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Intrathecal chemotherapy for recurrent central nervous system intraocular lymphoma
Intrathecal Chemotherapy for Recurrent Central Nervous System Intraocular Lymphoma John O. Mason, III, MD,1 David H. Fischer, MD2 Purpose: To report the use of intrathecal chemotherapy for two patients with recurrent central nervous system (CNS) intraocular lymphoma. Design: Two interventional case reports. Participants: The clinical course of two patients with documented recurrent CNS intraocular lymphoma were retrospectively reviewed. Intervention: Both patients had previously undergone external beam radiation therapy to the orbit and brain, as well as systemic methotrexate (MTX) and intrathecal cytarabine (Ara-C), for primary CNS intraocular lymphoma. Both patients developed recurrent CNS intraocular lymphoma and treatment involved intrathecal MTX and Ara-C delivered by means of an Ommaya reservoir. Main Outcome Measure: Survival and resolution of intraocular lymphoma. Results: Complete remission of the CNS intraocular lymphoma was seen in both patients. Both patients maintain reading visual acuity in at least one eye. Both patients remain disease free with lymphoma in remission for greater than 5 years after initial diagnosis. Conclusions: Intrathecal chemotherapy for recurrent CNS intraocular lymphoma seems to be effective in preserving vision and possibly increasing survival. Ophthalmology 2003;110:1241–1244 © 2003 by the American Academy of Ophthalmology.
Two clinically distinct forms of non-Hodgkin’s lymphoma, central nervous system (CNS), and systemic lymphoma, frequently involve the eye. The CNS type arises within the brain, spinal cord, leptomeninges, or eye and may spread throughout the CNS. In contrast, systemic NHL usually arises outside the CNS, and eye involvement occurs by invasion through the choroidal circulation. A number of studies suggest that intraocular lymphoma, in the absence of systemic lymphoma, is a subset of CNS lymphoma.1,2 Primary intraocular lymphoma is a rare condition that has a poor visual and systemic prognosis, in that CNS involvement occurs in approximately 50% to 80% of patients.3–5 The combination of radiation and chemotherapy has been shown to be effective in inducing remission of primary CNS intraocular lymphoma.5–7 However, visual prognosis and survival rates remain poor. Recurrent CNS intraocular lymphoma carries an even worse prognosis for vision and survival. The optimal management of recurrent disease remains unknown, but we have Originally received: March 27, 2002. Accepted: December 2, 2002. Manuscript no. 220239. 1 University of Alabama at Birmingham, Department of Ophthalmology, Birmingham, Alabama. 2 Wills Eye Hospital, Philadelphia, Pennsylvania. Support provided by Research to Prevent Blindness, New York, New York. Reprint requests to John O. Mason, III, MD, University of Alabama at Birmingham, Department of Ophthalmology, 700 South 18th Street, Suite 505, Birmingham, AL 35233. © 2003 by the American Academy of Ophthalmology Published by Elsevier Inc.
successfully treated two patients with recurrent CNS intraocular lymphoma with intrathecal chemotherapy involving methotrexate (MTX) and cytarabine (Ara-C) with an Ommaya reservoir.
Case Report 1 A 70-year-old white male was seen with a 6-month history of decreased vision in his right eye. Best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left eye. Ophthalmologic examination was remarkable for vitreous cells in the right eye. The left eye was unremarkable on clinical examination. The age of the patient and the vitreous cells in the right eye were suspicious for intraocular lymphoma, and a complete workup, including blood testing, magnetic resonance imaging (MRI), and lumbar puncture, was performed, all of which were normal. A vitrectomy to the right eye was performed, and cytologic analysis of the vitreous aspirate revealed no convincing evidence of lymphoma cells. The patient was seen 1 year later with vitreous cells in the left eye and underwent a vitrectomy, for which the vitreous aspirate cytology was consistent with primary intraocular lymphoma. Further testing (MRI and lumbar puncture) by an oncologist showed no evidence of CNS involvement. He was treated with high-dose MTX, 3600 CGY of external beam radiation therapy (EBRT) to the optic nerves and globe, and Ara-C given intrathecally through an Ommaya reservoir. Approximately 18 months after his diagnosis, clinical examination revealed optic nerve swelling in the right eye and vision decreased to light perception (Fig 1). Over the ensuing 2 weeks, white subretinal lesions were noted in the right eye compatible with a diagnosis of recurrent large cell lymphoma. MRI was performed and revealed CNS involvement. EBRT to the ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00268-9
1241
Ophthalmology Volume 110, Number 6, June 2003
Figure Figure Figure Figure
1. 2. 3. 4.
