Management of primary intraocular lymphoma - Springer Link

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PCNSL and PIOL can rarely present as T-cell lymphomas. PIOL is initially confined to neural structures, thus distin- guishing it from primary orbital lymphoma ...
Management of Primary Intraocular Lymphoma Stella K. Kim, MD*, Chi-Chao Chan, MD, and Dana J. Wallace, BS

Address *University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, #443, Houston, TX 77030, USA. E-mail: [email protected] Current Oncology Reports 2005, 7:74–79 Current Science Inc. ISSN 1523-3790 Copyright © 2005 by Current Science Inc.

Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma (PCNSL) in which malignant lymphoid cells invade the retina, vitreous body, or optic nerve head. It is usually a large B-cell nonHodgkin’s lymphoma. PIOL typically presents as a vitritis that is unresponsive to corticosteroid therapy. Diagnosis of PIOL requires pathologic confirmation of malignant cells in specimens of the cerebrospinal fluid, vitreous, or chorioretinal biopsies. The optimal therapy for PIOL has yet to be determined. It is generally believed that PIOL should be treated with a combination of systemic chemotherapy, including high-dose methotrexate and radiotherapy. However, several new developments for PIOL with central nervous system involvement have been reported, including intrathecal therapy and autologous stem-cell transplantation. In addition, intravitreal methotrexate has been successful in the treatment of isolated recurrent ocular disease. This article provides an overview of treatment modalities for initial, recurrent, and relapsed PIOL.

Introduction Primary intraocular lymphoma (PIOL) is a disease entity in which malignant lymphoid cells invade the vitreous body, retina, or optic nerve head. PIOL is considered a subset of primary central nervous system lymphoma (PCNSL), a diffuse large B-cell non-Hodgkin’s lymphoma that can originate in the brain, spinal cord, leptomeninges, or eye. PCNSL and PIOL can rarely present as T-cell lymphomas. PIOL is initially confined to neural structures, thus distinguishing it from primary orbital lymphoma and systemic non-Hodgkin’s lymphoma, which either involve or metastasize via the choroidal circulation to the uvea and ocular adnexa (orbit, lacrimal gland, and conjunctiva). The majority of patients with PIOL eventually have central nervous system (CNS) involvement, with 60% to 80% developing brain lesions or cells in the cerebrospinal fluid (CSF) within 29 months [1–3]. However, 15% to 25% of patients

with PCNSL develop ocular involvement [4]. The incidence of PIOL has increased dramatically due to the concomitant rise in PCNSL [5]. The median age of onset ranges from 50 to 60 years, and the male-to-female distribution is approximately 1.0 to 1.5 [2,5]. Ocular disease is bilateral in 80% of patients [1]. Patients with PIOL present most commonly with blurry vision or floaters. Clinical examination shows uveitis in the anterior or mainly posterior chambers of the eye that is refractory to corticosteroid therapy. Examination of the fundus reveals multiple large yellow or cream-colored subretinal infiltrates, which may hypo- and hyperfluoresce on fluorescein angiography [6••,7]. Medical work-up should include neuroradiologic imaging and a complete evaluation of the spinal fluid, which should include full cultures to rule out infectious causes and cytology to determine CNS involvement. If cytology is positive in the CSF sample or from a stereotactic brain biopsy, a diagnosis of PCNSL is confirmed, at which time further invasive ocular diagnostic testing is unnecessary. In patients without brain lesions or CSF findings, a diagnostic vitrectomy should be performed [8,9]. Whereas diagnosis requires pathologic confirmation of malignant cells, molecular studies for immunoglobulin heavy-chain gene rearrangements and cytokine analysis can also aid in the diagnosis of lymphoma [10••,11,12••,13–16]. The optimal treatment for PIOL or PCNSL with ocular involvement has yet to be determined. Because PIOL is relatively rare, the literature consists mostly of small case series, making comparison of treatment regimens difficult. Randomized clinical trials comparing the efficacy of various therapies are not feasible. Finally, although several clinical trials have been conducted for PNCSL, the results of these studies are often difficult to extrapolate to isolated ocular disease. This review discusses recent developments in the treatment of initial and recurrent PIOL (Table 1).

