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Complete remission of brain metastases from ovarian carcinoma with carboplatin
European Journal of Obstetrics & Gynecology and Reproductive Biology 78 (1998) 91–93
Complete remission of brain metastases from ovarian carcinoma with carboplatin 1, Gennaro Cormio *, Antonio Gabriele, Andrea Maneo, Gerardo Zanetta, Cristina Bonazzi, Fabio Landoni
Gynecologic Oncology Unit, University of Milano, Istituto di Scienze Biomediche, Ospedale S. Gerardo, Monza, Italy Received 26 August 1997; received in revised form 30 October 1997; accepted 18 December 1997
Abstract Central nervous system involvement by epithelial ovarian carcinoma is rare. We report the case of a 49 year old woman with stage IV serous carcinoma of the ovary who developed multiple cerebral and cerebellar metastases 7 months after achieving complete response to platin-based chemotherapy. Eight courses of carboplatin (400 mg / m 2 ) were administered and after the second cycle complete remission of the brain deposits occured. The treatment afforded rapid subjective and objective relief and was associated with a good quality of life. Abdominal recurrent disease was diagnosed 22 months after treatment for brain involvement. Paltin-based chemotherapy was reinstated, but the patient died from progressive adbominal disease without any sign of cerebral involvement and any neurological symptomatology. Carboplatin should be considered for the treatment of ovarian carcinoma metastatic to the brain. 1998 Elsevier Science Ireland Ltd. Keywords: Brain metastasis; Ovarian carcinoma; Carboplatin
1. Introduction The central nervous system has traditionally been considered an uncommon site for metastatic disease from epithelial ovarian carcinoma, and this complication has been reported to occur in about 1% of patients [1,2]. Traditionally neurosurgery and radiotherapy have been employed in patients with brain metastases. Both treatment modalities, may provide a significant palliation, improving the quality of life in most patients. However, they carry an associated morbidity and mortality, and long-term remission occurs only in a limited number of cases [2,3]. To date, only few reports have dealt with the use of chemotherapy to treat patients with central nervous system metastases from ovarian carcinoma [3–6], and the role of chemotherapy in this setting remains unclear. *Corresponding author. Tel.: 139 80 5478986; fax: 139 80 5473248. Visiting Research Fellow from the Department of Gynecology and Obstetrics, University of Bari, ITALY.
1
We present the case of a patient who achieved complete remission of multiple cerebral and cerebellar metastases from ovarian carcinoma with single-agent carboplatin, and review the literature on this rare topic.
2. Case report A 49 year old woman presented with abdominal swelling and a pelvic mass in September 1993. A stage IV poorly differentiated, serous carcinoma of the ovary was diagnosed. She underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy and subcolic omentectomy, followed by 6 courses of cisplatin 75 mg / m 2 and cyclophosphamide 750 mg / m 2 at 3 weekly intervals. At the completion of chemotherapy the patient underwent second-look laparotomy and microscopic residual disease was found only in two biopsies. Six pulses of paclitaxel 175 mg / m 2 were administered until June 1994. The patient did well until January 1995, when complained
0301-2115 / 98 / $19.00 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0301-2115( 98 )00009-8
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G. Cormio et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 78 (1998) 91 – 93
of nausea, vomiting, vertigo and persisting sinus-type headaches. A cranial MR scan revealed multiple metastases in both the cerebellar and cerebral cortex. Biopsy of the lesions was not attempted. CT scan of the thorax, abdomen and pelvis showed no clinical evidence of recurrent disease. Serum CA-125 level was 542 IU / ml. Acute symptomatic relief was gained using dexamethasone and treatment using carboplatin 400 mg / m 2 at 3 weekly interval was commenced. A cranial MR scan following the first two pulses of chemotherapy demonstrated complete disappearance of the brain deposits; CA-125 also returned to normal values. At the completion of the eight pulse of carboplatin in May 1995 total-body CT scan was made and no sign of disease could be detected. The patient did well until March 1997 when complained of abdominal swelling and an increase in CA-125 to 145 IU / ml. Abdomino-pelvic CT scan revealed the presence of ascitis and multiple peritoneal nodules (less than 2 cm); a cranial MR scan however, was negative and neurological examination was normal. Platin-based chemotherapy was reinstated, but rapid progression of the abdominal disease was noted and the patient died in July 1997 without any sign of recurrent cerebral disease. Autopsy was not permitted.