Color photograph, right eye, showing optic nerve swelling and subretinal white lesions. Fluorescein angiography, left eye, showing alternating areas of hyperfluorescence and hypofluorescence in the macula. Color photograph, left eye, showing large white subretinal lesions. Color photograph, left eye, after intrathecal chemotherapy, showing total resolution of white subretinal lesions.
brain was performed. Three months after this treatment, optic nerve swelling had completely resolved in the right eye, but optic atrophy ensued with vision remaining light perception. Vision in the left eye remained 20/25. Two years after initial diagnosis, the left eye developed white subretinal lesions temporal to the macula, and fluorescein angiography revealed alternating areas of hyperfluorescence and hypofluorescence (Fig 2). MRI confirmed recurrent CNS intraocular lymphoma. Intrathecal MTX, as well as intrathecal Ara-C, induced prompt regression of the subretinal infiltrates in the left eye, and the patient has maintained a visual acuity of 20/25 in the left eye. The patient, now 5 years after his initial diagnosis, has had no recurrences of CNS or intraocular lymphoma.
Case Report 2 A 53-year-old white male was diagnosed with CNS lymphoma by MRI and lumbar puncture and was treated by his oncologist with EBRT to the brain and orbits, intravenous MTX, and intravenous Ara-C. Six months after the diagnosis, the patient developed decreasing vision in the left eye and was referred for evaluation. Initial visual acuity was 20/20 in the right eye and 20/100 in the
1242
left eye. The right eye was clinically unremarkable. The left eye exhibited sheets of cells in the vitreous cavity. Intraocular lymphoma was suspected, and the patient underwent a vitrectomy to the left eye. The cytologic analysis revealed atypical lymphocytes, not lymphoma cells. The vision improved to 20/20. An MRI and lumbar puncture were normal. Two years after the initial diagnosis, the patient developed recurrent decreased vision to 20/70 in the left eye and white subretinal infiltrates in the left eye. A vitrectomy and subretinal biopsy were performed. Cytologic analysis revealed atypical lymphocytes with no definitive evidence of lymphoma cells. The MRI and lumbar puncture were normal. Twenty-six months after the diagnosis, the patient developed vitreous cells in the right eye and enlarging subretinal infiltrates in the left eye (Fig 3). The vision was 20/100 in the right eye and 20/100 in the left eye. Vitrectomy was performed in the right eye, and cytologic analysis revealed lymphoma cells. MRI and lumbar puncture were performed and were consistent with a diagnosis of CNS lymphoma. The patient was treated with intrathecal Ara-C and intrathecal MTX, which caused total regression of the subretinal infiltrates (Fig 4), as well as the vitreous cells. The patient’s visual acuity remains 20/25 in both eyes. The patient is now 5 years after the initial diagnosis and has had no further recurrences of CNS or intraocular lymphoma.
