and recurrent childhood brain tumors. J Clinic Oncol 5: 459--463, 1987 11. Walker RW, Dantis E, Shapiro WR: Treatment of recur-
rent glioma with carboplatin (CBDCA). Proc Am Soc Clin Oncol 6: 72, 1987 12. Follezou JY, Fauchon F, Chiras J: Intraarterial infusion of carboplatin in the treatment of malignant gliomas: A phase II study. Neoplasma 36: 349-352, 1989
Address for offprints: M. Poisson, Clinique Neurologique, H6pital de la Salp~tri~re, 47, Boulevard de l'H6pital, 75651 Paris Cedex 13, France
Treatment of recurrent malignant supratentorial gliomas with carboplatin (CBDCA) M. Poisson, 1 Y. P6r60n, 1 J. Chiras 2 and J.Y. Delattre 1 1Department of Neurology, 2 Department of Neuroradiology, La Salp6tridre, Paris, France
Key words: recurrent malignant glioma, carboplatin Summary
Twenty patients with malignant supratentorial gliomas progressing after radiation therapy and chemotherapy with nitrosoureas received intravenous carboplatin, 450 mg/m 2. Courses of therapy were repeated every four weeks. Therapeutic evaluation was performed monthly using neurologic examination and CT scan of the brain. Of 19 patients evaluable for response, 2 (10%) responded to therapy and 6 (30%) had stable disease. The estimated median time to tumor progression for responding and stable patients was 6 months. Median duration of survival was 6 months for all patients. Of 20 patients evaluable for toxicity, none had renal or auditory toxicity. Side effects consisted of hematologic toxicity in 4 patients (20%): one patient had grade 4 toxicity requiring discontinuation of carboplatin and 3 patients had grade 2-3 toxicity. Abbreviation: HECNU - 1-(2-chloroethyl)-l-nitroso-3-(2-hydroxyethyl) urea
The treatment of malignant gliomas is disappointing. When surgery, radiation therapy and chemotherapy with a nitrosourea are used the median time to tumor progression is about 8 months [1]. At this stage, a few patients may benefit from reoperation. Reirradiation is highly neurotoxic and there is no benefit to expect when another nitrosourea is used. Therefore, the only alternative is often to try another class of chemotherapeutic drug. Platinum analogues are possible second line chemotherapeutic agents for recurrent malignant gliomas. Aida and Bodell [2] did not find cross resistance between chlornitrosoureas and cisplatinum on human malignant gliomas cell lines. Intraarterial infusions of cisplatin have been occasionally useful in patients with recurrent malignant gliomas, including patients previously treated with nitrosoureas [3]. Unfortunately, intraarterial cisplatin may induce severe neurological and ophthalmological complications [3]. Intravenous cisplatin has been success-
ful in various neoplasms including CNS malignancies [4] but the administration of this drug was associated with a variety of toxicites. Carboplatin (cis-diammine-1, 1-cyclobutane dicarboxylate platinum II) is a second generation cisplatin analogue that has shown less GI toxicity, neurotoxicity and renal toxicity than the parent compound [5]. Carboplatin is as effective as cisplatin in several human tumors [6, 7]. Furthermore, carboplatine crosses the blood-brain barrier to a greater extent than cisplatin [8]. We undertook a phase II study of carboplatine for recurrent malignant supratentorial gliomas.