3. Discussion An increased incidence of central nervous system metastases from ovarian carcinoma, has been attributed to prolonged survival achieved in the last decades with the use of aggressive cytoreductive surgery and effective platin-based chemotherapy [1,7]. Most cytotoxic drugs, in fact, do not cross or cross poorly the ‘‘intact’’ blood–brain barrier, and the brain may act as a ‘‘pharmacologic sanctuary’’ for metastatic disease. Long-term survival may explain the development of previous occult neoplastic foci in the central nervous system into symptomatic clinically detectable metastatic localizations [2,7]. The management of brain metastases from ovarian carcinoma is dependent on several factors including number and location of the metastasis, the general health condition of the patients, and the presence of the disease outside the central nervous system. Survival after diagnosis of brain metastases from ovarian carcinoma is usually very poor, and the morbidity and mortality associated with various treatment modalities are high. This has led some investigators to suggest that it might not be appropriate to treat brain metastases [1,7]. Surgical resection followed by whole-brain radiotherapy is a viable option in patients with solitary and / or resectable metastases in presence of control of systemic disease [2]. Patchell et al. demonstrated that patients with single brain metastases treated with surgery plus radiotherapy had a longer survival, longer duration of neurologic improvement and lower rate of recurrence of brain metastases
compared to patients treated with whole-brain radiotherapy alone [8]. However, about half of the patients have single central nervous system lesions [2], thus amenable to surgical resection, and the role of surgery in multiple brain metastases remains controversial [9,10]. Moreover, neurosurgical treatment carries a high mortality rate ranging between 10–15% [8–10]. Several strategies have been proposed for unresectable brain metastases including intra-arterial chemotherapy, radiation therapy in association with cisplatin infusion, reversible osmotic blood–brain barrier modifiers, without however, any clear improvement in survival time [11]. Radiotherapy has been commonly used but the reported overall survival is very dismal, ranging between 5 and 10 months, and whole-brain irradiation incurs in a high incidence of permanent neurological deficit [2]. The role of chemotherapy in the management of central nervous system metastases remains unclear. Recent reports have demonstrated objective response of CNS metastases from ovarian cancer [4–6] and the addition of systemic chemotherapy, especially platin-based regimen, improves local control of brain metastases and may help to control disease outside the CNS and thus improve the median survival [3]. Carboplatin has been used with some success in the treatment of primary and recurrent cerebral tumors in children [12] and for secondary cerebral deposits from lung cancer [13]. Despite its high molecular weight and low lipid solubility carboplatin does seem to cross the blood–brain barrier which has probably been damaged by the tumor. Brain tumor concentrations of carboplatin have been shown to be higher than those of surrounding tissue, particularly cerebrospinal fluid, while it also achieves an eight times greater level than cisplatin in brain tissue [14]. Cooper and colleagues reported three women treated with carboplatin for cerebral metastases from ovarian carcinoma. Two achieved a partial response and one had complete remission of the cerebral lesions [6]. Vlasveld et al. reported an ovarian cancer patient who achieved complete remission of the brain metastases after a single dose of carboplatin (800 mg / m 2 ) [5]. Aiba and colleagues reported a patient who achieved complete remission of cerebellar metastasis following three courses of cisplatin, adriamycin and cyclophosphamide [4]. It is interesting to note that our patient developed brain metastases 7 months after the completion of second-line chemotherapy with paclitaxel, suggesting that this drug has limited influence on preventing cerebral involvement. This is in agreement with a previous report in which a patient treated with paclitaxel achieved a complete clinical response of abdominal and pelvic disease, but simultaneously developed central nervous system metastases. The Authors concluded that paclitaxel failed to cross the blood–brain barrier [15]. Carboplatin should be considered in patients with inoperable or multiple brain metastases from ovarian car-
G. Cormio et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 78 (1998) 91 – 93
cinoma. This platin analogue is simple to administer on an outpatient basis, is generally well-tolerated, and has been shown in this and in previous reports [5,6] to cause significant remission of central nervous system metastases. Another advantage is that, unlike surgery and radiotherapy, carboplatin is potentially effective against occult recurrent disease outside the central nervous system. Carboplatin may afford rapid subjective and objective relief of the neurologic symptomatolgy, and may result in a significant improvement in survival times with a good quality of life.
