Clinical Oncology xxx (2014) 1e7 Contents lists available at ScienceDirect
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Original Article
Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy D.K. Woolf *, H. Kuhan y, O. Shoffren y, E.M. Akinnawo y, B. Sivagurunathan y, H. Boyce y, P.N. Plowman y * Mount y
Vernon Cancer Centre, Northwood, UK St Bartholomews’ Hospital, London, UK
Received 8 June 2014; received in revised form 16 September 2014; accepted 24 September 2014
Abstract Aims: Low-grade ocular adnexal lymphoma is a rare disease and often treated with local radiotherapy to varying doses. Most previously reported studies have a very heterogeneous patient population and treatments. We report the outcomes from a 10 year cohort of patients at our institution treated with primary radiation therapy. Materials and methods: We analysed a retrospective case series of patients with stage IE low-grade ocular adnexal lymphoma including a review of case notes, histological reports and radiotherapy charts. We assessed local and distant tumour control and relapse rates in addition to toxicity. Disease-free survival was estimated using the KaplaneMeier method. Results: In total, 81 patients and 85 orbits were treated with primary radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Seventy-nine per cent were treated with standard MV external beam radiotherapy to the whole orbit and 21% with a lens-sparing technique. The median follow-up was 4.4 years (range 0.2e10.4). Local control rates were 100%, with 5% of patients experiencing disease relapse elsewhere. No patients died from lymphoma. Cumulative acute toxicity rates were 51% (mainly erythema and conjunctivitis) and late toxicity rates were 8% (mainly cataract). The lens-sparing technique was associated with a significant reduction in cataract rate (P ¼ 0.013) and an increase in acute toxicity (P < 0.001). Conclusions: This study has shown excellent local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Lens-sparing radiotherapy; ocular adnexal lymphoma; ocular radiotherapy
Introduction Primary ocular adnexal lymphoma (orbital lymphoma) is a rare disease and accounts for less than 1% of all lymphomas and between 5 and 15% of extranodal presentations [1,2]. Radiotherapy is considered to be the standard treatment for low-grade lymphoma that is localised to the orbit (stage IE) [3], normally treated with 30 Gy in 15 fractions [4]. However, most previously reported studies have included patients treated over 20 years ago, often with now dated staging techniques and histological classification and
Author for correspondence: D.K. Woolf, Mount Vernon Cancer Centre, Northwood, UK. Tel: þ44-1923-844852. E-mail address: [email protected] (D.K. Woolf).
had a heterogeneous patient population in terms of grade and stage of disease. There was also a wide range of radiotherapy techniques and, in particular, doses used within each study, in addition to various systemic therapies, making outcomes difficult to interpret. We report the results of a large cohort of patients treated with radiotherapy alone within a single institution for localised ocular adnexal lymphoma over a 10 year period.
Materials and Methods A retrospective review of medical records was conducted for all patients diagnosed and treated with radiotherapy for ocular adnexal lymphoma between June 2002 and July 2012. Inclusion criteria were: stage IE disease as per the
http://dx.doi.org/10.1016/j.clon.2014.10.002 0936-6555/Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7
Ann-Arbor classification [5], primary treatment with radiotherapy, no systemic therapy except on relapse and low-grade histology. Patient demographics and lymphoma characteristics were recorded, as were radiotherapy details, including technique and dose fractionation. Toxicity data were also collected, as were relapse details. The study was conducted as per the STROBE guidelines. Work-up After a biopsy was carried out and a histological diagnosis obtained, all patients had a magnetic resonance imaging scan of the orbit to confirm the extent of disease and a computerised tomography scan from the head to the pelvis to ensure metastatic disease was not present. Radiotherapy Technique For disease confined to the conjunctiva (i.e. disease not found behind the equator of the globe on magnetic resonance imaging scan) patients were treated with a kV technique. This used an anterior 300 kV photon field with a 5 cm circle aperture. Shielding was provided by the placement of a custom-made contact lens under local anaesthetic between the eyelids (Figure 1). Mounted on this contact lens was a lead cylinder (Figure 2) that shielded the lens, thereby reducing the dose to the centre of the eye and with the intention of lowering the risk of cataract formation. For patients with disease beyond the conjunctiva, the whole orbit was treated with a MV photon technique. The patient was treated in a custom-made thermoplastic immobilisation shell and a wedged pair of anterior and anterolateral fields was used in order to create a homogenous dose distribution to treat the whole orbit. The eye was closed and bolus was utilised for anterior disease. The target volume for conjunctiva-only disease was the whole conjunctiva and for orbital, lacrimal gland and eyelid disease the target was the whole orbit. When bilateral orbital disease was present, a parallel opposed technique was used, often with 15 wedges as normal tissue compensators. The
Fig 2. The contact lens with mounted lead shield.
