Intraocular Lymphoma: Update on Diagnosis and Management

Chi-Chao Chan, MD; Dana J. Wallace, BS

Disclosures

Cancer Control. 2004;11(5) 

In This Article

Treatment

The treatment of PCNSL and PIOL differs from the treatment of systemic lymphoma. Therapies that have proven effective for systemic lymphoma have not been successful in PCNSL and PIOL.[70] In addition, resection, while usually applicable to brain tumors, does not play a role in the therapy of PCNSL.[11] Whole-brain radiation was once the mainstay of PCNSL therapy. A prospective, multicenter, phase II trial examined whole-brain radiation (40 Gy with a 20-Gy boost to the tumor) in 41 patients with PCNSL. The response rate was 90%, but 68% of patients relapsed. Median survival was only 11.6 months.[71]

It is generally believed that chemotherapy is the first line of treatment for PCNSL.[11] High-dose methotrexate (MTX) should be included in all therapies, as it penetrates the blood-brain barrier and has a complete response rate of 50% to 80%.[72] Chemotherapy and radiotherapy combination regimens increase median survival to 40 months, with almost 25% of patients surviving for 5 years or more.[73] However, ocular disease recurs in 50% of cases. In addition, these results must be weighed against complications of delayed neurotoxic effects.[74,75]

Many issues are still unresolved, including the best MTX-based chemotherapy regimen, the role of chemotherapy-only treatments, the necessity of intrathecal chemotherapy, the role, dosage, and schedule of whole-brain radiotherapy, and the role of blood-brain barrier disruption.[10,11,76,77]

For intraocular lymphoma, radiotherapy was once the treatment of choice.[6,78] For disease limited to the eye, radiotherapy alone (30 Gy to both eyes[20,79]) often led to a prolonged disease-free state.[20] Ocular recurrences were common, and most patients developed CNS disease within 14 to 84 months.[16,78] Furthermore, many side effects of radiation were observed, including cataract formation, radiation retinopathy, optic neuropathy, dry eye syndrome, and prolonged corneal epithelial defects.[6,21,78] However, other case series have not noted any radiotherapy complications after follow-up of 24 to 140 months.[16,20]

The major difficulty with using chemotherapy to treat patients with ocular involvement is the blood-ocular barrier. This barrier results from tight junctions located between vascular endothelial cells and also between pigmented epithelial cells of the anterior uvea (blood-aque-ous barrier) and the retina (blood-retinal barrier).[80] However, MTX and cytosine arabinoside (Ara-C) are able to penetrate the blood-ocular barrier and have become mainstays of therapy.[81]

Systemic and Intrathecal Treatments. Several trials of systemic chemotherapy for intraocular disease have been conducted. A study of 9 patients examined a high-dose MTX schedule consisting of induction (8 g/m2 MTX every 14 days until complete response), consolidation (8 g/m2 MTX administered every 14 days for 2 doses), and maintenance (8 g/m2 MTX administered every 28 days for 11 doses).[82] MTX levels 4 hours after infusion were higher than 1 µm in both the vitreous and aqueous humors, indicating cytotoxic levels. The patient population included 7 patients with concurrent PCNSL and PIOL and 2 with isolated PIOL. Seven of the 9 patients had a response in the eye, while 2 of 9 had refractory eye disease and required orbital radiation that led to complete response. All 7 patients with disease in the brain had complete responses of their brain disease. Two patients died of CNS progression at 17 and 27 months, while 1 patient was lost to follow-up. The range of follow-up on the remaining 6 patients was varied, but they remained disease-free from 8+ to 85+ months. While this study showed high MTX levels in the vitreous, the evidence of disease recurrence corroborates other studies' findings that it may be difficult to maintain sufficient levels of MTX in the vitreous humor after intravenous infusion.[83]

Another trial of intravenous MTX (8 g/m2) in induction, maintenance, and consolidation phases in 5 patients with PCNSL with intraocular involvement showed complete response of brain lesions in 4 patients and partial response in 1.[84] Four of the 5 patients with ocular symptoms responded.

Other systemic trials have been used with Ara-C, alone and in combination with MTX.[81,85,86] Valluri et al[86] used systemic chemotherapy consisting of MTX and high-dose Ara-C in 3 patients with PIOL (2 with concomitant CNS involvement). Both ocular and intracranial disease resolved, with remission for at least 24 months. A trial of Ara-C alone (2 to 3 g/m2) included 6 patients with intraocular lymphoma.[85] Of the 6 patients, 4 were previously untreated, 1 had relapsed after radiation treatment, and 1 had received chemotherapy for systemic lymphoma. Five of the patients responded (1 complete and 4 partial).

Ocular complications from systemic MTX include periorbital edema, blepharitis, conjunctival hyperemia, increased lacrimation, and photophobia in up to 25% of patients. Complications of Ara-C include conjunctivitis, keratitis, and ocular irritation. Most of these side effects are reversible and may be treated with topical lubrications and topical corticosteroids.[86]

A study of 22 patients with PIOL (21 with CNS involvement) examined varying treatments of chemotherapy followed by radiotherapy in 13 patients, chemotherapy alone in 3 patients, and radiotherapy either alone or followed by chemotherapy in 5 patients.[87] One patient was not treated. Chemotherapy combined with ocular irradiation resulted in better control of ocular disease. Median failure-free survival for the entire series was 10 months, with a 2-year failure-free survival rate of 34%. This study also noted that the detection of ocular relapse was associated with shorter survival at 2 years (12% vs 55%).

