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Continuous intrathecal perfusion of methotrexate for carcinomatous meningitis with pharmacokinetic studies: Two case studies
Clinical Oncology (1997) 9:189-190 © 1997 The Royal College of Radiologists
Clinical Oncology
Case Report Continuous Intrathecal Perfusion of Methotrexate for Carcinomatous Meningitis with Pharmacokinetic Studies: Two Case Studies T. Petit, P. Dufour, A. S. Korganov, F. Maloisel and F. Oberling Centre Hospitalo-Universitaire de Strasbourg, Strasbourg, France
Abstract. We report two patients suffering from carcinomatous meningitis who were treated by continuous intrathecal perfusion of methotrexate.
Breast cancer; Carcinomatous meningitis; Continuous intrathecal perfusion; Methotrexate Keywords:
INTRODUCTION
The diagnosis of carcinomatous meningitis is now being made with increasing frequency due to the improving rates of survival in patients treated for metastatic neoplasms [1]. Those most likely to be complicated by meningeal metastasis are malignant haemopathies, and breast and lung cancers. The diagnosis is a rather ominous prognostic indicator, with a median survival of 4-6 weeks in untreated patients [2]. The standard treatment is intrathecal injection of antimitotic agents, either by repeated administration or through an Ommaya reservoir placed under the scalp and communicating with one of the lateral ventricules [3]. The drug most commonly used is methotrexate (MTX), which has significant neurotoxicity that is considerably accentuated by radiation therapy [4]. The median survival for treated patients is 6 months, with 25% of survivors at 1 year [1]. We present two patients with carcinomatous meningitis who were treated with intrathecal continuous perfusion of MTX, with pharmacokinetic studies in the first. The CSF samples have been stored and recently analysed for work towards a thesis.
CASE REPORT
A female patient presented at age 42 years with a right axillary tumour. Axillary dissection revealed 24 nodes affected by invasive duct carcinoma. Mammography did not show any tumour in the right breast. The tumour was staged and graded To, N2, Mo, SBR III, R H - . Treatment consisted of four cycles of adjuvant chemotherapy according to the VAC regimen (vindesine 3 mg/m 2 day 1, Correspondence and offprint requests to: Dr T. Petit, Medical Oncology Department, Paul Strauss Cancer Center, 3 rue de la porte de l'H6pital, 67085 Strasbourg, France.
adriamycin 75 mg/m a day 1, cyclophosphamide 1200 rag/ m 2 day 1, repeated every 3 weeks), localized radiation therapy with 60 Gy to the breast and axilla, and hormonal therapy with tamoxifen. Five months after the completion of chemotherapy, a disseminated cerebral metastasis was confirmed on CT scanning in the face of the onset of vomiting and motor deficit in the right upper extremity. The administration of 40 Gy of irradiation to the brain brought about clinical improvement. Two months after the end of radiation treatment, a meningeal syndrome became apparent. Cytological examination of the cerebrospinal fluid (CSF) revealed the presence of neoplastic cells and CSF protein of 15.2 g/l. One intraventricular and one lumbar epidural catheter were inserted for CSF sampling and the lumbar epidural injection of MTX. The protocol combined intrathecal MTX 10 rag/day over 5 days by means of a pump linked to the lumbar epidural catheter and intravenous calcium folinate 15 nag every 6 hours for 5 days. The calcium folinate was commenced 24 hours after initiation of the MTX perfusion. The level of MTX in the CSE remained greater than 1 x 10 -5 molB over the 5 days of its administration, while remaining below 1 x 10 -7 tool/1 in the blood. Serum levels of calcium folinate were 1 x 10 . 8 tool/1 on day l, 1.4 x 10 -7 mol/1 on day 2, 7.3 x 10 -7 tool/1 on day 3, 2 x 10 -7 mol/1 on day 4, and 1 x 10 . 7 tool/1 on day 5. The concentration of calcium folinate in the CSF was 2 x 10 -7 mol/1 between days 1 and 5 (Fig. 1). On day 3, there was no evidence of neoplastic cells in the CSF and the protein levels had fallen to 0.72 g/1. This was accompanied by a rapid regression of the neurological deficits. The patient remained stable for a period of 6 weeks but died suddenly at home. An autopsy was not performed. The second patient presented at the age of 40 years with an invasive duct carcinoma of the right breast. She underwent a quadrantectomy and axillary dissection. The tumour was staged and graded T1, N+ (5/19), Mo, SBR II, R H - . Subsequent treatment consisted of six cycles of chemotherapy according to the FAC regimen (5-FU 500 mg/m a day 1 and day 8, adriamycin 50 mg/m 2 day 1, cyclophosphamide 500 mg/m 2 day 1 and day 8, with cycles repeated every 3 weeks), localized radiation therapy and hormonal therapy with tamoxifen. After 5 years of follow-up, disseminated bone and cutaneous metastases appeared. A chemotherapy regimen was commenced (mitoxantrone 12 mg/m 2 day 1, navelbine 25 mg/m 2 day 1 and day 8, with the cycle repeated every 3 weeks) in combination with hormonal therapy with medroxyprogesterone acetate. After a good initial response with five cycles of this therapy, a recurrence of the cutaneous lesions was detected, as well as liver metastases. A second line protocol was initiated (cisplatin 20 mg/m a day 1 to day 5, F-FU 1 g/m 2 continuous
