Radiotherapy in orbital lymphoma: optimizing the backbone to build upon

Treatment for primary orbital lymphoma (POL) has not changed significantly for several decades. Radiotherapy is highly effective, and the role of chemotherapy or antibiotics (for marginal zone lymphoma [MZL] subtype) is less well defined. The best practice is still unclear due to the low incidence of POL and lack of prospective clinical trials (PCTs), and this is compounded by the unreliable histological classification and distinction between indolent non-Hodgkin lymphoma (NHL) versus benign lymphoid hyperplasia (BLH) in many older series of POL prior to the era of immunohistochemistry [1]. The traditional use of radiotherapy in POL is based on retrospective studies that showed a high rate of local control (95–100%), particularly in indolent NHL histological subtypes, using moderate-dose radiotherapy from 25 to 40 Gy [2–4]. Radiotherapy-related ocular complications, in particular serious late retinopathy and optic neuropathy, appeared to be increased with doses above 35 Gy [2,5,6], whereas local recurrences, when present, were usually after doses of < 25–30 Gy [2,3]. In recent years there has been a trend toward employing reduced radiation dose, without apparent compromise in local control; although the optimal radiation dose and fractionation remains unclear, 24–30 Gy is widely accepted as the lowest effective dose [3,4,7]. In the MZL subtype in particular, a lower dose of radiation compared to that recommended for non-gastric non-orbital sites is preferred [4].

In this issue of Leukemia and Lymphoma, Tran and colleagues [8] report the efficacy of low-dose radiotherapy and fractionation (total 24–25 Gy in 1.5–2 Gy fractions) in a retrospective analysis of 24 patients with orbital MZL, 22 of whom were stage IEA. Only one local failure occurred at the electron beam penumbra, attributed to marginal miss. Two further relapses, one in the contralateral orbit and one systemic relapse, occurred in patients with initial stage IEA disease. Five-year progression-free survival and overall survival were 81% and 100%, respectively. These results are comparable, if not better than expected, for non-orbital localized low-grade lymphomas treated with radiotherapy with curative intent, where distal relapse occurs in up to 40–50% of patients [9]. MZL, however, is particularly radiation-sensitive, and the efficacy seen here with 25 Gy, which confirms results from one other series [4], may not apply to the other 15–20% of POL of other indolent and aggressive NHL histological subtypes. Toxicity-wise, a dose of ≤ 30 Gy in 1.8–2 Gy fractions is not usually associated with significant long-term ocular toxicities [5]. With both lower total dose and fractionations, Tran and colleagues report no severe acute toxicities and, more importantly, no severe late toxicities such as radiation retinopathy, visual loss, corneal ulceration, optic nerve damage or glaucoma, apart from cataracts that are amenable to surgery. Indeed this provides a strong impetus to further investigate a lower-dose schedule; however, until results are confirmed in prospective clinical trials, this proposal cannot be heralded as standard of care as it is based on retrospective analyses of small numbers of patients.

So taking this into consideration, how can we build on the information provided by Tran and colleagues to improve outcome for patients with POL? Clearly radiotherapy is the backbone on which to add, and hence defining the minimum effective dose that ensures local control yet respects the vulnerability of surrounding ocular structures is important and challenging. In this respect, prospective clinical trials to assess various radiotherapy doses for different histological subtypes and subsites of POL are required. We eagerly await results from the Trans Tasman Radiation Oncology Group and Australasian Lymphoma and Leukaemia Group (TROG/ALLG) phase II trial that tests 24 Gy in 1.5–2 Gy fractions for orbital MZL. Questions regarding radiotherapy technique, including the required target volume (entire vs. partial orbital irradiation) for different subsites of disease, degree of protection from smaller fractions and lens shielding, and the use of bolus to improve efficacy, also need to be evaluated prospectively, as there are few data or little consensus available for POL.

In building on the radiotherapy backbone, identification of patients with high risk of outfield recurrences who may benefit from (neo)adjuvant immunotherapy or chemotherapy is important, and should be explored in the future. Neoadjuvant immunochemotherapy clearly has a role in systemic involvement or localized aggressive type POL, but has a limited role in stage I–II indolent POL. Nevertheless, distant relapse still occurs in up to 25% of the latter cases, and given the stable expression of CD20 on B-cell lymphomas, the adjuvant use of anti-CD20 antibodies, rituximab or the more potent second-generation GA101 or ofatumumab, should be explored. Similarly, radioimmunotherapy using anti-CD20 antibodies with radioactive conjugates such as Y-90 ibritumomab tiuxetan (Zevalin^™) may be used to improve the rates of distant relapse in POL, and could potentially reduce the dose of radiotherapy given to normal ocular structures compared to external beam radiotherapy. Indeed in this regard, pilot studies have shown promising results [10]. Prospective evaluation of adjuvant antibiotic therapy in cases of detectable microbial pathogens such as Chlamydia psittaci should be pursued, as continuous and persistent inflammation due to chronic infection may contribute to B-cell clonal expansion and eventual POL relapse. Finally, novel biological agents such as the anti-vascular endothelial growth factor, bevacizumab, have been anecdotally reported to be effective against ocular BLH, as well as having protective effects against radiation retinopathy. Perhaps it is both the low incidence of POL and the relatively favorable outcome from radiotherapy that underlie the inertia to establish prospective clinical trials to date. However, the outcome for POL could further improve, as up to 25% of patients with localized disease are not cured, and in an era in which many novel biological agents with acceptable toxicities are available for lymphoma, all attempts should be made to build on the radiotherapy backbone, once the backbone itself is optimized.

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