standard dose prescription was 30 Gy in 15 fractions over 21 days as per Bessell et al. [4], although this was only adopted as standard departmental policy from 2005. Follow-up All patients were seen for a toxicity assessment on a weekly basis during radiotherapy and for follow-up 6 weeks post-treatment. They were then seen every 6 months for the next year and on an annual basis after that. Patients were not discharged from follow-up, although some opted to return to the referring centre. For the purpose of this analysis, we defined loss to follow-up as a patient not being seen within 6 months of their planned appointment schedule. At each follow-up visit, toxicity was evaluated both by side-effects reported by patients and a clinical examination. Patients were also assessed for tumour response/relapse both in the orbit and at distant sites. Further investigations were requested if appropriate. An examination was conducted by a radiation oncologist and formal ophthalmological examinations and visual acuity testing were not carried out routinely. Statistics
Fig 1. The contact lens with a lead shield placed between the eyelids and about to be, but not yet, positioned over the cornea.
A statistical analysis was carried out with SPSS statistical software (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.). Relapsefree survival was assessed using the KaplaneMeier
Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7
method and the differences between radiotherapy techniques were compared using the t-test. The database was locked on 30 January 2014.
Results In total, 81 patients with a total of 85 primary ocular adnexal lymphomas were treated with primary external beam radiotherapy at our centre over a 10 year period (July 2002 to June 2012). Four of the 81 patients had bilateral disease and all of these received bilateral radiotherapy. The median age of patients at the point of diagnosis was 58.2 (range 22.6e90.7) with a relatively equal gender distribution (Table 1). The histological subtype of the tumours is shown in Table 1 and all cases were biopsy proven, including both orbits for bilateral disease. Most tumours were mucosa-associated lymphoid tissue (MALT) lymphomas (88%) and most of the remainder were follicular (6%). Three patients (4%) were documented in the notes to have a low-grade ocular adnexal lymphoma, but the original histology could not be located from the referring centre. All those with bilateral disease had the same histological subtype in both eyes. Seventy-eight tumours (92%) were treated with 30 Gy in 15 fractions over 3 weeks, of which 77% received treatment with a MV technique and 23% received treatment with a kV technique. All of those treated with kV X-rays had a conjunctival lymphoma and all except one had MALT histology (the other having follicular histology). Differing dose fractionations were delivered to the patient with a low-grade T-cell lymphoma (35 Gy in 20 fractions). The other tumours receiving differing dose fractionations of 32 Gy in 16 fractions (2%) or 34 Gy in 17 fractions (5%) were treated before the creation of a uniform departmental policy in 2005. The median follow-up in this study was 4.4 years (range 0.2e10.4). Thirty-one patients (31 tumours) were lost to
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follow-up, mainly due to patients returning to their referring hospital for follow-up. In total, four patients (5%) experienced disease relapse (Figure 3). One developed biopsy-proven metastatic MALT lymphoma, 7 years after radiotherapy (34 Gy in 17 fractions) for an orbital tumour in the breast/chest wall. A second patient, treated for a MALT lymphoma of the lacrimal gland, developed contralateral lacrimal gland disease 2.5 years after primary radiotherapy and was successfully treated with radiotherapy (30 Gy in 15 fractions). A third patient who was also treated for a lacrimal gland tumour developed a parotid nodal relapse of her MALT lymphoma 5 months after her primary radiotherapy treatment. This relapse was also treated with radiotherapy (30 Gy in 15 fractions) with success, although she relapsed again 3 years subsequently with a jugulodigastric node, confirmed on histology to have transformed to a diffuse large B-cell lymphoma. The fourth patient, who was treated for an eyelid tumour, developed biopsy-proven MALT lymphoma in her lung 13 months after the initial radiotherapy. No patients have died of their disease during follow-up and no patients have experienced a local relapse, giving overall survival and local control figures of 100%. Acute and late toxicities from radiotherapy in this study are presented in Table 2. Of note, 22% of orbits treated experienced acute conjunctivitis and 22% also had acute erythema. All acute toxicities had resolved by the 6 month follow-up appointment. Seven per cent of orbits treated, developed patient-reported cataracts, with one patient who received bilateral treatment developing cataracts in both eyes. Of the 18 orbits treated with 300 kV photons; seven (39%) experienced conjunctivitis and seven (39%) also experienced erythema with the conjunctivitis and erythema rate among the standard external beam radiotherapy group being 15%; the difference in acute toxicity rates between the two techniques was statistically significant (P < 0.001). None of the patients treated with 300 kV
Table 1 Summary of patient characteristics (n ¼ 81) and treatment details (n ¼ 85) Gender Age Histological subtype
Radiotherapy dose fractionation (n ¼ 85)
Completed radiotherapy Subsite
Male Female Median (range) MALT Follicular T-cell B-precursor lymphoblastic lymphoma Unknown (low-grade) 30 Gy in 15 fractions with 300 kV (superficial) 30 Gy in 15 fractions with 6 MV photons 30 Gy in 15 fractions with mixed energy photons (6 þ 15 MV) 32 Gy in 16 fractions with 6 mMV photons 34 Gy in 17 fractions with 6 MV photons 35 Gy in 20 fractions with 6 MV photons Orbit Conjunctiva Lacrimal gland Lid
37 44 58.2 71 5 1 1 3 18 57 3 2 4 1 85 56 14 11 4
(22.6e90.7) (88%) (6%) (1%) (1%) (4%) (21%) (67%) (4%) (2%) (5%) (1%) (100%) (66%) (16%) (13%) (5%)
MALT, mucosa-associated lymphoid tissue. Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7 Table 2 Acute and late toxicity of all orbits treated (n ¼ 85). No grade 4/5 toxicities were reported Toxicity
Grade 1
Grade 2
Grade 3
Acute conjunctivitis Acute erythema Acute dry eye Acute photophobia Acute watery eye Acute uveitis Late cataract Late diplopia
17 17 3 1 1 0 0 1
2 2 0 0 0 1 1 0
0 0 0 0 0 0 5 0
* y z
Fig 3. KaplaneMeier curve for disease-free survival.