190
T. Petit et al. 1 10-1
10 -2
10 -3
10 -4
E
10 -s
10 -6
10 -7
10-8
10 .9 0
1
2
3
4
5
6
Days
Fig. 1. Pharmacokinetic studies. ~ serum concentration of methotrexate; R cerebrospinal fluid concentration of methotrexate; A serum concentration of calcium folinate; x cerebrospinal fluid concentration of calcium folinate. perfusion over 5 days). Nine cycles were administered, leading to the disappearance of the cutaneous metastases and a stabilization of the hepatic lesions. The treatment was followed up with aminoglutethamide hormonal therapy. The patient was admitted 2 months later with dementia, which rapidly degenerated into a reactive coma. A lumbar puncture revealed carcinomatous meningitis with a CSF protein of 1.37 g/1. There was no evidence of cerebral metastases on CT scanning. The continuous intrathecal perfusin of MTX over 5 days led to normalization of CSF laboratory values on the third day of treatment. There was a corresponding clinical improvement, with the patient recovering most of her previous functions. CSF studies remained normal for 3 months, when the patient succumbed, due to progression of the hepatic secondaries.
DISCUSSION Methotrexate is an antagonist of folinic acid and inhibits dihydrofolate reductase. This inhibition leads to a lack of tetrahydrofolate, with a consequent depletion of purine bases. It is also a weak inhibitor of thymidylate synthetase, which reinforces its inhibitory effects on DNA synthesis. The use of MTX in high doses requires salvage by folinic acid 24 hours following its perfusion (according to the
protocol used). Pharmacokinetic surveillance of this agent is required to determine the appropriate close of folinic acid, the administration of which should be discontinued when the MTX level is less than 5 x 10 - 8 mol/1 [5]. Systemic diffusion of MTX occurs after its intrathecal administration. Bleyer et al. demonstrated that a therapeutic meningeal concentration of MTX of 1 x 10 . 6 mol/1 may be achieved by the injection of 1 mg every 12 hours, without reaching systemic toxic levels [3]. In contrast, the injection of MTX 12 mg twice a week will not achieve the desired prolonged therapeutic concentration but instead will lead to high, potentially neurotoxic, concentrations with each injection. The diffusion of MTX into the blood is not negligible, with the attainment of a serum concentration of 1 x 10 . 7 tool/1 8 hours after an intrathecal injection of 6.25 mg/m a [6]. In view of this si~gnificant serum level, salvage with folinic acid (25 mg/m every 6 hours) is necessary, commencing 24 hours after the initiation of MTX therapy until the serum concentration falls below 1 x 10 _8 tool/1. The intrathecal diffusion of calcium folinate, and of its active metabolite 5methyltetrahydrofolate, is dose-dependent representing less than 1/100 of the serum concentration. The use of calcium folinate thus allows a reduction in the systemic side effects of MTX without interfering with the MTX level in the CSF. These pharmacokinetic characteristics of MTX in the CSF have led us to use continuous perfusion of MTX to avoid a potentially myelotoxic peak concentration, while maintaining a prolonged therapeutic concentration in the CSF. Contrary to the results obtained by Metha et al., we found that the concentrations of calcium folinate in the blood and the CSF were equivalent [7]. Nevertheless, the MTX/calcium folinate ratio was very different in the two compartments: 1 x 102 in t h e C S F a n d 1 x 10-1 in the blood. The treatment was effective, with no side effects, and with the persistent normalization of CSF parameters 1 month after termination of the treatment.
References
1. Yap HY, Yap BS, Rasmussen S, et al. Treatment for meningeal carcinomatosis in breast cancer. Cancer 1982;49:219-22. 2. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759-772. 3. Bleyer WA, Poplack DG, Simon RM. 'Concentration x time' methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood 1978;51:83542. 4. Baum ES, Koch HF, Corby DG, et al. Intrathecal methotrexate. Lancet 1970;i:649. 5. Bertino JR. Ode to methotrexate. J. Clin Oncol 1993;11:5-14. 6. Shapiro WR, Young DF, Metha BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975;293:161-6. 7. Metha BM, Glass JP, Shapiro WR. Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-Ommaya methotrexate administration in patients with meningeal carcinomatosis. Cancer Res 1983;43:435-8.