Intrathecal Chemotherapy 䡠 Mason and Fischer
Discussion Intraocular lymphoma is a rare condition that often masquerades as chronic vitritis.8 The initial diagnosis may be delayed and may require multiple vitreous specimens because of the difficulty of identifying lymphoma cells from biopsy specimens.9,10 Radiation and chemotherapy play a major role in achieving remission in patients with CNS and intraocular involvement. However, the median survival remains approximately 3 years.7 In cases of isolated ocular lymphoma, 50% to 80% will eventually develop CNS involvement.3– 6 Therapy for intraocular lymphoma has proved disappointing, with a high incidence of CNS lymphoma leading to death. Radiation has been the standard local treatment for both CNS and ocular disease. Although isolated radiotherapy for CNS intraocular lymphoma achieves a high rate of initial control of disease, it results in much shorter survival times compared with its use in treatment of lymphomas elsewhere in the body.11 Radiotherapy alone in the treatment of CNS lymphoma has a low cure rate and high local recurrence rate. Therefore, isolated radiotherapy is no longer the standard of treatment, having been supplanted by regimens containing chemotherapy. Because no clear advantage has been established for one particular protocol, the literature is abundant with anecdotal protocols using combinations of chemotherapy with and without EBRT. The success of MTX-containing regimens over other therapeutic protocols has become fairly certain.6 MTX intravenously penetrates into the brain parenchyma proportionate to serum levels.12 When administered intrathecally, cerebral spinal fluid distribution is good, but there is little penetration into the parenchyma.13 In contrast, intrathecal Ara-C penetrates the blood– brain barrier well and achieves good parenchymal levels. Blay et al 6 retrospectively analyzed prognostic factors for survival in 226 patients treated with a variety of regimens. Patients receiving chemotherapy with or without radiotherapy had a significantly better survival rate compared with those treated with radiation alone. Patients treated with regimens including methotrexate had a better survival than patients treated with other regimens. A retrospective analysis of patients treated with combined radiotherapy and chemotherapy (including MTX) to a group treated with radiotherapy alone showed the combination therapy to have a twofold greater median survival time.7 Therefore, initial therapy for CNS intraocular lymphoma should, at a minimum, include chemotherapy containing MTX. However, there is no best treatment protocol for recurrent CNS intraocular lymphoma. The small number of patients diagnosed with CNS lymphoma each year make a prospective controlled therapeutic trial difficult, and this is made even more challenging knowing that even fewer patients live long enough to develop recurrent intraocular disease. However, patients with recurrent intraocular lymphoma do present a diagnostic dilemma. Should we treat only the eye, knowing that most of these patients may well have recurrence of CNS lymphoma? Or, should we treat systemically, which has been shown in prior reports to cause CNS and intraocular regression of lymphoma cells?14 –16 Intravitreal injections of MTX have been reported in a small number of patients with intraocular lymphoma.17 Although
intravitreal injections may be an adjunctive treatment for intraocular lymphoma, the drawback is that multiple injections must be given over long periods of time. In addition, intravitreal injections do not address the problem of CNS recurrence. Freilich et al,18 in 1996, did report that intrathecal and intravenous MTX (with intravenous vincristine and oral procarbazine) achieved intraocular regression in two patients. Our data suggest that intrathecal chemotherapy alone may be beneficial for recurrent intraocular lymphoma. The mechanism by which intrathecal delivery of chemotherapy results in intraocular lymphoma regression is more uncertain. We propose that intrathecal administration of MTX and Ara-C results in high plasma levels, which may persist and cause increased intraocular penetration, and therefore lymphoma regression. Intrathecal MTX administration has been previously reported to result in slow absorption into the plasma from the cerebrospinal fluid, resulting in MTX plasma levels that persist two to three times longer than an equivalent intravenous dose. Because of its pharmacokinetics, intrathecal MTX administration can result in prolonged cytotoxic levels and could produce systemic cell death in a sensitive tumor.19 At least one report has shown toxic systemic MTX levels after intrathecal MTX administration.20 Intrathecal MTX and intrathecal Ara-C caused regression of intraocular lymphoma in both of our patients. We believe that therapy directed at the entire CNS (intrathecal) may not only cause regression of recurrent ocular disease but also may prevent further CNS recurrences and prolong survival. Our data suggest that aggressive intrathecal chemotherapy treatment of recurrences may result in a more favorable outcome in some cases. Further case series with a larger number of patients are necessary to evaluate this promising treatment for recurrent intraocular lymphoma.