References [1] Mayer RJ, Berkowitz RS, Griffiths CT. Central nervous system involvement by ovarian carcinoma: a complication of prolonged survival with metastatic disease. Cancer 1978;41:776–83. [2] Cormio G, Maneo A, Parma G, Pittelli MR, Miceli DM, Bonazzi C. Central nervous system metastases in patients with ovarian carcinoma. Ann Oncol 1995;6(6):571–4. [3] Rodriguez GC, Soper JT, Berchuck A et al. Improved palliation of cerebral metastases in epithelial ovarian cancer using a combined modality approach including radiation therapy, chemotherapy and surgery. J Clin Oncol 1992;10(10):1553–60. [4] Aiba T, Koyama M, Watanabe T, Miyazawa N. Brain metastases of ovarian cancer treated with chemotherapy including cisplatin: A case report. No Shinkei Geka (Neurol Surg) 1989;17(2):159–61. [5] Vlasveld LT, Beynen JH, Boogerd W, Ten-Bokkel-Huinink WW, Rodenhuis S. Complete remission of brain metastases of ovarian cancer following high-dose carboplatin: A case report and pharmacokinetic study. Cancer Chemother Pharmacol 1990;25(5):382– 3.
93
[6] Cooper KG, Kitchener HC, Parkin DE. Cerebral metastases from epithelial ovarian carcinoma treated with carboplatin. Gynecol Oncol 1994;55:318–23. [7] Budd GT, Webster KD, Reimer RR, Martimbean P, Livingston RB. Treatment of advanced ovarian cancer with cisplatin, adriamycin and cyclophosphamide: effect of treatment and incidence of intracranial metastases. J Surg Oncol 1983;29:192–5. [8] Patchell RA, Tibbs PA, Walsh JW et al. A randomized trial of surgery in the treatment of single metastases to the brain. New Engl J Med 1990;322:494–500. [9] Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg 1993;79:210–6. [10] Hazuka MB, Burleson WD, Stroud DN, Leonard CE, Lillehei KO, Kinzie JJ. Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J Clin Oncol 1993;11:369–73. [11] Wright DC, Delaney TF, Buckner JC. Treatment of metastatic cancer to the brain. In: De Vita VT Jr, Hellman S, Rosemberg SA, editors. Cancer: principles and practice of oncology. 4th ed. Philadelphia: Lippincott, 1993:2170–2186. [12] Allen JC, Walker RW, Luk E, Jannings M, Barfoot F. Carboplatin and recurrent childhood brain tumors. J Clin Oncol 1987;5:459–63. [13] Groen HJ, Smit EF, Haaxma-Reiche H, Postmus PE. Carboplatin as a second line treatment for recurrent or progressive brain metastases from small cell lung cancer. Eur J Cancer 1993;29:1696–9. [14] Wagstaff AJ, Ward A, Benfield R, Heel RC. Carboplatin: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs 1989;37:162–90. [15] Seewaldt VL, Figge DC, Greer BJ, Tamimi HK, Brown SD, Cain JM. Primary central nervous system recurrence after paclitaxel tharapy for epithelial ovarian malignancy. Gynecol Oncol 1994;55:456–8.