photons experienced a cataract, whereas the cataract rate among the standard external beam radiotherapy group was 9%, with this difference being statistically significant (P ¼ 0.013). All of the orbits experiencing toxicity were treated to a dose of 30 Gy in 15 fractions except one of the patients with a grade 2 cataract that was treated with 35 Gy in 20 fractions.
Discussion This study has confirmed that low-grade ocular adnexal lymphoma can be effectively managed with a conservative dose of radiotherapy of 30 Gy in 15 fractions over 3 weeks, resulting in no local relapses and manageable rates of toxicity. Other centres have often used differing dose/fractionations with differing outcomes, which are important to review when considering the optimum treatment regimen. We searched for all articles published from 2000 to 2013 that included outcome data on stage IE low-grade lymphoma of the ocular adnexa (Table 3). A significant number of studies included patients with stage 1E MALT lymphoma, but were too heterogeneous to readily apply to our patient population as they had significant use of chemotherapy, mixed stages without results given by stage or sparse radiotherapy details [16e26]. Out of those relevant to our population we identified eight manuscripts (Table 3) that contained 13 patients where individual radiotherapy doses were given and who experienced a local relapse: eight were treated to a dose under 30 Gy, three were treated to 30 Gy and two were treated to a dose above 30 Gy (both from one study [9]). This is despite only a minority receiving a dose of under 30 Gy.
(20%)* (20%)y (4%) (1%) (1%)z (0%) (0%) (1%)
(2%) (2%)z (0%) (0%) (0%) (1%)z (1%) (0%)
(0%) (0%) (0%) (0%) (0%) (0%) (6%) (0%)
Seven patients treated with 300 kV photons. Six patients treated with 300 kV photons. One patient treated with 300 kV photons.
Radiotherapy dose does therefore seem to be of relevance in increasing local control rates, but local salvage rates are high, either from re-irradiation or surgery, and it is unclear if better local control is associated with a reduction in distant relapse, which is the cause of much of the morbidity and mortality of ocular adnexal lymphoma. The FORT study has shown the efficacy of 24 Gy for indolent lymphoma, although most patients had follicular lymphoma and the number of MALT lymphomas was low (14%) [27]. Other centres treating extranodal MALT lymphomas have chosen to de-escalate doses of radiotherapy to the orbit in comparison with other sites such as the salivary glands, stomach and thyroid (25 Gy versus 30 Gy) [28]. However, it was notable that their local recurrence rates in the orbit were higher. Future studies should consider the option of dose de-escalation as the literature remains inconclusive and it is impossible to recommend a dose fractionation with certainty, although we will continue to use 30 Gy in 15 fractions. Given that the rate of local control from radiotherapy is high, and the outcomes particularly from MALT lymphoma are good [29], the doses used need to be carefully balanced with toxicity. We have shown a cumulative acute toxicity rate of 51%, most of which were grade 1, and all of which resolved over six months. The main late toxicity was a cataract rate of 7%, although the high prevalence of this condition in the population (30% in over 65 year olds [30]) makes the relationship to treatment difficult to prove. We would have expected a higher rate of cataract formation in our patient population. The pathogenesis of radiationrelated cataracts is debated and a threshold radiation dose for cataract development has not been established, but instead there seems to be a linear model of risk [31e33]. However, for patients developing radiation-related cataracts the outcome from surgery has been shown to be excellent [34]. The use of a lens-sparing technique prevented cataract formation, but was associated with a higher rate of acute erythema and conjunctivitis. This can be readily explained by the increase surface dose that is associated with the use of kV photons in comparison with MV photons. Twenty-one per cent of patients in our study were treated with a kV lens-sparing technique without compromise of local control rates. This approach was used for
Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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Table 3 Previous reports of radiotherapy for localised stage IE lymphoma of the ocular adnexa Reference
No. of patients
Stage
Dose range in Gy (median)
[6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
89 46 46 66 24 53 78z 30 39 70
IE IE IE IE IEeIVy IeIIx IE IEeIIx IE IE
25e30 (25) 5.4e30.6 (30.6) 21.6e45 (30.6) 20e45 (30) 24e25.2 (24) 24e30 30e50 (30.6) 28.8e45.8 (30) 4e45 (30) 23.4e45 (30.6)
* y z x {
Gy per fraction
Use of lead shield (%)
Local control rate
Distant control rate
2.5 1.8e2.0 1.8e2.0 1.8e2.0 1.5e2.0 1.5e2.0 1.6e2.0 1.5e2.0 { 1.8
Y (57%) Y* Y (65%) Y (59%) Y (17%) Y (21%) Y (53%) Y (10%) N N
98% 93% 93% 97% 88% 100% 100% 100% 97% 94%
83% 100% 98% 96% 96% 92% 87% 93% 85% 89%
Uncertain how many patients had treatment with a lead shield. Two patients had stage IV disease. 26% of patients also received systemic therapy. One patient had a stage IIE tumour. Uncertain fractionation.