Received for publication April 1996 Accepted following revision April 1997
Clinical Oncology
Case Report Continuous Intrathecal Perfusion of Methotrexate for Carcinomatous Meningitis with Pharmacokinetic Studies: Two Case Studies T. Petit, P. Dufour, A. S. Korganov, F. Maloisel and F. Oberling Centre Hospitalo-Universitaire de Strasbourg, Strasbourg, France
Abstract. We report two patients suffering from carcinomatous meningitis who were treated by continuous intrathecal perfusion of methotrexate.
Breast cancer; Carcinomatous meningitis; Continuous intrathecal perfusion; Methotrexate Keywords:
INTRODUCTION
The diagnosis of carcinomatous meningitis is now being made with increasing frequency due to the improving rates of survival in patients treated for metastatic neoplasms [1]. Those most likely to be complicated by meningeal metastasis are malignant haemopathies, and breast and lung cancers. The diagnosis is a rather ominous prognostic indicator, with a median survival of 4-6 weeks in untreated patients [2]. The standard treatment is intrathecal injection of antimitotic agents, either by repeated administration or through an Ommaya reservoir placed under the scalp and communicating with one of the lateral ventricules [3]. The drug most commonly used is methotrexate (MTX), which has significant neurotoxicity that is considerably accentuated by radiation therapy [4]. The median survival for treated patients is 6 months, with 25% of survivors at 1 year [1]. We present two patients with carcinomatous meningitis who were treated with intrathecal continuous perfusion of MTX, with pharmacokinetic studies in the first. The CSF samples have been stored and recently analysed for work towards a thesis.
CASE REPORT
A female patient presented at age 42 years with a right axillary tumour. Axillary dissection revealed 24 nodes affected by invasive duct carcinoma. Mammography did not show any tumour in the right breast. The tumour was staged and graded To, N2, Mo, SBR III, R H - . Treatment consisted of four cycles of adjuvant chemotherapy according to the VAC regimen (vindesine 3 mg/m 2 day 1, Correspondence and offprint requests to: Dr T. Petit, Medical Oncology Department, Paul Strauss Cancer Center, 3 rue de la porte de l'H6pital, 67085 Strasbourg, France.
adriamycin 75 mg/m a day 1, cyclophosphamide 1200 rag/ m 2 day 1, repeated every 3 weeks), localized radiation therapy with 60 Gy to the breast and axilla, and hormonal therapy with tamoxifen. Five months after the completion of chemotherapy, a disseminated cerebral metastasis was confirmed on CT scanning in the face of the onset of vomiting and motor deficit in the right upper extremity. The administration of 40 Gy of irradiation to the brain brought about clinical improvement. Two months after the end of radiation treatment, a meningeal syndrome became apparent. Cytological examination of the cerebrospinal fluid (CSF) revealed the presence of neoplastic cells and CSF protein of 15.2 g/l. One intraventricular and one lumbar epidural catheter were inserted for CSF sampling and the lumbar epidural injection of MTX. The protocol combined intrathecal MTX 10 rag/day over 5 days by means of a pump linked to the lumbar epidural catheter and intravenous calcium folinate 15 nag every 6 hours for 5 days. The calcium folinate was commenced 24 hours after initiation of the MTX perfusion. The level of MTX in the CSE remained greater than 1 x 10 -5 molB over the 5 days of its administration, while remaining below 1 x 10 -7 tool/1 in the blood. Serum levels of calcium folinate were 1 x 10 . 8 tool/1 on day l, 1.4 x 10 -7 mol/1 on day 2, 7.3 x 10 -7 tool/1 on day 3, 2 x 10 -7 mol/1 on day 4, and 1 x 10 . 7 tool/1 on day 5. The concentration of calcium folinate in the CSF was 2 x 10 -7 mol/1 between days 1 and 5 (Fig. 1). On day 3, there was no evidence of neoplastic cells in the CSF and the protein levels had fallen to 0.72 g/1. This was accompanied by a rapid regression of the neurological deficits. The patient remained stable for a period of 6 weeks but died suddenly at home. An autopsy was not performed. The second patient presented at the age of 40 years with an invasive duct carcinoma of the right breast. She underwent a quadrantectomy and axillary dissection. The tumour was staged and graded T1, N+ (5/19), Mo, SBR II, R H - . Subsequent treatment consisted of six cycles of chemotherapy according to the FAC regimen (5-FU 500 mg/m a day 1 and day 8, adriamycin 50 mg/m 2 day 1, cyclophosphamide 500 mg/m 2 day 1 and day 8, with cycles repeated every 3 weeks), localized radiation therapy and hormonal therapy with tamoxifen. After 5 years of follow-up, disseminated bone and cutaneous metastases appeared. A chemotherapy regimen was commenced (mitoxantrone 12 mg/m 2 day 1, navelbine 25 mg/m 2 day 1 and day 8, with the cycle repeated every 3 weeks) in combination with hormonal therapy with medroxyprogesterone acetate. After a good initial response with five cycles of this therapy, a recurrence of the cutaneous lesions was detected, as well as liver metastases. A second line protocol was initiated (cisplatin 20 mg/m a day 1 to day 5, F-FU 1 g/m 2 continuous