Complete remission of brain metastases from ovarian carcinoma with carboplatin 1, Gennaro Cormio *, Antonio Gabriele, Andrea Maneo, Gerardo Zanetta, Cristina Bonazzi, Fabio Landoni
Gynecologic Oncology Unit, University of Milano, Istituto di Scienze Biomediche, Ospedale S. Gerardo, Monza, Italy Received 26 August 1997; received in revised form 30 October 1997; accepted 18 December 1997
Abstract Central nervous system involvement by epithelial ovarian carcinoma is rare. We report the case of a 49 year old woman with stage IV serous carcinoma of the ovary who developed multiple cerebral and cerebellar metastases 7 months after achieving complete response to platin-based chemotherapy. Eight courses of carboplatin (400 mg / m 2 ) were administered and after the second cycle complete remission of the brain deposits occured. The treatment afforded rapid subjective and objective relief and was associated with a good quality of life. Abdominal recurrent disease was diagnosed 22 months after treatment for brain involvement. Paltin-based chemotherapy was reinstated, but the patient died from progressive adbominal disease without any sign of cerebral involvement and any neurological symptomatology. Carboplatin should be considered for the treatment of ovarian carcinoma metastatic to the brain. 1998 Elsevier Science Ireland Ltd. Keywords: Brain metastasis; Ovarian carcinoma; Carboplatin
1. Introduction The central nervous system has traditionally been considered an uncommon site for metastatic disease from epithelial ovarian carcinoma, and this complication has been reported to occur in about 1% of patients [1,2]. Traditionally neurosurgery and radiotherapy have been employed in patients with brain metastases. Both treatment modalities, may provide a significant palliation, improving the quality of life in most patients. However, they carry an associated morbidity and mortality, and long-term remission occurs only in a limited number of cases [2,3]. To date, only few reports have dealt with the use of chemotherapy to treat patients with central nervous system metastases from ovarian carcinoma [3–6], and the role of chemotherapy in this setting remains unclear. *Corresponding author. Tel.: 139 80 5478986; fax: 139 80 5473248. Visiting Research Fellow from the Department of Gynecology and Obstetrics, University of Bari, ITALY.
1
We present the case of a patient who achieved complete remission of multiple cerebral and cerebellar metastases from ovarian carcinoma with single-agent carboplatin, and review the literature on this rare topic.
2. Case report A 49 year old woman presented with abdominal swelling and a pelvic mass in September 1993. A stage IV poorly differentiated, serous carcinoma of the ovary was diagnosed. She underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy and subcolic omentectomy, followed by 6 courses of cisplatin 75 mg / m 2 and cyclophosphamide 750 mg / m 2 at 3 weekly intervals. At the completion of chemotherapy the patient underwent second-look laparotomy and microscopic residual disease was found only in two biopsies. Six pulses of paclitaxel 175 mg / m 2 were administered until June 1994. The patient did well until January 1995, when complained
0301-2115 / 98 / $19.00 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0301-2115( 98 )00009-8
92
G. Cormio et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 78 (1998) 91 – 93
of nausea, vomiting, vertigo and persisting sinus-type headaches. A cranial MR scan revealed multiple metastases in both the cerebellar and cerebral cortex. Biopsy of the lesions was not attempted. CT scan of the thorax, abdomen and pelvis showed no clinical evidence of recurrent disease. Serum CA-125 level was 542 IU / ml. Acute symptomatic relief was gained using dexamethasone and treatment using carboplatin 400 mg / m 2 at 3 weekly interval was commenced. A cranial MR scan following the first two pulses of chemotherapy demonstrated complete disappearance of the brain deposits; CA-125 also returned to normal values. At the completion of the eight pulse of carboplatin in May 1995 total-body CT scan was made and no sign of disease could be detected. The patient did well until March 1997 when complained of abdominal swelling and an increase in CA-125 to 145 IU / ml. Abdomino-pelvic CT scan revealed the presence of ascitis and multiple peritoneal nodules (less than 2 cm); a cranial MR scan however, was negative and neurological examination was normal. Platin-based chemotherapy was reinstated, but rapid progression of the abdominal disease was noted and the patient died in July 1997 without any sign of recurrent cerebral disease. Autopsy was not permitted.