disease confined to the conjunctival sac and despite the lead shield providing midline protection to the eye and shielding to the whole midline retro-ocular orbit there was not an increase in local orbital relapse. Other lens-sparing techniques have been described in the literature, including the use of electrons to cover the anterior orbit with the use of lead lens blocks placed on the cornea with or without a contact lens [9,12] or the use of a pencil beam block in an anterior photon or electron field [35]. There is no clear association between the use of these techniques and local relapses, although the limited total numbers of patients reported in the literature means it is difficult to form firm conclusions. There is also a theoretical potential for a reduction in local control if a lower radiotherapy dose is used in combination with a lens-sparing technique, as this technique can result in the back of the orbit receiving less than the prescription isodose. Optimal staging of low-grade ocular lymphoma is controversial. Jenkins et al. [36] have shown that 19% will have distant involvement at diagnosis and we therefore carry out a staging computed tomography scan in all patients. Neither a positron emission tomography (PET) scan nor a bone marrow examination was routinely carried out in this group of patients, all of which had low-grade histology. This area is controversial and a retrospective study of 16 patients with ocular adnexal lymphoma has shown one patient (6%) with a stage IE follicular lymphoma that was upstaged by the addition of a PET scan to their staging protocol [37]. Other authors do not recommend the routine use of PET [38]. Bone marrow examination has a relatively low pickup rate of between 2 and 8% and given the invasive nature of this procedure we would not routinely recommend it [39,40]. There are some limitations to this study, in particular its retrospective nature. Working in a tertiary referral centre reduces our follow-up data, as some patients returned to the referring centre and may have introduced an element of selection bias. A small number of patients (9%), all treated in the first half of the cohort, received higher doses of
radiotherapy to the departmental standard, although given the overall local control rates of 100% this is unlikely to have been a significant factor. We have classified the patients in this study according to the Ann-Arbor system in use at the time. However, the latest American Joint Committee on Cancer staging system (7th edition) [41] now incorporates a new classification of ocular adnexal lymphoma, which has been shown to predict outcome better than the Ann-Arbor system [42], although this has less prognostic importance than histology or treatment given [43], but we were unable to retrospectively stage our patients according to this system with any accuracy. Our study does suffer from a lack of formal ophthalmological toxicity data, in particular visual acuity details. The strengths of this study include the homogeneous tumour stage and grade, standardised dose and fractionation of radiotherapy, a relatively large patient cohort in comparison with the literature and a reasonable follow-up duration. We also report a significant number of patients who received kV radiotherapy. Although local control is important in this group of patients, low-grade ocular adnexal lymphoma can have a substantial risk of distant relapse, which in our study was 5%, with a median follow-up of 4.4 years, although other studies have shown a higher distant relapse rate of up to 55% [44], which may be reduced by systemic therapy [12]. Other approaches include doxycycline for those who tested positive for chlamydia psittaci infection [45,46], rituximab alone [47] and 90Y ibritumomab tiuxetan (Zevalin) [48]. There is, therefore, a suggestion that we should consider either the addition or substitution of systemic therapy to radiotherapy. However, in our experience, although the alternatives need careful consideration, the best technique radiotherapy remains the standard of care. The use of systemic therapy is controversial and we believe that a multicentre trial 2 2 factorial design randomised study [49] between radiotherapy with 24 Gy and 30 Gy radiotherapy and the addition of rituximab or placebo should be considered.
Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7
Conclusions Our study has shown 100% local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. We would recommend the use of this regimen, alongside the consideration of a lens-sparing approach where appropriate, in the treatment of this disease.