References 1. Paulus W. Classification, pathogenesis and molecular pathology of primary CNS lymphomas. J Neurooncol 1999;43: 203– 8. 2. Schabet M. Epidemiology of primary CNS lymphoma. J Neurooncol 1999;43:199 –201. 3. Char DH, Ljung BM, Miller T, Phillips T. Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Ophthalmology 1988;95:625–30. 4. Merchant A, Foster CS. Primary intraocular lymphoma. Int Ophthalmol Clin 1977;37:101–15. 5. DeAngelis LM. Current management of primary central nervous system lymphoma. Oncol 1995;9:63,71; discussion 71,75– 6,78. 6. Blay JY, Conroy T, Chevreau C, et al. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 1998;16:864 –71. 7. DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol 1992;10:635– 43.
1243
Ophthalmology Volume 110, Number 6, June 2003 8. Rothova A, Ooijman F, Kerkhoff F, et al. Uveitis masquerade syndromes. Ophthalmology 2001;108:386 –99. 9. Peterson K, Gordon KB, Heinemann MH, DeAngelis LM. The clinical spectrum of ocular lymphoma. Cancer 1993;72: 843–9. 10. Ciulla TA, Pesavento RD, Yoo S. Subretinal aspiration biopsy of ocular lymphoma. Am J Ophthalmol 1997;123:420 –2. 11. Nelson DF. Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neurooncol 1999;43: 241–7. 12. Balis FM, Poplack DG. Central nervous system pharmacology of anti-leukemic drugs. Am J Pediatric Hematol Oncol 1989; 11:74 – 86. 13. Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculosisternal perfusion. J Pharmacol Exp Ther 1975;195:73– 83. 14. Maher EA, Fine HA. Primary CNS lymphoma. Semin Oncol 1999;26:346 –56. 15. Strauchen JA, Dalton J, Friedman AH. Chemotherapy in the
1244
16.
17.
18.
19.
20.
management of intraocular lymphoma. Cancer 1989;63:1918 – 21. Baumann MA, Ritch PS, Hande KR, et al. Treatment of intraocular lymphoma with high-dose Ara-C. Cancer 1986;57: 1273–5. Fishburne BC, Wilson DJ, Rosenbaum JT, Neuwelt EA. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol 1997;115:1152– 6. Freilich RJ, Delattre JY, Monjour A, DeAngelis LM. Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurol 1996;46: 435–9. Jacobs SA, Bleyer WA, Chabner BA, Johns DG. Altered plasma pharmacokinetics of methotrexate administered intrathecally. Lancet 1975;1:465– 6. Simmons EO, Somberg KA. Acute tumor lysis syndrome after intrathecal methotrexate administration. Cancer 1991;67: 2062–5.
Two clinically distinct forms of non-Hodgkin’s lymphoma, central nervous system (CNS), and systemic lymphoma, frequently involve the eye. The CNS type arises within the brain, spinal cord, leptomeninges, or eye and may spread throughout the CNS. In contrast, systemic NHL usually arises outside the CNS, and eye involvement occurs by invasion through the choroidal circulation. A number of studies suggest that intraocular lymphoma, in the absence of systemic lymphoma, is a subset of CNS lymphoma.1,2 Primary intraocular lymphoma is a rare condition that has a poor visual and systemic prognosis, in that CNS involvement occurs in approximately 50% to 80% of patients.3–5 The combination of radiation and chemotherapy has been shown to be effective in inducing remission of primary CNS intraocular lymphoma.5–7 However, visual prognosis and survival rates remain poor. Recurrent CNS intraocular lymphoma carries an even worse prognosis for vision and survival. The optimal management of recurrent disease remains unknown, but we have Originally received: March 27, 2002. Accepted: December 2, 2002. Manuscript no. 220239. 1 University of Alabama at Birmingham, Department of Ophthalmology, Birmingham, Alabama. 2 Wills Eye Hospital, Philadelphia, Pennsylvania. Support provided by Research to Prevent Blindness, New York, New York. Reprint requests to John O. Mason, III, MD, University of Alabama at Birmingham, Department of Ophthalmology, 700 South 18th Street, Suite 505, Birmingham, AL 35233. © 2003 by the American Academy of Ophthalmology Published by Elsevier Inc.
successfully treated two patients with recurrent CNS intraocular lymphoma with intrathecal chemotherapy involving methotrexate (MTX) and cytarabine (Ara-C) with an Ommaya reservoir.
