Discussion
Radiotherapy for patients with marginal zone lymphoma of the ocular adnexa achieved good local control with acceptable toxicity (18). Recently, a Japanese study reported that a median dose of 30 Gy in 15 fractions achieved excellent long-term local control for primary marginal zone lymphoma of the ocular adnexa (12). The contralateral orbit is known as the predominant site of distant relapse, although rare (12,16,18). These results indicated that achieving local control was important for patients with primary marginal zone lymphoma of the ocular adnexa and that an investigation of the optimal dose was required.
Currently, the recommended treatment for ocular adnexal lymphoma is to irradiate the entire bony orbit with a dose of 24–25 Gy in 1.5–2.0-Gy fractions, except for cases in which the disease is limited to the conjunctiva (19). This dose is lower than previously published doses (7,11,13). Two studies reported outcomes and a dose analysis for local control of marginal zone lymphoma of ocular adnexa. Fung et al reported that a dose of ≥30 Gy was superior to a dose of <30 Gy in terms of local control for 53 patients with a median observation period of 82 months. Accordingly, they indicated that the optimal dose for ocular adnexal lymphoma was 30.6–32.4 Gy in 1.8 Gy per fraction (7). Bayraktar et al reported that 3/18 patients who received a dose of <30.6 Gy relapsed, while 3/58 patients who received a dose of 30.6 Gy relapsed during a median observation period of 5 years. As the former group had a significantly higher relapse rate, they recommended a dose of at least 30.6 Gy for ocular adnexal lymphoma (14).
In our study, all patients were irradiated at a dose of 30 Gy in 2.0 per fraction at the iso-center, and all patients attained local control. However, 25% of the patients were irradiated at 1.8 Gy or lower in the GTV, and doses to the posterior retrobulbar space were 10% lower compared with the anterior space. These results suggested that a dose of 27 Gy in 1.8 Gy per fraction provided favorable local control. Goda et al reported that a radiation dose of 25 Gy in 2.5 Gy per fraction achieved 97% local control after 7 years (13). A dose of 25 Gy in 2.5 Gy per fraction was found to be equivalent to a dose of 27 Gy in 1.8 Gy per fraction, calculated by the linear quadrant model (20).
Several studies have been performed to evaluate low doses for marginal zone lymphoma of the ocular adnexa. Tran et al reported that 24 tumors receiving a dose of 24–25 Gy in 1.5–1.8 Gy per fraction were controlled during a median observation period of 41 months, except for 1 patient who had a local relapse due to a marginal miss (15); they estimated that the irradiated dose in the relapse area was 5–23 Gy.
Regarding low-dose radiotherapy of 4 Gy in 2 fractions, both follicular and marginal zone lymphoma have been studied. Fasola et al reported that 20 patients with a total of 27 sites of ocular adnexal lymphoma were treated with a radiation dose of 4 Gy in 2 fractions (21). The complete response rate was 85% during a median observation period of 26 months. Patient histology showed follicular lymphoma in 55% and marginal zone lymphoma in 40% of the patients. This response rate was lower compared with that observed in the present study, although the majority had follicular lymphoma. Hoskin et al reported a randomized non-inferiority study comparing a dose of 4 Gy in 2 fractions with 24 Gy in 12 fractions (22). Of the 614 sites treated in 548 patients, 86% were follicular lymphomas and 14% were marginal zone lymphomas. A dose of 4 Gy in 2 fractions did not achieve non-inferiority, compared with a dose of 24 Gy in 12 fractions. Local progression was observed in two groups: One which was administered a dose of 24 Gy to 21 sites, and a second which was administered 4 Gy to 70 sites. The results of Fasola et al compared favorably with those of Hoskin et al, although the latter study included more cases of follicular lymphoma. Fasola et al treated ocular adnexal lymphoma via 3D conformal radiotherapy, except for cases involving conjunctival tumors. In the study of Hoskin et al, a proportion of the patients were treated by anteroposterior-posteroanterior photon fields.
In Peffer et al, partial orbit treatment was compared with entire orbit treatment in 23 patients (23). A total of 33% of patients who underwent partial orbit radiotherapy had a relapse in previously uninvolved areas not included in the initial target volume. By contrast, no patients who underwent entire orbit treatment experienced a relapse. Accordingly, it was asserted that irradiation encompassing the entire orbit was necessary and that 25 Gy was effective for local control. As it was difficult to identify the extension of lymphoma to the retrobulbar area, a CTV encompassing the entire orbit is considered to be appropriate.
Kaushik et al reported a risk of retinopathy in 67 patients who received a radiotherapy dose of 18.9–54.0 Gy (24). Eight patients who were irradiated at a dose of 24–40 Gy developed retinopathy at a median of 27 months. The daily fractionated dose of ≥2.0 Gy was a significant risk factor for retinopathy, compared to a dose of 1.8 Gy. A total dose of 30 Gy or more was not a significant risk, compared to <30 Gy. As the retina was unavoidable in several cases, a daily dose of 1.8 Gy may be favorable in preventing the onset of retinopathy.
In the present study, no difference in outcome was observed between the conjunctiva and the retrobulbar space as the primary location site. Similarly, Harada et al also reported the absence of prognostic differences between the conjunctiva and other anatomical subsites (12). The same dose was adequate among ocular adnexal anatomical subsites. Goda et al reported that the lacrimal gland and retrobulbar space were associated with high distant relapse rates compared with the conjunctiva (13). The distant relapse rates in Asian studies (12,16), including ours, were relatively lower compared with those reported in Western studies (7,13). The relapse rates in lacrimal gland lymphoma in Western studies (7,13) were higher compared with Asian studies (12,16), and our study may elucidate the reason for this difference. Attention must be focused on the possibility of a distant relapse in lacrimal gland lymphoma.
It was previously demonstrated that electron radiotherapy provides favorable local control (7,11,13) and reduces cataract formation (12) when the lymphoma is located only in the conjunctiva. The association between dose and cataract has been difficult to elucidate, as several patients had cataract due to advanced age. In the present study, the primary endpoint for cataract formation was set to the date of cataract surgery. Electron therapy was more likely to prolong the interval to cataract surgery compared with photon therapy, but the difference was not statistically significant.
The use of an antibiotic therapy targeting Chlamydia psittaci in marginal zone lymphoma of the ocular adnexa has been attempted. According to the majority of the studies, complete response was obtained in only 20% of the cases (25). From the data, radiotherapy remains the standard treatment, and the addition of antibiotics during radiotherapy may reduce the necessary dose of radiotherapy.
Based on these findings, the optimal dose for the D95 to the GTV currently appears to be 27 Gy in 15 fractions when the lymphoma is located in the retrobulbar space. An entire orbit CTV is most effectively irradiated at a D95 of 25 Gy in 15 fractions. When the lymphoma is limited to the conjunctiva, the GTV is most effectively irradiated at the same dose using electron therapy with a contact lens, whereas irradiation of the retrobulbar space is omitted.