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Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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Original Article
Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy D.K. Woolf *, H. Kuhan y, O. Shoffren y, E.M. Akinnawo y, B. Sivagurunathan y, H. Boyce y, P.N. Plowman y * Mount y
Vernon Cancer Centre, Northwood, UK St Bartholomews’ Hospital, London, UK
Received 8 June 2014; received in revised form 16 September 2014; accepted 24 September 2014
Abstract Aims: Low-grade ocular adnexal lymphoma is a rare disease and often treated with local radiotherapy to varying doses. Most previously reported studies have a very heterogeneous patient population and treatments. We report the outcomes from a 10 year cohort of patients at our institution treated with primary radiation therapy. Materials and methods: We analysed a retrospective case series of patients with stage IE low-grade ocular adnexal lymphoma including a review of case notes, histological reports and radiotherapy charts. We assessed local and distant tumour control and relapse rates in addition to toxicity. Disease-free survival was estimated using the KaplaneMeier method. Results: In total, 81 patients and 85 orbits were treated with primary radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Seventy-nine per cent were treated with standard MV external beam radiotherapy to the whole orbit and 21% with a lens-sparing technique. The median follow-up was 4.4 years (range 0.2e10.4). Local control rates were 100%, with 5% of patients experiencing disease relapse elsewhere. No patients died from lymphoma. Cumulative acute toxicity rates were 51% (mainly erythema and conjunctivitis) and late toxicity rates were 8% (mainly cataract). The lens-sparing technique was associated with a significant reduction in cataract rate (P ¼ 0.013) and an increase in acute toxicity (P < 0.001). Conclusions: This study has shown excellent local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Lens-sparing radiotherapy; ocular adnexal lymphoma; ocular radiotherapy
Introduction Primary ocular adnexal lymphoma (orbital lymphoma) is a rare disease and accounts for less than 1% of all lymphomas and between 5 and 15% of extranodal presentations [1,2]. Radiotherapy is considered to be the standard treatment for low-grade lymphoma that is localised to the orbit (stage IE) [3], normally treated with 30 Gy in 15 fractions [4]. However, most previously reported studies have included patients treated over 20 years ago, often with now dated staging techniques and histological classification and
Author for correspondence: D.K. Woolf, Mount Vernon Cancer Centre, Northwood, UK. Tel: þ44-1923-844852. E-mail address: [email protected] (D.K. Woolf).
had a heterogeneous patient population in terms of grade and stage of disease. There was also a wide range of radiotherapy techniques and, in particular, doses used within each study, in addition to various systemic therapies, making outcomes difficult to interpret. We report the results of a large cohort of patients treated with radiotherapy alone within a single institution for localised ocular adnexal lymphoma over a 10 year period.
Materials and Methods A retrospective review of medical records was conducted for all patients diagnosed and treated with radiotherapy for ocular adnexal lymphoma between June 2002 and July 2012. Inclusion criteria were: stage IE disease as per the
http://dx.doi.org/10.1016/j.clon.2014.10.002 0936-6555/Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7
Ann-Arbor classification [5], primary treatment with radiotherapy, no systemic therapy except on relapse and low-grade histology. Patient demographics and lymphoma characteristics were recorded, as were radiotherapy details, including technique and dose fractionation. Toxicity data were also collected, as were relapse details. The study was conducted as per the STROBE guidelines. Work-up After a biopsy was carried out and a histological diagnosis obtained, all patients had a magnetic resonance imaging scan of the orbit to confirm the extent of disease and a computerised tomography scan from the head to the pelvis to ensure metastatic disease was not present. Radiotherapy Technique For disease confined to the conjunctiva (i.e. disease not found behind the equator of the globe on magnetic resonance imaging scan) patients were treated with a kV technique. This used an anterior 300 kV photon field with a 5 cm circle aperture. Shielding was provided by the placement of a custom-made contact lens under local anaesthetic between the eyelids (Figure 1). Mounted on this contact lens was a lead cylinder (Figure 2) that shielded the lens, thereby reducing the dose to the centre of the eye and with the intention of lowering the risk of cataract formation. For patients with disease beyond the conjunctiva, the whole orbit was treated with a MV photon technique. The patient was treated in a custom-made thermoplastic immobilisation shell and a wedged pair of anterior and anterolateral fields was used in order to create a homogenous dose distribution to treat the whole orbit. The eye was closed and bolus was utilised for anterior disease. The target volume for conjunctiva-only disease was the whole conjunctiva and for orbital, lacrimal gland and eyelid disease the target was the whole orbit. When bilateral orbital disease was present, a parallel opposed technique was used, often with 15 wedges as normal tissue compensators. The
Fig 2. The contact lens with mounted lead shield.
standard dose prescription was 30 Gy in 15 fractions over 21 days as per Bessell et al. [4], although this was only adopted as standard departmental policy from 2005. Follow-up All patients were seen for a toxicity assessment on a weekly basis during radiotherapy and for follow-up 6 weeks post-treatment. They were then seen every 6 months for the next year and on an annual basis after that. Patients were not discharged from follow-up, although some opted to return to the referring centre. For the purpose of this analysis, we defined loss to follow-up as a patient not being seen within 6 months of their planned appointment schedule. At each follow-up visit, toxicity was evaluated both by side-effects reported by patients and a clinical examination. Patients were also assessed for tumour response/relapse both in the orbit and at distant sites. Further investigations were requested if appropriate. An examination was conducted by a radiation oncologist and formal ophthalmological examinations and visual acuity testing were not carried out routinely. Statistics
Fig 1. The contact lens with a lead shield placed between the eyelids and about to be, but not yet, positioned over the cornea.