Case Report 1 A 70-year-old white male was seen with a 6-month history of decreased vision in his right eye. Best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left eye. Ophthalmologic examination was remarkable for vitreous cells in the right eye. The left eye was unremarkable on clinical examination. The age of the patient and the vitreous cells in the right eye were suspicious for intraocular lymphoma, and a complete workup, including blood testing, magnetic resonance imaging (MRI), and lumbar puncture, was performed, all of which were normal. A vitrectomy to the right eye was performed, and cytologic analysis of the vitreous aspirate revealed no convincing evidence of lymphoma cells. The patient was seen 1 year later with vitreous cells in the left eye and underwent a vitrectomy, for which the vitreous aspirate cytology was consistent with primary intraocular lymphoma. Further testing (MRI and lumbar puncture) by an oncologist showed no evidence of CNS involvement. He was treated with high-dose MTX, 3600 CGY of external beam radiation therapy (EBRT) to the optic nerves and globe, and Ara-C given intrathecally through an Ommaya reservoir. Approximately 18 months after his diagnosis, clinical examination revealed optic nerve swelling in the right eye and vision decreased to light perception (Fig 1). Over the ensuing 2 weeks, white subretinal lesions were noted in the right eye compatible with a diagnosis of recurrent large cell lymphoma. MRI was performed and revealed CNS involvement. EBRT to the ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00268-9
1241
Ophthalmology Volume 110, Number 6, June 2003
Figure Figure Figure Figure
1. 2. 3. 4.
Color photograph, right eye, showing optic nerve swelling and subretinal white lesions. Fluorescein angiography, left eye, showing alternating areas of hyperfluorescence and hypofluorescence in the macula. Color photograph, left eye, showing large white subretinal lesions. Color photograph, left eye, after intrathecal chemotherapy, showing total resolution of white subretinal lesions.
brain was performed. Three months after this treatment, optic nerve swelling had completely resolved in the right eye, but optic atrophy ensued with vision remaining light perception. Vision in the left eye remained 20/25. Two years after initial diagnosis, the left eye developed white subretinal lesions temporal to the macula, and fluorescein angiography revealed alternating areas of hyperfluorescence and hypofluorescence (Fig 2). MRI confirmed recurrent CNS intraocular lymphoma. Intrathecal MTX, as well as intrathecal Ara-C, induced prompt regression of the subretinal infiltrates in the left eye, and the patient has maintained a visual acuity of 20/25 in the left eye. The patient, now 5 years after his initial diagnosis, has had no recurrences of CNS or intraocular lymphoma.
Case Report 2 A 53-year-old white male was diagnosed with CNS lymphoma by MRI and lumbar puncture and was treated by his oncologist with EBRT to the brain and orbits, intravenous MTX, and intravenous Ara-C. Six months after the diagnosis, the patient developed decreasing vision in the left eye and was referred for evaluation. Initial visual acuity was 20/20 in the right eye and 20/100 in the
1242
left eye. The right eye was clinically unremarkable. The left eye exhibited sheets of cells in the vitreous cavity. Intraocular lymphoma was suspected, and the patient underwent a vitrectomy to the left eye. The cytologic analysis revealed atypical lymphocytes, not lymphoma cells. The vision improved to 20/20. An MRI and lumbar puncture were normal. Two years after the initial diagnosis, the patient developed recurrent decreased vision to 20/70 in the left eye and white subretinal infiltrates in the left eye. A vitrectomy and subretinal biopsy were performed. Cytologic analysis revealed atypical lymphocytes with no definitive evidence of lymphoma cells. The MRI and lumbar puncture were normal. Twenty-six months after the diagnosis, the patient developed vitreous cells in the right eye and enlarging subretinal infiltrates in the left eye (Fig 3). The vision was 20/100 in the right eye and 20/100 in the left eye. Vitrectomy was performed in the right eye, and cytologic analysis revealed lymphoma cells. MRI and lumbar puncture were performed and were consistent with a diagnosis of CNS lymphoma. The patient was treated with intrathecal Ara-C and intrathecal MTX, which caused total regression of the subretinal infiltrates (Fig 4), as well as the vitreous cells. The patient’s visual acuity remains 20/25 in both eyes. The patient is now 5 years after the initial diagnosis and has had no further recurrences of CNS or intraocular lymphoma.