Treatment of Initial Primary Intraocular Lymphoma To understand the treatment considerations of PIOL, a brief background of PCNSL treatment is helpful. Treatment of PCNSL is quite different from that of other brain tumors and systemic lymphomas. Surgical resection usually does not play a role in the treatment of PCNSL [4]. In addition, chemotherapy regimens that are successful in systemic

MTX, 0.4 mg in induction (biweekly until response), consolidation (1 dose/wk for 1 month), and maintenance (monthly for 1 year) MTX, 0.4 mg in induction (biweekly until response), consolidation (1 dose/wk for 1 month), and maintenance (monthly for 1 year)

5 of 5

4 of 5

Regimens not reported Chemotherapy regimens included methylprednisolone, high-dose on an individual basis MTX (intravenous and intrathecal), Ara-C, thiotepa, cisplatin, VP-16 (intravenous and intrathecal), vincristine, cyclophosphamide, doxorubicin, procarbazine, CCNU, dexamethasone, and etoposide; ESHAP (cisplatin, 100 mg/m2 in 96 hours; VP-16, 40 mg/m2/d on days 1 to 4, Ara-C, 2 g/m2 on day 5, and methylprednisolone, 500 mg/d on days 1 to 4); whole-brain and ocular irradiatiation, 20 to 60 Gy

6 (1 PCNSL with ocular involvement)

1 complete, 4 partial responses

7 of 7

7 of 9

7 PCNSL with ocular involvement; 2 PIOL 5 PCNSL with ocular involvement

2 PCNSL with ocular involvement

1 complete response

2 of 2

5 of 8

7 of 11 (including 5 of 8 with CNS disease) 2 of 2

11 (8 PCNSL with ocular involvement)

2 of 2





2 of 2

16 of 16

4 of 4



CNS response

2

16

4

1 of 1

Ocular response

Ara-C—cytosine arabinoside; CNS—central nervous system; MTX—methotrexate; PIOL—primary intraocular lymphoma; PCNSL—primary central nervous system lymphoma.

Chemotherapy and radiation Valluri et al. [34], Soussain et al. [42••], Cassoux et al. [7], Ferreri et al. [36], Hoffman et al. [2]

Patients, n

Intravitreal MTX, 0.4 mg, and thiotepa, 2 mg, in induction (MTX twice 1 weekly, thiotepa once weekly for 3 weeks), consolidation (biweekly ×3), and maintenance (monthly ×3)

Regimen

Intrathecal chemotherapy Mason et al. [41] Intrathecal MTX and Ara-C High-dose chemotherapy with stem cell rescue Soussain et al. [42••] Thiotepa, 250 mg/m2/d ×3; busulfan, total of 10 mg/kg over 3 days; and cyclophosphamide, 60 mg/kg/d ×2 followed by hematopoietic stem cell rescue Abrey et al. [43] MTX, 3.5 g/m2 ×5 cycles; and Ara-C, 3 g/m2 ×2 for 2 cycles; followed by carmustine, 300 mg/m2; etoposide, 100 mg/m2; cytarabine, 200 mg/m2, and melphalan, 140 mg/m2 (BEAM) followed by autologous stem cell rescue Systemic chemotherapy High-dose methotrexate Batchelor et al. [32] 8 g/m2 induction (every 14 days until response), consolidation (2 doses every 14 days), and maintenance (11 doses every 28 days) Batchelor et al. [33] 8 g/m2 induction (every 14 days until response), consolidation (2 doses every 14 days), and maintenance (11 doses every 28 days) High-dose Ara-C Strauchen et al. [35] 2 to 3 g/m2

Smith et al. [39••]

Methotrexate Fishburne et al. [38]

Combined regimens de Smet et al. [30]