A statistical analysis was carried out with SPSS statistical software (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.). Relapsefree survival was assessed using the KaplaneMeier
Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7
method and the differences between radiotherapy techniques were compared using the t-test. The database was locked on 30 January 2014.
Results In total, 81 patients with a total of 85 primary ocular adnexal lymphomas were treated with primary external beam radiotherapy at our centre over a 10 year period (July 2002 to June 2012). Four of the 81 patients had bilateral disease and all of these received bilateral radiotherapy. The median age of patients at the point of diagnosis was 58.2 (range 22.6e90.7) with a relatively equal gender distribution (Table 1). The histological subtype of the tumours is shown in Table 1 and all cases were biopsy proven, including both orbits for bilateral disease. Most tumours were mucosa-associated lymphoid tissue (MALT) lymphomas (88%) and most of the remainder were follicular (6%). Three patients (4%) were documented in the notes to have a low-grade ocular adnexal lymphoma, but the original histology could not be located from the referring centre. All those with bilateral disease had the same histological subtype in both eyes. Seventy-eight tumours (92%) were treated with 30 Gy in 15 fractions over 3 weeks, of which 77% received treatment with a MV technique and 23% received treatment with a kV technique. All of those treated with kV X-rays had a conjunctival lymphoma and all except one had MALT histology (the other having follicular histology). Differing dose fractionations were delivered to the patient with a low-grade T-cell lymphoma (35 Gy in 20 fractions). The other tumours receiving differing dose fractionations of 32 Gy in 16 fractions (2%) or 34 Gy in 17 fractions (5%) were treated before the creation of a uniform departmental policy in 2005. The median follow-up in this study was 4.4 years (range 0.2e10.4). Thirty-one patients (31 tumours) were lost to
3
follow-up, mainly due to patients returning to their referring hospital for follow-up. In total, four patients (5%) experienced disease relapse (Figure 3). One developed biopsy-proven metastatic MALT lymphoma, 7 years after radiotherapy (34 Gy in 17 fractions) for an orbital tumour in the breast/chest wall. A second patient, treated for a MALT lymphoma of the lacrimal gland, developed contralateral lacrimal gland disease 2.5 years after primary radiotherapy and was successfully treated with radiotherapy (30 Gy in 15 fractions). A third patient who was also treated for a lacrimal gland tumour developed a parotid nodal relapse of her MALT lymphoma 5 months after her primary radiotherapy treatment. This relapse was also treated with radiotherapy (30 Gy in 15 fractions) with success, although she relapsed again 3 years subsequently with a jugulodigastric node, confirmed on histology to have transformed to a diffuse large B-cell lymphoma. The fourth patient, who was treated for an eyelid tumour, developed biopsy-proven MALT lymphoma in her lung 13 months after the initial radiotherapy. No patients have died of their disease during follow-up and no patients have experienced a local relapse, giving overall survival and local control figures of 100%. Acute and late toxicities from radiotherapy in this study are presented in Table 2. Of note, 22% of orbits treated experienced acute conjunctivitis and 22% also had acute erythema. All acute toxicities had resolved by the 6 month follow-up appointment. Seven per cent of orbits treated, developed patient-reported cataracts, with one patient who received bilateral treatment developing cataracts in both eyes. Of the 18 orbits treated with 300 kV photons; seven (39%) experienced conjunctivitis and seven (39%) also experienced erythema with the conjunctivitis and erythema rate among the standard external beam radiotherapy group being 15%; the difference in acute toxicity rates between the two techniques was statistically significant (P < 0.001). None of the patients treated with 300 kV
Table 1 Summary of patient characteristics (n ¼ 81) and treatment details (n ¼ 85) Gender Age Histological subtype
Radiotherapy dose fractionation (n ¼ 85)
Completed radiotherapy Subsite
Male Female Median (range) MALT Follicular T-cell B-precursor lymphoblastic lymphoma Unknown (low-grade) 30 Gy in 15 fractions with 300 kV (superficial) 30 Gy in 15 fractions with 6 MV photons 30 Gy in 15 fractions with mixed energy photons (6 þ 15 MV) 32 Gy in 16 fractions with 6 mMV photons 34 Gy in 17 fractions with 6 MV photons 35 Gy in 20 fractions with 6 MV photons Orbit Conjunctiva Lacrimal gland Lid
37 44 58.2 71 5 1 1 3 18 57 3 2 4 1 85 56 14 11 4
(22.6e90.7) (88%) (6%) (1%) (1%) (4%) (21%) (67%) (4%) (2%) (5%) (1%) (100%) (66%) (16%) (13%) (5%)
MALT, mucosa-associated lymphoid tissue. Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7 Table 2 Acute and late toxicity of all orbits treated (n ¼ 85). No grade 4/5 toxicities were reported Toxicity
Grade 1
Grade 2
Grade 3
Acute conjunctivitis Acute erythema Acute dry eye Acute photophobia Acute watery eye Acute uveitis Late cataract Late diplopia
17 17 3 1 1 0 0 1
2 2 0 0 0 1 1 0
0 0 0 0 0 0 5 0
* y z
Fig 3. KaplaneMeier curve for disease-free survival.
