The optimal therapy for PVRL is not defined. Grimm et al. [25
] reported, from an IPCG series of 221 immunocompetent patients with PCNSL and/or PVRL, that there was no difference with respect to disease progression or OS with the use of local versus systemic therapies. However, it is important to keep in mind that that study was an uncontrolled, multicenter, retrospective study involving many different treatments. Thus, it was not conclusively demonstrated whether or not ocular therapy has an impact on survival. At this time, some experts suggest reserving systemic therapy for those with CNS disease and using local therapy for disease confined to the eye; careful follow-up is indicated, and if there is evidence of CNS disease then treatment with systemic therapy should be used.
Local therapies include ocular radiation and intravitreal chemotherapy [65
]. There has been no study to compare these treatment options, but there does not appear to be a significant difference with respect to local tumor control or treatment-related visual compromise. At the present time, some experts prefer intravitreal chemotherapy whereas others prefer ocular radiation as first-line therapy [66
]. Until studies are done to adequately address this question, the treatment decision should probably be based on patient considerations, such as disease laterality, the distance the patient must travel for treatment, and patient preference. In general, intravitreal chemotherapy is only injected into the eye with PVRL lesions.
External-beam radiotherapy (EBRT) typically involves a total of 35–40 Gy delivered in ~15 interrupted fractions (2 Gy per fraction) using opposed lateral beams to include the entirety of both eyes in the treatment ports. Using this technique, the rates of local recurrence and visually significant radiation retinopathy have been reported to be very low [42
]. It is not necessary to attempt to spare the lens, which can be a cause of treatment failure by leaving untreated lymphoma cells in the anterior vitreous, because cataracts are easily managed using standard surgical techniques. EBRT may be preferable in patients with bilateral disease, whereas intravitreal chemotherapy (see below) may be preferred in patients with unilateral disease or in patients with previous ocular radiation. If EBRT is to be used in a patient with unilateral disease, both eyes should be treated because PVRL almost always becomes bilateral.
Intravitreal methotrexate was shown to be efficacious in small nonrandomized trials [23
]. Frenkel et al. [23
] reported on the largest series of 44 eyes of 26 patients with PVRL. They demonstrated clinical remission after a mean of 6.4 ± 3.4 (range, 2–16) injections of methotrexate. Intravitreal rituximab was shown to penetrate the entire retina [24
]. The half-life is approximately 5 days, so an intravitreal injection probably has efficacy for approximately 3–4 weeks [74
]. Small, nonrandomized studies have demonstrated the activity of intravitreal rituximab monotherapy for PVRL [75
]. There is also some evidence that the combination of intravitreal methotrexate and rituximab may be effective for PVRL, although the results are preliminary and based on small patient numbers [77
]. This alternating, combination approach is potentially attractive because it decreases the need for multiple methotrexate injections with concomitant toxicity. Regardless of which local therapy is used, there is a high likelihood of local recurrence and CNS involvement. The detection of early, isolated ocular recurrence is difficult. Given the high risk for subsequent CNS involvement, it would seem reasonable to perform intermittent MRI of the brain. Notably, of the 56% of the 47 patients who relapsed, 62% had CNS lesions [24
Because PVRLs are often high grade and can be associated with PCNSL in ~20% of cases, systemic chemotherapy has been investigated as a treatment modality, often with regimens that are used for the therapy of PCNSL. The reported systemic chemotherapy options can be divided into single-agent chemotherapy, combination chemotherapy, and high-dose chemotherapy plus autologous stem cell transplantation (ASCT).
An initial case report by Baumann et al. [78
] reviewed the treatment of a 59-year-old female patient originally diagnosed with DLBCL of the breast who had intraocular relapse 1 year after primary therapy. She eventually achieved a complete remission (CR) for >1 year after treatment with high-dose arabinofuranosyl cytidine (Ara-C) at 2–3 g/m2
. A second report on six patients treated with high-dose Ara-C at 2–3 g/m2
given at two different intervals demonstrated responses in seven of eight patients (one CR, six partial remissions [PRs]) [79
]. The patient achieving a CR eventually relapsed, but was able to regain the CR after a second administration of high-dose Ara-C, which was then given as a monthly maintenance infusion. All the patients who achieved only a PR received radiation therapy as consolidation; therefore, the duration of remission from single-agent Ara-C could not be determined. Because of the efficacy of high-dose methotrexate in PCNSL patients, Batchelor et al. [27
] reported on nine patients with intraocular involvement of lymphoma treated with methotrexate at 8 g/m2
. Potentially cytotoxic, micromolar levels of methotrexate were detectable in the aqueous and vitreous humor in most patients. Of the nine patients, two had PVRL alone, five had PVRL and PCNSL, and two had PVRL, CNS, and systemic disease as well. An intraocular response was reported in seven patients, with CRs in six and a PR in one. All seven patients with CNS involvement had resolution of their CNS disease. Relapse occurred in three of the seven responders. In a recent, prospective, single-center study by Jahnke et al. [80
], 10 patients with PVRL were treated with ifosfamide or trofosfamide. There was a 100% response rate (nine CRs, one PR). The median PFS interval was 18 months, with a median OS duration of 32 months. Of the seven relapses, five were ocular and two were CNS. Thus, this class of agents plus high-dose Ara-C appears to have good penetration into the intraocular space and should be investigated further alone or in combination in the treatment of PVRL patients.