Patients and methods
Twenty patients suffering from recurrent malignant supratentorial gliomas received intravenous infusions of carboplatin (Table 1). There were 12
140
men and 8 women aged 30 to 70 years (mean 49). Tumor histology was glioblastoma multiforme in 10 patients, anaplastic astrocytoma in.7 patients, anaplastic oligodendroglioma in 2 patients. In one patient, the diagnosis of malignant glioma was made by CT scan and angiography. Patients had been previously treated with surgery, radiation therapy and chemotherapy. Surgery was performed in 19/ 20 patients (1 had complete resection, 11 had partial resection and 7 had tumor biopsy). All patients had received radiation therapy: 19 patients had received a dose of 50 to 60 Gray using 1.8 Gy per fraction 5 times a week on a generous focal field (including the tumor and adjacent parenchyma) and 1 patient had received a course of whole brain radiation therapy delivering 30 Gy in 10 fractions over two weeks. All patients had received nitrosoureas: 8 patients had intraarterial (IA) H E C N U (mean cumulative dose of 525 mg), 10 patients had IA H E C N U and intravenous (IV) BCNU or CCNU per os (PO) (mean cumulative dose of 900 mg) and 2 patients had IV BCNU or PO CCNU (mean cumulative dose of 800 mg). Each patient had received a mean number of 4 courses of nitro-
soureas and the median time to tumor progression following onset of nitrosoureas was 7.5 months. Tumor progression was documented by clinical examination showing neurological deterioration and by evidence of tumor progression on successive CT scan or magnetic resonance image scan (MRI). Mean Karnofsky index prior to carboplatin infusions ranged from 40 to 90 (mean, 60). Maximum diameter of the area of contrast enhancement on CT ranged from 20 to 100 mm. Eligibility requirements included WBC > 3 4 0 0 m m 3, platelets >130 000ram 3, hemoglobin > 10g/dl. In addition, serum creatinin, transaminases, and bilirubin levels had to be within normal limits. Carboplatin was administered IV at a dose of 450 mg per meter square (with a maximum dose of 1000mg) [9]. Courses of therapy were repeated every four weeks. The number of courses per patient ranged from 1 to 11 (mean, 4). Neurological and GI tolerance was judged on clinical examinations repeated every four weeks. Patients were also followed by blood counts, measurement of blood urea nitrogen, serum creatinin and SGOT repeated every 2 weeks. Therapeutic effects was
Table 1. Patients characteristics Total number of patients Sex (M/F) Mean age (range) Mean Karnofsky index at onset of carboplatin, (range) Histology of the tumor • Glioblastoma multiforme • Anaplastic astrocytoma • Anaplastic oligodendroglioma • Unknown Previous treatments • Surgery • Radiation therapy • Chemotherapy with nitrosoureas Intraarterial Intraarterial and systemic Systemic Largest diameter of contrast enhancement on CT (ram) at onset of carboplatin • 20-40 mm • >40mm Evaluable for toxicity Evaluable for response
20 12 M/8 F 49 years (30-70) 60 (40-90) Number of patients 10 7 2 1 19 20 20 8 2 10 5 15 20 19
141 judged using Karnofsky scale and CT examinations. Patients were considered responders when they improved clinically and on CT scan. A partial response consisted of a reduction of 25 to 90% of the mean diameter of contrast enhancement on CT, and a complete response was defined as a complete response or a reduction over 90% of the mean diameter of the contrast enhancement on CT scan. We accepted a 90% reduction of the tumor diameter as complete response because, in our experience, a small non progressive residual abnormal area is often observed at the tumor site. Stable disease was defined as a neurological stabilization for at least three months, without change in corticosteroid dosage, and when the mean diameter of contrast enhancement on CT did not change more than 25%. A neurological deterioration requiring an increase of at least 40 mg of methylprednisolone during 15 days or more was considered a treatment failure, even if there was no change of the tumor size on CT scan. Progression of the mean diameter of contrast enhancement over 25% on CT was another evidence of treatment failure.
tients developed peripheral neuropathy or auditory toxicity. Audiogram was normal in one patient who had received a cumulative dose of 7000 mg of carboplatine. Three patients who were also receiving sodium valproate developed increase of serum SGOT levels between 50 and 150% of the normal values. Blood toxicity over grade I occurred in four patients (20%) (Table 2). Blood toxicity was noted within two weeks after the first course in 3 patients. One patient developed a grade 4 pancytopenia requiring blood transfusions. Blood counts improved within two weeks but carboplatin was discontinued because the risk of subsequent toxicity was felt to be too high. Another patient developed a grade 3 thrombocytopenia improving within two weeks. The subsequent two courses were administered every 6 weeks with a 20% dose reduction without toxicity. The third patient had a grade II thrombocytopenia and leucopenia. Treatment was discontinued in this patient because of neurological deterioration. Finally, a transient grade 2 thrombopenia was noted after the third treatment in one patient.