Intrathecal Chemotherapy 䡠 Mason and Fischer
Discussion Intraocular lymphoma is a rare condition that often masquerades as chronic vitritis.8 The initial diagnosis may be delayed and may require multiple vitreous specimens because of the difficulty of identifying lymphoma cells from biopsy specimens.9,10 Radiation and chemotherapy play a major role in achieving remission in patients with CNS and intraocular involvement. However, the median survival remains approximately 3 years.7 In cases of isolated ocular lymphoma, 50% to 80% will eventually develop CNS involvement.3– 6 Therapy for intraocular lymphoma has proved disappointing, with a high incidence of CNS lymphoma leading to death. Radiation has been the standard local treatment for both CNS and ocular disease. Although isolated radiotherapy for CNS intraocular lymphoma achieves a high rate of initial control of disease, it results in much shorter survival times compared with its use in treatment of lymphomas elsewhere in the body.11 Radiotherapy alone in the treatment of CNS lymphoma has a low cure rate and high local recurrence rate. Therefore, isolated radiotherapy is no longer the standard of treatment, having been supplanted by regimens containing chemotherapy. Because no clear advantage has been established for one particular protocol, the literature is abundant with anecdotal protocols using combinations of chemotherapy with and without EBRT. The success of MTX-containing regimens over other therapeutic protocols has become fairly certain.6 MTX intravenously penetrates into the brain parenchyma proportionate to serum levels.12 When administered intrathecally, cerebral spinal fluid distribution is good, but there is little penetration into the parenchyma.13 In contrast, intrathecal Ara-C penetrates the blood– brain barrier well and achieves good parenchymal levels. Blay et al 6 retrospectively analyzed prognostic factors for survival in 226 patients treated with a variety of regimens. Patients receiving chemotherapy with or without radiotherapy had a significantly better survival rate compared with those treated with radiation alone. Patients treated with regimens including methotrexate had a better survival than patients treated with other regimens. A retrospective analysis of patients treated with combined radiotherapy and chemotherapy (including MTX) to a group treated with radiotherapy alone showed the combination therapy to have a twofold greater median survival time.7 Therefore, initial therapy for CNS intraocular lymphoma should, at a minimum, include chemotherapy containing MTX. However, there is no best treatment protocol for recurrent CNS intraocular lymphoma. The small number of patients diagnosed with CNS lymphoma each year make a prospective controlled therapeutic trial difficult, and this is made even more challenging knowing that even fewer patients live long enough to develop recurrent intraocular disease. However, patients with recurrent intraocular lymphoma do present a diagnostic dilemma. Should we treat only the eye, knowing that most of these patients may well have recurrence of CNS lymphoma? Or, should we treat systemically, which has been shown in prior reports to cause CNS and intraocular regression of lymphoma cells?14 –16 Intravitreal injections of MTX have been reported in a small number of patients with intraocular lymphoma.17 Although