Study

Table 1. Treatment of primary intraocular lymphoma

1



3 of 9

1 of 2

4 of 11

1 of 2

3 of 6



0 of 1

Relapse

Management of Primary Intraocular Lymphoma • Kim et al. 75

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non-Hodgkin’s lymphoma, such as CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, and prednisone), are ineffective in PCNSL due to the presence of the blood– brain barrier [17]. Although the high initial response to whole-brain irradiation has made it the mainstay of PCNSL, its rapid relapse rate makes it a less than ideal therapy [18]. Thus, chemotherapy has become an important treatment modality in PCNSL. High-dose methotrexate (MTX) penetrates the blood–brain barrier and has a complete response rate of 50% to 80% [19••]. When MTX is added to radiotherapy, median survival increases from 11.6 months to 40 months, with 25% of patients surviving for 5 or more years [20]. However, disadvantages of MTX include delayed neurotoxic effects of radiotherapy and a 50% recurrence rate of ocular disease [21,22].

Orbital radiotherapy As in PCNSL, radiation was also once the main therapy for PIOL. When disease is isolated to the eye, orbital radiation can lead to a prolonged disease-free state. Standard doses usually range from 30 to 45 Gy to both eyes [1,23,24] However, recurrence and progression to CNS disease are quite common as well. A study by Margolis et al. [25] examined eight patients (13 eyes) who received radiotherapy in doses of 35 to 45 Gy. Vision improved in 10 of 13 eyes, but most patients had relapsing disease in the CNS and died 5 to 39 months after diagnosis. Similar findings have been reported by other investigators [24,26]. Unfortunately, the limitations of orbital radiation are not insignificant. For example, it cannot be repeated if PIOL recurs, and it has no effect on prevention or treatment of PCNSL. Moreover, toxicities include dry eye syndrome, persistent corneal epithelial defects, cataract formation, radiation retinopathy, and optic neuropathy [1,25,27]. Systemic high-dose methotrexate chemotherapy The blood–ocular barrier is a major factor in therapy for ocular disease. The blood–ocular barrier arises from tight junctions among vascular endothelial cells and retinal pigmented epithelial cells [28]. MTX and cytosine arabinoside (Ara-C) are able to penetrate this barrier and thus have become mainstays of systemic therapies [29]. Furthermore, high-dose MTX is able to reach micromolar concentrations in the vitreous body after intravenous therapy [30–32]. High-dose MTX-based regimens have been studied in several trials. One study used a high-dose MTX schedule in nine patients. The schedule consisted of induction (8 g/m2 of MTX every 14 days until complete response), consolidation (8 g/m2 every 14 days for 2 doses), and maintenance (8 g/m2 every 28 days for 11 doses). This regimen was able to maintain micromolar concentrations in the vitreous humor, aqueous humor, and CSF. The patients included seven with concomitant CNS lymphoma and ocular involvement and one with isolated ocular disease. Seven of nine patients had a complete response in the eye, whereas two required orbital radiation. All seven with brain disease had a complete

response. Three of seven had eventual relapse. Toxicities of this therapy included two episodes of grade 3 anemia and one of grade 3 neutropenia. No neurotoxicity was observed based on a mini–mental status examination [32]. Another study, by Batchelor et al. [33] used a similar schedule of high-dose MTX in 25 patients with PCSNL. Of the five patients with ocular involvement, four had response in the eye, whereas all five had response in the brain (four complete responses and one partial response). Ara-C has been studied alone and in combination with MTX and other chemotherapeutic agents [29,34,35]. With MTX as a single agent at 2 to 3 g/m2 in six PIOL patients (one with CNS involvement), one complete and four partial responses were initially noted [35]. In combination with other chemotherapeutic agents, Ara-C achieved a synergistic effect [34].