photons experienced a cataract, whereas the cataract rate among the standard external beam radiotherapy group was 9%, with this difference being statistically significant (P ¼ 0.013). All of the orbits experiencing toxicity were treated to a dose of 30 Gy in 15 fractions except one of the patients with a grade 2 cataract that was treated with 35 Gy in 20 fractions.
Discussion This study has confirmed that low-grade ocular adnexal lymphoma can be effectively managed with a conservative dose of radiotherapy of 30 Gy in 15 fractions over 3 weeks, resulting in no local relapses and manageable rates of toxicity. Other centres have often used differing dose/fractionations with differing outcomes, which are important to review when considering the optimum treatment regimen. We searched for all articles published from 2000 to 2013 that included outcome data on stage IE low-grade lymphoma of the ocular adnexa (Table 3). A significant number of studies included patients with stage 1E MALT lymphoma, but were too heterogeneous to readily apply to our patient population as they had significant use of chemotherapy, mixed stages without results given by stage or sparse radiotherapy details [16e26]. Out of those relevant to our population we identified eight manuscripts (Table 3) that contained 13 patients where individual radiotherapy doses were given and who experienced a local relapse: eight were treated to a dose under 30 Gy, three were treated to 30 Gy and two were treated to a dose above 30 Gy (both from one study [9]). This is despite only a minority receiving a dose of under 30 Gy.
(20%)* (20%)y (4%) (1%) (1%)z (0%) (0%) (1%)
(2%) (2%)z (0%) (0%) (0%) (1%)z (1%) (0%)
(0%) (0%) (0%) (0%) (0%) (0%) (6%) (0%)
Seven patients treated with 300 kV photons. Six patients treated with 300 kV photons. One patient treated with 300 kV photons.
Radiotherapy dose does therefore seem to be of relevance in increasing local control rates, but local salvage rates are high, either from re-irradiation or surgery, and it is unclear if better local control is associated with a reduction in distant relapse, which is the cause of much of the morbidity and mortality of ocular adnexal lymphoma. The FORT study has shown the efficacy of 24 Gy for indolent lymphoma, although most patients had follicular lymphoma and the number of MALT lymphomas was low (14%) [27]. Other centres treating extranodal MALT lymphomas have chosen to de-escalate doses of radiotherapy to the orbit in comparison with other sites such as the salivary glands, stomach and thyroid (25 Gy versus 30 Gy) [28]. However, it was notable that their local recurrence rates in the orbit were higher. Future studies should consider the option of dose de-escalation as the literature remains inconclusive and it is impossible to recommend a dose fractionation with certainty, although we will continue to use 30 Gy in 15 fractions. Given that the rate of local control from radiotherapy is high, and the outcomes particularly from MALT lymphoma are good [29], the doses used need to be carefully balanced with toxicity. We have shown a cumulative acute toxicity rate of 51%, most of which were grade 1, and all of which resolved over six months. The main late toxicity was a cataract rate of 7%, although the high prevalence of this condition in the population (30% in over 65 year olds [30]) makes the relationship to treatment difficult to prove. We would have expected a higher rate of cataract formation in our patient population. The pathogenesis of radiationrelated cataracts is debated and a threshold radiation dose for cataract development has not been established, but instead there seems to be a linear model of risk [31e33]. However, for patients developing radiation-related cataracts the outcome from surgery has been shown to be excellent [34]. The use of a lens-sparing technique prevented cataract formation, but was associated with a higher rate of acute erythema and conjunctivitis. This can be readily explained by the increase surface dose that is associated with the use of kV photons in comparison with MV photons. Twenty-one per cent of patients in our study were treated with a kV lens-sparing technique without compromise of local control rates. This approach was used for
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Table 3 Previous reports of radiotherapy for localised stage IE lymphoma of the ocular adnexa Reference
No. of patients
Stage
Dose range in Gy (median)
[6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
89 46 46 66 24 53 78z 30 39 70
IE IE IE IE IEeIVy IeIIx IE IEeIIx IE IE
25e30 (25) 5.4e30.6 (30.6) 21.6e45 (30.6) 20e45 (30) 24e25.2 (24) 24e30 30e50 (30.6) 28.8e45.8 (30) 4e45 (30) 23.4e45 (30.6)
* y z x {
Gy per fraction
Use of lead shield (%)
Local control rate
Distant control rate
2.5 1.8e2.0 1.8e2.0 1.8e2.0 1.5e2.0 1.5e2.0 1.6e2.0 1.5e2.0 { 1.8
Y (57%) Y* Y (65%) Y (59%) Y (17%) Y (21%) Y (53%) Y (10%) N N
98% 93% 93% 97% 88% 100% 100% 100% 97% 94%
83% 100% 98% 96% 96% 92% 87% 93% 85% 89%
Uncertain how many patients had treatment with a lead shield. Two patients had stage IV disease. 26% of patients also received systemic therapy. One patient had a stage IIE tumour. Uncertain fractionation.