190
T. Petit et al. 1 10-1
10 -2
10 -3
10 -4
E
10 -s
10 -6
10 -7
10-8
10 .9 0
1
2
3
4
5
6
Days
Fig. 1. Pharmacokinetic studies. ~ serum concentration of methotrexate; R cerebrospinal fluid concentration of methotrexate; A serum concentration of calcium folinate; x cerebrospinal fluid concentration of calcium folinate. perfusion over 5 days). Nine cycles were administered, leading to the disappearance of the cutaneous metastases and a stabilization of the hepatic lesions. The treatment was followed up with aminoglutethamide hormonal therapy. The patient was admitted 2 months later with dementia, which rapidly degenerated into a reactive coma. A lumbar puncture revealed carcinomatous meningitis with a CSF protein of 1.37 g/1. There was no evidence of cerebral metastases on CT scanning. The continuous intrathecal perfusin of MTX over 5 days led to normalization of CSF laboratory values on the third day of treatment. There was a corresponding clinical improvement, with the patient recovering most of her previous functions. CSF studies remained normal for 3 months, when the patient succumbed, due to progression of the hepatic secondaries.
DISCUSSION Methotrexate is an antagonist of folinic acid and inhibits dihydrofolate reductase. This inhibition leads to a lack of tetrahydrofolate, with a consequent depletion of purine bases. It is also a weak inhibitor of thymidylate synthetase, which reinforces its inhibitory effects on DNA synthesis. The use of MTX in high doses requires salvage by folinic acid 24 hours following its perfusion (according to the
protocol used). Pharmacokinetic surveillance of this agent is required to determine the appropriate close of folinic acid, the administration of which should be discontinued when the MTX level is less than 5 x 10 - 8 mol/1 [5]. Systemic diffusion of MTX occurs after its intrathecal administration. Bleyer et al. demonstrated that a therapeutic meningeal concentration of MTX of 1 x 10 . 6 mol/1 may be achieved by the injection of 1 mg every 12 hours, without reaching systemic toxic levels [3]. In contrast, the injection of MTX 12 mg twice a week will not achieve the desired prolonged therapeutic concentration but instead will lead to high, potentially neurotoxic, concentrations with each injection. The diffusion of MTX into the blood is not negligible, with the attainment of a serum concentration of 1 x 10 . 7 tool/1 8 hours after an intrathecal injection of 6.25 mg/m a [6]. In view of this si~gnificant serum level, salvage with folinic acid (25 mg/m every 6 hours) is necessary, commencing 24 hours after the initiation of MTX therapy until the serum concentration falls below 1 x 10 _8 tool/1. The intrathecal diffusion of calcium folinate, and of its active metabolite 5methyltetrahydrofolate, is dose-dependent representing less than 1/100 of the serum concentration. The use of calcium folinate thus allows a reduction in the systemic side effects of MTX without interfering with the MTX level in the CSF. These pharmacokinetic characteristics of MTX in the CSF have led us to use continuous perfusion of MTX to avoid a potentially myelotoxic peak concentration, while maintaining a prolonged therapeutic concentration in the CSF. Contrary to the results obtained by Metha et al., we found that the concentrations of calcium folinate in the blood and the CSF were equivalent [7]. Nevertheless, the MTX/calcium folinate ratio was very different in the two compartments: 1 x 102 in t h e C S F a n d 1 x 10-1 in the blood. The treatment was effective, with no side effects, and with the persistent normalization of CSF parameters 1 month after termination of the treatment.
References
1. Yap HY, Yap BS, Rasmussen S, et al. Treatment for meningeal carcinomatosis in breast cancer. Cancer 1982;49:219-22. 2. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759-772. 3. Bleyer WA, Poplack DG, Simon RM. 'Concentration x time' methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood 1978;51:83542. 4. Baum ES, Koch HF, Corby DG, et al. Intrathecal methotrexate. Lancet 1970;i:649. 5. Bertino JR. Ode to methotrexate. J. Clin Oncol 1993;11:5-14. 6. Shapiro WR, Young DF, Metha BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975;293:161-6. 7. Metha BM, Glass JP, Shapiro WR. Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-Ommaya methotrexate administration in patients with meningeal carcinomatosis. Cancer Res 1983;43:435-8.
Received for publication April 1996 Accepted following revision April 1997