Combination regimens Most of the case series in the literature include patients who received many different regimens consisting of various combinations of therapies with or without radiation. Because of the small number of patients receiving each therapy it is difficult to make comparisons. However, Ferreri et al. [36] noted that ocular failure was less common in patients treated with chemotherapy and ocular irradiation. A study of 22 patients with PIOL (21 with CNS involvement) examined varying chemotherapy regimens followed by radiotherapy in 13 patients, chemotherapy alone in three patients, and radiotherapy, alone or followed by chemotherapy, in five patients. One patient was not treated. In this study, chemotherapy combined with ocular irradiation resulted in better control of ocular disease. The median failure-free survival duration for the entire series was 10 months. Valluri et al. [34] used a combination of systemic chemotherapy with MTX and high-dose Ara C, radiotherapy to the brain and orbits, and intrathecal MTX in three patients (two with CNS disease). Brain and eye disease resolved for at least 2 years in all patients. Complications from systemic MTX include periorbital edema, blepharitis, conjunctival hyperemia, increased lacrimation, and photophobia, observed in as many as 25% of patients. Complications of Ara-C include conjunctivitis, keratitis, and ocular irritation. These side effects are considered low-grade toxicities because they are treatable with topical lubricants and corticosteroids [34].

Treatment Of Recurrent and Refractory Primary Intraocular Lymphoma Intravitreal chemotherapy Although intravenous MTX is able to maintain cytotoxic levels in the eye, these levels usually are maintained only for several hours. However, intravitreal administration maintains therapeutic doses for 5 days [37]. Fishburne et al. [38] examined the role of intravitreal MTX as an adjunct to radiation and chemotherapy. Their dosing regimen

Management of Primary Intraocular Lymphoma • Kim et al.

included induction of biweekly injections until clinical response was observed, consolidation of one weekly dose for one month, and maintenance therapy once a month for 1 year. Complete remission was achieved in all four studied patients, with follow-up of 9 to 19 months [38]. A study by Smith et al. [39••] confirmed these findings. Using the identical injection schedule, they evaluated 16 patients (26 eyes). Four eyes were cleared of tumor after a diagnostic vitrectomy, whereas the remaining eyes required 12 injections for the patients to achieve complete remission. Six eyes relapsed, but all patients achieved remission after a repeat course of intravitreal MTX [39••]. Intravitreal MTX and thiotepa may also play a role in isolated refractory disease. These two drugs injected intravitreally caused tumor clearance in a patient who had persistent disease despite 45 Gy of radiation and multiagent systemic and intrathecal chemotherapy. The patient was free of disease for at least 156 days [37]. Although intravitreal MTX is successful in the treatment of isolated eye disease and avoids systemic toxicity, it has several shortcomings [40]. Complications of intravitreal injections include vitreous hemorrhage, retinal detachment, and cataracts [38]. In the study by Smith et al. [39••], the most frequent complications seen with intravitreal MTX were cataract (73%), corneal epitheliopathy (58%), maculopathy (42%), vitreous hemorrhage (8%), optic nerve atrophy (4%), and sterile endophthalmitis (4%). Moreover, MTX does not prevent disease in the contralateral globe, and, as with orbital radiation, it does not prevent CNS disease progression.

Intrathecal chemotherapy Methotrexate administered intrathecally does not reach detectable levels in the eye [30]. However, when MTX was used in combination with Ara-C, successful treatment of recurrent CNS and intraocular lymphoma was noted in two patients [41]. These patients remained free of disease for at least 3 years after completion of this regimen. Thus, in patients with a previous history of CNS disease who are treated with intrathecal regimens, further intrathecal treatments can be considered for recurrent eye disease. Stem cell transplantation Autologous stem cell transplantation in conjunction with intensive chemotherapy has also been used for refractory or recurrent PCNSL and PIOL. Soussain et al. [42••] examined 22 patients with PCNSL, 11 of whom had PIOL. Their highdose chemotherapy regimen included three doses of thiotepa, 250 mg/m2; busulfan, 10 mg/kg; and two doses of cyclophosphamide, 60 mg/kg followed by hematopoietic stem cell rescue. Of these 11 patients, three had isolated ocular disease and eight had concomitant CNS disease. Five of the eight patients with CNS disease responded partially or completely, with survival duration of 18 to 70 months or more. Of the remaining three patients, one had systemic progression and died in 3 months. Two patients had ocular recurrences, one of which