Results
Therapeutic effects
Tolerance
19/20 patients could be evaluated for therapeutic response (Table 3). An objective response was noted in 2/19 patients (10%). One patient suffering from anaplastic astrocytoma had a complete response lasting 8+ months and one patient suffering from anaplastic oligodendroglioma had a partial response lasting 3+ months. Stabilization lasting 3 to 9+ months was observed in 6/19 patients (30%): 4 patients had glioblastoma and 2 an anaplastic
Tolerance was evaluated in 20 patients. Vomiting of short duration affected 6/20 patients (30%) usually beginning two hours after chemotherapy and lasting 6 to 8 hr. Intravenous fluid replacement was not required. Serum creatinine levels did not change and there was no trend toward increasing serum creatinine with repeated therapy. No pa-
Table 2. Hematologic toxicity Grade a Patients (N)
0 11
1 5
2 2
3 1
4 1
White blood cells 103 Platelets 103
> 4 > 100
3.0-3.9 75-99
2.0-2.9 50-74
1.0-1.9 25-49
< 1 < 25
a
Grade of toxicity according to W H O scale.
142 astrocytoma. The median duration of response + stabilization was 6 months. Estimated median duration of survival for the entire group was 6 months: 7 patients died of progressive disease (2 to 6 months after carboplatin onset) while 12 patients are living 3 to 12 months after the onset of carboplatin.
175 mg/m 2 were given intravenously followed by a three weeks rest, for a single course. Two patients (10%) (one with anaplastic astrocytoma and one with glioblastoma multiforme) had a partial response of 4 and 9+ months duration, respectively. Seven patients (36%) had stable disease (4 patients with glioblastoma multiforme, 2 with brainstem gliomas, one with ependymoma) for 3 to 11+ months. Our patients are somewhat different from those of Walker et al., since we treated only adults with supratentorial malignant gliomas who had received previous radiation therapy and who had failed chemotherapy with a nitrosourea. Furthermore, carboplatin was administered at a dose of 450 mg/m 2 every 4 weeks. However, our results are almost similar to those of Walker et al. [11] since 2 of our patients had a response of 3+ and 8+ months and 6 patients (30%) had stable disease to 3 to 9+ months duration. Therefore, both protocols of carboplatin administration have similar therapeutic effects. We could not identify predictive
Discussion
There are few reports on the use of carboplatin for glial tumors. Carboplatin was administered to children with a variety of recurrent brain tumors at a dose of 100 to 175 mg per meter square IV repeated every week for 4 weeks and followed by a 3 weeks rest [10]. An objective response was observed in 6/14 patients suffering from medulloblastomas but neither response nor stabilization was found in 4 recurrent malignant gliomas. Walker et al. [11] used carboplatin in 19 adults with recurrent supraor infra-tentorial gliomas. Four weekly doses of
Table 3. Characteristics of patients who responded or stabilized with carboplatin
Patients Age
Effects of carboplatin Sex
Tumor (1)
Cumulative dose of nitrosoureas (mg)
KI (2)
N (3)
KI (4)
Response (5) CR
63
F
GBM
61
M
GBM
44
M
GBM
57
M
GBM
44
F
AA
40
F
AA
35
M
AA
30
F
OA
HECNU IA 5OO HECNU IA 500 BCNU IV 950 HECNU IA + BCNU IV 800 HECNU IA 45O HECNU IA + CCNU 900 HECNU IA 500 HECNU IA 500
PR
Duration of stabilization
Duration of survival
S
70
11
70
+
9+
9+
40
5
50
+
3
6
80
3
80
+
4+
4+
50
4
50
+
4+
4+
80
7
80
+
6
7+
40
10
50
+
9
12+
60
5
80
8+
8+
50
3
60
3+
3+
+ +
(1) Tumor histology: GBM: glioblastoma multiforme, AA: anaplastic astrocytoma, 'OA: anaplastic oligodendroglioma. (2) KI: Karnofsky Index at onset of carboplatin. (3) N: Number of carboplatin courses. (4) Karnofsky index after carboplatin. (5) Response CR: complete response, PR: partial response, S: stabilization.