Combination chemotherapy trials in PVRL patients are extremely limited because the majority of studies have incorporated radiation into the treatment regimen and cannot provide an accurate assessment of the chemotherapeutic effect alone. Sandor et al. [81
] reported on 14 patients, including five with intraocular involvement, treated with a complex treatment schema incorporating i.v. as well as i.t. chemotherapy without irradiation. Patients received i.v. methotrexate, vincristine, and thiotepa as well as i.t. methotrexate and Ara-C in 21-day cycles. There was a 100% response rate (11 CRs, three PRs). At a median of 4.5 years of follow-up, the PFS rate was 34.3% and the OS rate was 68.8%. Thus, although a high initial response was seen, the duration was limited and additional therapy is likely needed. Most recently, the use of methotrexate, rituximab, and temozolomide was advocated for the therapy of PCNSL patients, but studies are still ongoing.
Several groups have reported their experience with high-dose chemotherapy and ASCT. Soussain et al. [82
] reported on 11 patients with PVRL who were treated with etoposide, methylprednisolone, high-dose Ara-C, and cisplatin and/or high-dose methotrexate. First-line therapy failed in 10 of 11 patients. Five of the refractory patients then underwent salvage chemotherapy with thiotepa, busulfan, and cyclophosphamide followed by high-dose chemotherapy and ASCT, and all achieved a CR. Unfortunately, two patients relapsed at a median of 6 months and three remained alive and in remission at a median follow-up of 14 months. Unpublished data from the Mayo Clinic (Rochester, MN) identified six patients (five with PVRL and one with PCNSL with ocular involvement) who had undergone ASCT following BCNU, etoposide, cytarabine, and melphalan conditioning. With a median follow-up of 3 years, 50% of patients remained in CR with no additional therapy. In a multicenter, phase II clinical trial, 43 patients with relapsed or refractory PCNSL, including 10 with intraocular involvement, were treated with salvage chemotherapy and 27 subsequently underwent high-dose chemotherapy with ASCT [83
]. Patients who underwent ASCT had longer PFS and OS times than those who did not, and on univariate analysis it did not appear that patients with intraocular involvement did worse than those without eye involvement. In summary, although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is an extremely high relapse rate. Systemic chemotherapy probably should be initiated only once there is evidence of PCNSL or systemic lymphoma.
Treatment toxicities depend on the therapeutic modality. For local therapy, toxicities include complications of intraocular injections seen with monthly injections of anti–vascular endothelial growth factor for neovascular age-related macular degeneration, the overall incidence of which is quite low [84
]. Complications of intravitreal injection include cataracts, vitreous hemorrhage, endophthalmitis, and retinal detachment [87
]. A specific toxicity of intravitreal methotrexate is epithelial keratopathy [23
], which can be reduced by a paracentesis before the injection [88
]. Also, cataracts and hypotony may develop; the latter is noted only after about 12 injections. Intravitreal rituximab rarely causes vitritis. Local irradiation can cause radiation retinopathy, especially if there are other predisposing risk factors such as diabetes mellitus or hypertension. The dose that might cause the development of radiation retinopathy is under contention, but the risk in the absence of other risk factors for the development of retinopathy is probably low up to 35 Gy but increases after that point [89
For systemic therapy, there is a risk for giving excessive frontal lobe radiation if local ocular radiation has been given and, in the future, the patient receives whole-brain radiotherapy. The converse is also a consideration. If there is concern that the patient might need whole-brain radiotherapy in the future, the use of local EBRT to the eye should be avoided. The toxicities seen with systemic therapy are inherent to each individual chemotherapeutic agent; however, in general, myelosuppression is the most commonly seen toxicity. Combination chemotherapy, especially when combined with stem cell transplantation, can result in neutropenia, increasing the risk for febrile neutropenia and potential mortality. Thus, vigilance must be maintained in patients receiving systemic chemotherapy.
Notwithstanding, at this time we recommend the following guidelines to treat PVRL patients who do not enroll in a clinical trial:
- Without CNS or systemic involvement: (a) If only one eye involved, use local therapy. Whether it is local intravitreal methotrexate and rituximab given alone or carefully given between 30–35 Gy of EBRT is still under contention. (b) If both eyes involved, there is still a preference toward local therapy, although systemic treatment should not be excluded. The addition of intravitreal chemotherapeutic agents to systemic therapy should be considered.
- With CNS involvement: (a) High-dose methotrexate-based therapy (possibly with systemic rituximab) is recommended in conjunction with local therapy given the limited penetration of systemic agents into the vitreous cavity. (b) Whole brain radiotherapy in conjunction with ocular radiotherapy should be considered in those who have failed systemic therapy and are too debilitated or do not meet the criteria for more aggressive therapy such as ASCT.
The National Comprehensive Cancer Network has also proposed an alternative but similar recommendation under the treatment guidelines for CNS cancers [92