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responded to orbital radiation, whereas the other died of a second tumor. Of the three patients with isolated ocular disease, two had a complete response. The last patient had intraocular recurrence at 3 months and died of a second tumor. Neurotoxicity was noted in one of 11 patients with PIOL and in seven of 22 patients in the study, and five patients died from treatment complications. Abrey et al. [43] reported a second study of intense chemotherapy with autologous stem cell rescue. Of the 14 patients included in this study, two had ocular disease. The group as a whole had a response rate of 57%. One of the patients with ocular disease had a complete response to the therapy and a survival duration of 36.8 months. However, the other patient had progressive disease after transplantation and received whole-brain irradiation for relapse in the brain.

Future Studies Several new therapies are on the horizon. Rituximab, an antiCD20 antibody, has been studied in a select set of patients with recurrent PCNSL (n=4) and systemic non-Hodgkin’s lymphoma with leptomeningeal involvement (n=2). Dosing regimens included 10 to 40 mg of rituximab administered intravenously and intraventricularly (n=2), intraventricularly (n=2), or intrathecally (n=2). Although rituximab resulted in total clearance of cells in the four patients with leptomeningeal involvement, the patients with solid parenchymal lymphomas progressed or showed minimal response [44]. One adverse event of neurotoxicity was reported, although all six patients remained stable based on the mini–mental status examination. Overall survival ranged from 2 to 16 months. Although this therapy requires intrathecal and intravitreal administration because of its poor penetration of the blood–brain barrier, its initial encouraging findings warrant further investigation [45–47]. Another important area of research in PIOL is the role of prognostic factors in treatment. Several definite prognostic factors have been identified in PCNSL, including age (patients >60 years fare worse) and performance status; possible additional factors include sex, serum lactic acid dehydrogenase, cerebrospinal protein level, and involvement of the corpus callosum, deep gray nuclei, brainstem, basal ganglia, and meninges [48–50]. At this time, there are no known prognostic factors for PIOL. A recent study suggested that early treatment of PIOL before CNS progression resulted in improved survival. In this study, 31 patients were retrospectively analyzed in two groups, one of patients treated for isolated eye disease (n=17) and the other group treated after CNS disease was diagnosed (n=14). Both groups received varying treatment regimens of systemic chemotherapy, chemotherapy and radiotherapy, or radiotherapy alone. In the group treated for isolated PIOL, the median survival duration was 60 months, compared with 35 months for those treated after the diagnosis of CNS disease. Although the group of patients with con-

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current ocular and CNS disease at the time of treatment had slightly fewer ocular and CNS relapses (71% vs 82%), the finding of improved prognosis with early PIOL treatment is provocative and further underscores the need for early diagnosis of this disease [51••].

Conclusions The optimal treatment of PIOL is yet to be determined. Treatment requires collaboration between the ophthalmologist and neuro-oncologist. The current consensus on treatment of PCNSL with eye involvement favors systemic high-dose MTX-based chemotherapy with orbital radiation. Management of isolated eye disease has been similar, although promising results from high-dose systemic MTX while avoiding the possible ocular toxicities from orbital radiation has moved the trend toward systemic chemotherapy as the initial definitive treatment. In patients with recurrent intraocular lymphoma, after chemotherapy and orbital radiation have been tried, intravitreal MTX should be considered. Future studies are needed to determine the optimal high-dose MTX-based chemotherapy regimen, the timing of radiation, and the role of intravitreal MTX in initial disease presentation. Novel therapies such as antiCD20 antibody, stem cell transplantation, and medications that break down the blood–brain barrier should be considered in the treatment of PIOL.

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