intravitreal injections may be an adjunctive treatment for intraocular lymphoma, the drawback is that multiple injections must be given over long periods of time. In addition, intravitreal injections do not address the problem of CNS recurrence. Freilich et al,18 in 1996, did report that intrathecal and intravenous MTX (with intravenous vincristine and oral procarbazine) achieved intraocular regression in two patients. Our data suggest that intrathecal chemotherapy alone may be beneficial for recurrent intraocular lymphoma. The mechanism by which intrathecal delivery of chemotherapy results in intraocular lymphoma regression is more uncertain. We propose that intrathecal administration of MTX and Ara-C results in high plasma levels, which may persist and cause increased intraocular penetration, and therefore lymphoma regression. Intrathecal MTX administration has been previously reported to result in slow absorption into the plasma from the cerebrospinal fluid, resulting in MTX plasma levels that persist two to three times longer than an equivalent intravenous dose. Because of its pharmacokinetics, intrathecal MTX administration can result in prolonged cytotoxic levels and could produce systemic cell death in a sensitive tumor.19 At least one report has shown toxic systemic MTX levels after intrathecal MTX administration.20 Intrathecal MTX and intrathecal Ara-C caused regression of intraocular lymphoma in both of our patients. We believe that therapy directed at the entire CNS (intrathecal) may not only cause regression of recurrent ocular disease but also may prevent further CNS recurrences and prolong survival. Our data suggest that aggressive intrathecal chemotherapy treatment of recurrences may result in a more favorable outcome in some cases. Further case series with a larger number of patients are necessary to evaluate this promising treatment for recurrent intraocular lymphoma.
References 1. Paulus W. Classification, pathogenesis and molecular pathology of primary CNS lymphomas. J Neurooncol 1999;43: 203– 8. 2. Schabet M. Epidemiology of primary CNS lymphoma. J Neurooncol 1999;43:199 –201. 3. Char DH, Ljung BM, Miller T, Phillips T. Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Ophthalmology 1988;95:625–30. 4. Merchant A, Foster CS. Primary intraocular lymphoma. Int Ophthalmol Clin 1977;37:101–15. 5. DeAngelis LM. Current management of primary central nervous system lymphoma. Oncol 1995;9:63,71; discussion 71,75– 6,78. 6. Blay JY, Conroy T, Chevreau C, et al. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 1998;16:864 –71. 7. DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol 1992;10:635– 43.
1243
Ophthalmology Volume 110, Number 6, June 2003 8. Rothova A, Ooijman F, Kerkhoff F, et al. Uveitis masquerade syndromes. Ophthalmology 2001;108:386 –99. 9. Peterson K, Gordon KB, Heinemann MH, DeAngelis LM. The clinical spectrum of ocular lymphoma. Cancer 1993;72: 843–9. 10. Ciulla TA, Pesavento RD, Yoo S. Subretinal aspiration biopsy of ocular lymphoma. Am J Ophthalmol 1997;123:420 –2. 11. Nelson DF. Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neurooncol 1999;43: 241–7. 12. Balis FM, Poplack DG. Central nervous system pharmacology of anti-leukemic drugs. Am J Pediatric Hematol Oncol 1989; 11:74 – 86. 13. Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculosisternal perfusion. J Pharmacol Exp Ther 1975;195:73– 83. 14. Maher EA, Fine HA. Primary CNS lymphoma. Semin Oncol 1999;26:346 –56. 15. Strauchen JA, Dalton J, Friedman AH. Chemotherapy in the
1244
16.
17.
18.
19.
20.
management of intraocular lymphoma. Cancer 1989;63:1918 – 21. Baumann MA, Ritch PS, Hande KR, et al. Treatment of intraocular lymphoma with high-dose Ara-C. Cancer 1986;57: 1273–5. Fishburne BC, Wilson DJ, Rosenbaum JT, Neuwelt EA. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol 1997;115:1152– 6. Freilich RJ, Delattre JY, Monjour A, DeAngelis LM. Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurol 1996;46: 435–9. Jacobs SA, Bleyer WA, Chabner BA, Johns DG. Altered plasma pharmacokinetics of methotrexate administered intrathecally. Lancet 1975;1:465– 6. Simmons EO, Somberg KA. Acute tumor lysis syndrome after intrathecal methotrexate administration. Cancer 1991;67: 2062–5.