3. Discussion An increased incidence of central nervous system metastases from ovarian carcinoma, has been attributed to prolonged survival achieved in the last decades with the use of aggressive cytoreductive surgery and effective platin-based chemotherapy [1,7]. Most cytotoxic drugs, in fact, do not cross or cross poorly the ‘‘intact’’ blood–brain barrier, and the brain may act as a ‘‘pharmacologic sanctuary’’ for metastatic disease. Long-term survival may explain the development of previous occult neoplastic foci in the central nervous system into symptomatic clinically detectable metastatic localizations [2,7]. The management of brain metastases from ovarian carcinoma is dependent on several factors including number and location of the metastasis, the general health condition of the patients, and the presence of the disease outside the central nervous system. Survival after diagnosis of brain metastases from ovarian carcinoma is usually very poor, and the morbidity and mortality associated with various treatment modalities are high. This has led some investigators to suggest that it might not be appropriate to treat brain metastases [1,7]. Surgical resection followed by whole-brain radiotherapy is a viable option in patients with solitary and / or resectable metastases in presence of control of systemic disease [2]. Patchell et al. demonstrated that patients with single brain metastases treated with surgery plus radiotherapy had a longer survival, longer duration of neurologic improvement and lower rate of recurrence of brain metastases
compared to patients treated with whole-brain radiotherapy alone [8]. However, about half of the patients have single central nervous system lesions [2], thus amenable to surgical resection, and the role of surgery in multiple brain metastases remains controversial [9,10]. Moreover, neurosurgical treatment carries a high mortality rate ranging between 10–15% [8–10]. Several strategies have been proposed for unresectable brain metastases including intra-arterial chemotherapy, radiation therapy in association with cisplatin infusion, reversible osmotic blood–brain barrier modifiers, without however, any clear improvement in survival time [11]. Radiotherapy has been commonly used but the reported overall survival is very dismal, ranging between 5 and 10 months, and whole-brain irradiation incurs in a high incidence of permanent neurological deficit [2]. The role of chemotherapy in the management of central nervous system metastases remains unclear. Recent reports have demonstrated objective response of CNS metastases from ovarian cancer [4–6] and the addition of systemic chemotherapy, especially platin-based regimen, improves local control of brain metastases and may help to control disease outside the CNS and thus improve the median survival [3]. Carboplatin has been used with some success in the treatment of primary and recurrent cerebral tumors in children [12] and for secondary cerebral deposits from lung cancer [13]. Despite its high molecular weight and low lipid solubility carboplatin does seem to cross the blood–brain barrier which has probably been damaged by the tumor. Brain tumor concentrations of carboplatin have been shown to be higher than those of surrounding tissue, particularly cerebrospinal fluid, while it also achieves an eight times greater level than cisplatin in brain tissue [14]. Cooper and colleagues reported three women treated with carboplatin for cerebral metastases from ovarian carcinoma. Two achieved a partial response and one had complete remission of the cerebral lesions [6]. Vlasveld et al. reported an ovarian cancer patient who achieved complete remission of the brain metastases after a single dose of carboplatin (800 mg / m 2 ) [5]. Aiba and colleagues reported a patient who achieved complete remission of cerebellar metastasis following three courses of cisplatin, adriamycin and cyclophosphamide [4]. It is interesting to note that our patient developed brain metastases 7 months after the completion of second-line chemotherapy with paclitaxel, suggesting that this drug has limited influence on preventing cerebral involvement. This is in agreement with a previous report in which a patient treated with paclitaxel achieved a complete clinical response of abdominal and pelvic disease, but simultaneously developed central nervous system metastases. The Authors concluded that paclitaxel failed to cross the blood–brain barrier [15]. Carboplatin should be considered in patients with inoperable or multiple brain metastases from ovarian car-
G. Cormio et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 78 (1998) 91 – 93
cinoma. This platin analogue is simple to administer on an outpatient basis, is generally well-tolerated, and has been shown in this and in previous reports [5,6] to cause significant remission of central nervous system metastases. Another advantage is that, unlike surgery and radiotherapy, carboplatin is potentially effective against occult recurrent disease outside the central nervous system. Carboplatin may afford rapid subjective and objective relief of the neurologic symptomatolgy, and may result in a significant improvement in survival times with a good quality of life.