143 factors of response or stabilization to carboplatin such as sex, age, Karnofsky index, size and histology of the tumor, or previous response to nitrosoureas. Recently, Follezou et al. [12] treated 33 patients with recurrent malignant gliomas with intraarterial carboplatin at a dose of 400 mg/m 2 every 4 weeks. 19 patients could be evaluated for response. 5 of them (26%) had partial response for 3 to 10 months and 5 patients had stable disease for 2 to 7 months. Unfortunately, the nature of previous treatments is not detailed in their study and two patients had severe neurological complications. Carboplatin has less side effects than cisplatin. A1fen et al. [10] as well as Walker et al. [11] emphazised the good renal, neurological and GI tolerance. In this study, vomiting of short duration was observed in about one third of the patients, but it was readily controlled with antiemetics. Clinically, we did not observe neurological and auditory toxicity. The only serious toxicity was hematologic. Allen et al. [10] reported that 9/28 (32%) patients had a thrombopenia (less than 50 000) which was associated in two cases with a severe leucopenia. One patient with severe thrombocytopenia (20 000) died from intratumoral hemorrhage. Walker et al. [11] reported that 7/19 patients developed grade II-III hematological toxicity requiring blood transfusions in one case. Three of these patients had previously received nitrosoureas. In this study, 4 patients (20%) had a grade II or more hematologic toxicity. Hematologic toxicity occurred after the first treatment in three patients and after the third treatment in one patient. No patient died as a consequence of hematologic toxicity. Platelets and RBC transfusions were necessary in one patient who did not receive further treatment because the toxic risk was judged to be too high. In another patient with hematologic toxicity, treatment was discontinued because of tumor progression. In the two other patients, carboplatin was continued at a reduced dose (80% of the initial dose) and injections were repeated every 6 weeks instead of 4. One of these patients died from recurrent tumor while the other had stable disease. The previous doses of nitrosoureas were similar in patients who developed hematologic toxicity with carboplatin and in patients who did not. However, the single
patient who developed grade 4 hematological toxicity with carboplatin had previously presented a grade III hematologic toxicity with nitrosoureas. She had received a total dose of 950 mg of nitrosoureas. The three other patients had received 450 mg of intraarterial HECNU, 285 mg of BCNU IV, and 850 mg of IA H E C N U + CCNU PO, respectively without hematologic toxicity over grade 1. In summary, when patients previously treated with radiation therapy and nitrosoureas develop recurrent tumor, the administration of carboplatin induce tumor regression in 10% of the patients and stabilization in 30% indicating definite, although limited activity as second line therapy. Hematological toxicity occur in 20%, generally after the first course. Lower doses of carboplatin are probably indicated for patients who had previous grade II or more hematologic toxicity with nitrosoureas.
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144 9. Koeller JM, Trump DL, Tutsch KD, Earhart RH, Davis TE, Tormey DC" Phase I clinical trial and pharmacokinetics of carboplatin (NSC 241240) by single monthly 30-minute infusion. Cancer 57: 222-225, 1986 10. Allen JC, Walker R, Lucks E, Jennings M, Barfoot S, Tan C: Carboplatin and recurrent childhood brain tumors. J Clinic Oncol 5: 459--463, 1987 11. Walker RW, Dantis E, Shapiro WR: Treatment of recur-
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Address for offprints: M. Poisson, Clinique Neurologique, H6pital de la Salp~tri~re, 47, Boulevard de l'H6pital, 75651 Paris Cedex 13, France