disease confined to the conjunctival sac and despite the lead shield providing midline protection to the eye and shielding to the whole midline retro-ocular orbit there was not an increase in local orbital relapse. Other lens-sparing techniques have been described in the literature, including the use of electrons to cover the anterior orbit with the use of lead lens blocks placed on the cornea with or without a contact lens [9,12] or the use of a pencil beam block in an anterior photon or electron field [35]. There is no clear association between the use of these techniques and local relapses, although the limited total numbers of patients reported in the literature means it is difficult to form firm conclusions. There is also a theoretical potential for a reduction in local control if a lower radiotherapy dose is used in combination with a lens-sparing technique, as this technique can result in the back of the orbit receiving less than the prescription isodose. Optimal staging of low-grade ocular lymphoma is controversial. Jenkins et al. [36] have shown that 19% will have distant involvement at diagnosis and we therefore carry out a staging computed tomography scan in all patients. Neither a positron emission tomography (PET) scan nor a bone marrow examination was routinely carried out in this group of patients, all of which had low-grade histology. This area is controversial and a retrospective study of 16 patients with ocular adnexal lymphoma has shown one patient (6%) with a stage IE follicular lymphoma that was upstaged by the addition of a PET scan to their staging protocol [37]. Other authors do not recommend the routine use of PET [38]. Bone marrow examination has a relatively low pickup rate of between 2 and 8% and given the invasive nature of this procedure we would not routinely recommend it [39,40]. There are some limitations to this study, in particular its retrospective nature. Working in a tertiary referral centre reduces our follow-up data, as some patients returned to the referring centre and may have introduced an element of selection bias. A small number of patients (9%), all treated in the first half of the cohort, received higher doses of
radiotherapy to the departmental standard, although given the overall local control rates of 100% this is unlikely to have been a significant factor. We have classified the patients in this study according to the Ann-Arbor system in use at the time. However, the latest American Joint Committee on Cancer staging system (7th edition) [41] now incorporates a new classification of ocular adnexal lymphoma, which has been shown to predict outcome better than the Ann-Arbor system [42], although this has less prognostic importance than histology or treatment given [43], but we were unable to retrospectively stage our patients according to this system with any accuracy. Our study does suffer from a lack of formal ophthalmological toxicity data, in particular visual acuity details. The strengths of this study include the homogeneous tumour stage and grade, standardised dose and fractionation of radiotherapy, a relatively large patient cohort in comparison with the literature and a reasonable follow-up duration. We also report a significant number of patients who received kV radiotherapy. Although local control is important in this group of patients, low-grade ocular adnexal lymphoma can have a substantial risk of distant relapse, which in our study was 5%, with a median follow-up of 4.4 years, although other studies have shown a higher distant relapse rate of up to 55% [44], which may be reduced by systemic therapy [12]. Other approaches include doxycycline for those who tested positive for chlamydia psittaci infection [45,46], rituximab alone [47] and 90Y ibritumomab tiuxetan (Zevalin) [48]. There is, therefore, a suggestion that we should consider either the addition or substitution of systemic therapy to radiotherapy. However, in our experience, although the alternatives need careful consideration, the best technique radiotherapy remains the standard of care. The use of systemic therapy is controversial and we believe that a multicentre trial 2 2 factorial design randomised study [49] between radiotherapy with 24 Gy and 30 Gy radiotherapy and the addition of rituximab or placebo should be considered.
Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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D.K. Woolf et al. / Clinical Oncology xxx (2014) 1e7
Conclusions Our study has shown 100% local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. We would recommend the use of this regimen, alongside the consideration of a lens-sparing approach where appropriate, in the treatment of this disease.
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Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
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Please cite this article in press as: Woolf DK, et al., Outcomes of Primary Lymphoma of the Ocular Adnexa (Orbital Lymphoma) Treated with Radiotherapy, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.10.002