Intrathecal MTX may also play a role in treatment of PIOL. While intrathecal MTX alone was unable to reach detectable levels in the eye,[88] a study of 2 patients with recurrent CNS and intraocular lymphoma showed successful treatment with intrathecal MTX and Ara-C.[89] Intrathecal MTX may also be beneficial when combined with systemic chemotherapy regimens. A study of 14 patients with CNS disease (5 with ocular involvement) examined the role of chemotherapy alone including high-dose MTX (8.4 g/m2) with thiotepa, vincristine, dexamethasone, and intrathecal Ara-C and MTX.[90] Three of the 5 patients with ocular disease had complete responses. Two patients with partial responses were treated with local treatment and had a complete response (1 with intravitreous chemotherapy and the other with local radiation). Overall survival and progression-free survival rates at 57 months of follow-up were 68.8% and 34.3%, respectively.

Stem-Cell Transplantation. Intensive chemotherapy followed by autologous stem-cell transplant was reported to rescue patients with refractory or recurrent PCNSL and PIOL.[91,92] A study by Soussain et al[91] of 22 patients with PCNSL included 11 patients with PIOL (3 with isolated ocular disease and 8 with concomitant CNS involvement). Five of the 8 patients with CNS disease had partial or complete response and had survival times of 18+ to 70+ months. One of these patients had systemic progression and died in 3 months. Two had ocular recurrences. One had complete response with subsequent ocular radiotherapy, while the other died due to a second tumor. Two of the 3 patients with isolated ocular disease had complete response, while the other patient with isolated ocular disease had intraocular lymphoma recurrence at 3 months and then died of a second tumor. While only 1 of the 11 patients with PIOL experienced neurotoxicity, 7 of the 22 total patients experienced this side effect. In addition, this treatment is not recommended for patients older than 60 years of age because 5 of 7 patients in this age group died of treatment complications.[91] A study by Abrey et al[92] included 2 patients with ocular disease but information about their follow-up was limited. The encouraging data from these two studies suggests that this therapeutic approach may be useful in difficult cases but requires further evaluation.

Intravitreal Methotrexate. Radiotherapy alone was once used to treat patients with isolated ocular disease. Due to radiation complications and the fact that this treatment cannot be repeated if the patient relapses, intravitreal treatment has become more desirable for both isolated and recurrent ocular disease. As opposed to intravenous MTX, where cytotoxic levels are maintained only for several hours, intravitreal MTX is able to maintain therapeutic doses in the vitreous humor for 5 days.[93] Intravitreal MTX was first attempted on 4 patients (7 eyes) as an adjunctive treatment to radiation and enhanced chemotherapy using blood-brain barrier disruption by intra-arte-rial mannitol.[94] All 4 patients had remission of eye disease, with follow-up ranging from 9 to 19 months.

Another trial of intravitreal MTX involved an induction phase of twice weekly intravitreal MTX (400 µg) for 1 month, followed by weekly consolidation injections for 1 month, followed by monthly injections for 1 year in 26 eyes of 16 patients.[95] Eight of these patients initially had brain involvement, while 8 presented with ocular involvement. Follow-up ranged from 6 to 35 months, with a median of 18.5 months.While 4 eyes were cleared of tumor after a diagnostic vitrectomy, the remaining eyes were free of malignant cells after 12 injections. Disease recurred in 3 patients (6 eyes), but all achieved remission after a repeat course of intravitreal MTX. The most common complications were cataract, corneal epitheliopathy, and maculopathy. Less common complications were limbal stem cell damage, optic atrophy, and sterile endophthalmitis.

Intravitreal MTX may also play a role in the treatment of recurrent intraocular lymphoma. A patient with recurrent intraocular lymphoma after radiotherapy and repeated systemic chemotherapeutic regiments was treated with repeated intravitreal injections of MTX and thiotepa, leading to eradication of the tumor for at least 156 days.[93] While intravitreal MTX avoids systemic toxicity and can provide consistent therapeutic drug concentrations, it will not treat lesions in the CNS or other eye.

The optimal method of treatment of PIOL or PCNSL with ocular involvement is yet to be determined. Developing a consensus on the appropriate treatment is difficult due to the rarity of these malignancies. The literature is abundant with small case series that make comparing treatment regimens difficult ( Table 1 ). Furthermore, large, randomized clinical trials comparing the efficacy of radiation and chemotherapy to chemotherapy alone are neither feasible nor ethical. In addition, the results of PCNSL trials are difficult to extrapolate to PIOL.

The current consensus on the treatment of PCNSL with eye involvement is systemic high-dose MTX-based chemotherapy with radiation to the globes.[3] Isolated eye disease should be treated similarly, although complications from radiation and promising results with systemic high-dose MTX regimens may indicate that the latter is a better choice. Recurrence of intraocular lymphoma alone should be treated with intravitreal MTX. Future studies are needed to determine the optimal high-dose MTX-based chemotherapy regimens, the role of radiation, and the role of intravitreal MTX in initial disease presentation. Future therapeutic regimens may also include rituximab, a monoclonal antibody against CD20, which has been shown to have activity in systemic lymphoma.[97,98,99] Due to poor penetration of blood-brain barrier, rituximab will likely require intrathecal and intravitreal administration in the treatment of PCNSL and PIOL.[100,101,102]

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