References [1] Mayer RJ, Berkowitz RS, Griffiths CT. Central nervous system involvement by ovarian carcinoma: a complication of prolonged survival with metastatic disease. Cancer 1978;41:776–83. [2] Cormio G, Maneo A, Parma G, Pittelli MR, Miceli DM, Bonazzi C. Central nervous system metastases in patients with ovarian carcinoma. Ann Oncol 1995;6(6):571–4. [3] Rodriguez GC, Soper JT, Berchuck A et al. Improved palliation of cerebral metastases in epithelial ovarian cancer using a combined modality approach including radiation therapy, chemotherapy and surgery. J Clin Oncol 1992;10(10):1553–60. [4] Aiba T, Koyama M, Watanabe T, Miyazawa N. Brain metastases of ovarian cancer treated with chemotherapy including cisplatin: A case report. No Shinkei Geka (Neurol Surg) 1989;17(2):159–61. [5] Vlasveld LT, Beynen JH, Boogerd W, Ten-Bokkel-Huinink WW, Rodenhuis S. Complete remission of brain metastases of ovarian cancer following high-dose carboplatin: A case report and pharmacokinetic study. Cancer Chemother Pharmacol 1990;25(5):382– 3.
93
[6] Cooper KG, Kitchener HC, Parkin DE. Cerebral metastases from epithelial ovarian carcinoma treated with carboplatin. Gynecol Oncol 1994;55:318–23. [7] Budd GT, Webster KD, Reimer RR, Martimbean P, Livingston RB. Treatment of advanced ovarian cancer with cisplatin, adriamycin and cyclophosphamide: effect of treatment and incidence of intracranial metastases. J Surg Oncol 1983;29:192–5. [8] Patchell RA, Tibbs PA, Walsh JW et al. A randomized trial of surgery in the treatment of single metastases to the brain. New Engl J Med 1990;322:494–500. [9] Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg 1993;79:210–6. [10] Hazuka MB, Burleson WD, Stroud DN, Leonard CE, Lillehei KO, Kinzie JJ. Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J Clin Oncol 1993;11:369–73. [11] Wright DC, Delaney TF, Buckner JC. Treatment of metastatic cancer to the brain. In: De Vita VT Jr, Hellman S, Rosemberg SA, editors. Cancer: principles and practice of oncology. 4th ed. Philadelphia: Lippincott, 1993:2170–2186. [12] Allen JC, Walker RW, Luk E, Jannings M, Barfoot F. Carboplatin and recurrent childhood brain tumors. J Clin Oncol 1987;5:459–63. [13] Groen HJ, Smit EF, Haaxma-Reiche H, Postmus PE. Carboplatin as a second line treatment for recurrent or progressive brain metastases from small cell lung cancer. Eur J Cancer 1993;29:1696–9. [14] Wagstaff AJ, Ward A, Benfield R, Heel RC. Carboplatin: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs 1989;37:162–90. [15] Seewaldt VL, Figge DC, Greer BJ, Tamimi HK, Brown SD, Cain JM. Primary central nervous system recurrence after paclitaxel tharapy for epithelial ovarian malignancy. Gynecol Oncol 1994;55:456–8.