Interventions for orbital lymphangioma

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness of medical and surgical interventions for the reduction/treatment of orbital lymphangiomas in children and adults.

Background

Description of the condition

Lymphangiomas are common benign anomalies of the lymphatic and vascular systems, most commonly occurring in the head and neck region. These lesions are usually not recognized at birth but can become apparent after episodes of trauma or hemorrhage to the region of the lesion (Raichura 2017). A rare subset of lymphangiomas, orbital lymphangiomas, constitute around 1% to 4% of all orbital lesions, and typically present spontaneously as an orbital hemorrhage in children under the age of 16 (Lally 2016; Nassiri 2015). The International Orbital Society characterizes orbital lesions by flow: type 1 (no flow), type 2 (venous flow), and type 3 (arterial flow) lesions. Orbital lymphangiomas are currently classified as type 1 (no flow) lesions, having minimal internal blood flow, with little to no connection with the vascular system (Harris 1999). Along with flow characteristics, orbital lymphangiomas are further classified as:

1. superficial (presenting as a subcutaneous cyst);

2. deep (orbital infiltration);

3. combined (superficial and deep components);

4. complex (intracranial or head and neck infiltration) (Saha 2012).

Clinically, most patients present with symptoms in the first decade of life, with deeper lesions classically going unrecognized until a hemorrhage into the lesion leads to proptosis (Lally 2016; Saha 2012). Patients also may present with a sudden increase in swelling or proptosis during an episode of upper respiratory tract infection (Kalisa 2001). Occasionally, patients present with gradual progression of proptosis and a restriction of ocular motility (Saha 2012). Other presentations can include globe displacement, physical disfigurement, mechanical blepharoptosis (which can obstruct visual development and result in amblyopia), and compressive optic neuropathy if left untreated after an acute hemorrhage into the lesion (Saha 2012). Early and effective treatment, especially in children, is therefore crucial to preserving vision and preventing amblyopia.

Radiologic imaging allows proper diagnosis and assessment of the size and extent of these lesions. Lymphangiomas are classically characterized by multicystic lesions with pathognomonic fluid levels. They are often isointense on T1‐weighted magnetic resonance imaging and hyperintense on T2‐weighted imaging, presenting with internal septations. As mentioned above, these lesions are characterized as no‐flow [H3] lesions, therefore there is typically an absence of flow voids and enlarged feeder vessels (Raichura 2017).

In terms of treatment, which is described below, it is important to note that the lesions are generally unencapsulated and infiltrative. They can surround vital structures of the orbit, leading to the inability for complete excision by surgery without the risk of harm to these adjacent structures. Other methods of treatment, such as sclerotherapy, have therefore been used. However, these, too, have accompanying risks of increasing pressure in the orbit due to the volume of injecting fluid and resulting edema from inflammation due to the agents (Raichura 2017).

Description of the intervention

Due to their proximity to vital structures, such as the globe, optic nerve, and extraocular muscles, treatment for orbital lymphangiomas is complicated and includes a large array of approaches. The major interventions fall into four categories: local medication injections via sclerotherapy, systemic medication, surgery, and observation (if the lesion is not causing pain, physically disfiguring, or vision threatening).

Sclerotherapy

Sclerosants have been used for the treatment of orbital lymphangiomas for the past three decades. Specific agents include OK‐432 (Picibanil), sodium tetradecyl sulfate, doxycycline, ethanol, pingyangmycin, and bleomycin (Gandhi 2013). These agents are introduced under ultrasound guidance by puncturing the cystic cavity, aspirating the fluid, and injecting the sclerosing agent. By aspirating the fluid, a diagnosis of the lesion can be confirmed by cytology; increased space for the sclerosant is created; and the surface area in contact with the agent is increased. It is important to note that sclerotherapy has been reported to be effective in treating and resolving macrocystic lymphatic malformations, with less efficacy seen in their microcystic counterparts (Bagrodia 2015).

Systemic sildenafil

Sildenafil is a phosphodiesterase 5 (PDE‐5) inhibitor, which increases the levels of cyclic guanosine monophosphate in smooth muscles, leading to vasodilatory effects (Gandhi 2013). Systemic sildenafil therapy is a novel approach to treating lymphatic malformations that has shown positive results in both orbital and non‐orbital lymphatic lesions. A low dose of oral sildenafil citrate has been shown to be a safe and effective method of decreasing the volume of lymphatic malformations in some children, especially those whose lesions are characterized as macrocystic or mixed (Wang 2017). Malformations have been shown to be reduced using a dose of 1 mg/kg/day of sildenafil and increasing the dose to 3 mg/kg/day, with longer‐term use (seven months) (Gandhi 2013; Wang 2017).

Systemic sirolimus

Sirolimus is a target of rapamycin (mTOR), which stops the integration of signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation by regulating ribosomal biogenesis and protein synthesis. The blocking of this pathway leads to a reduction in vascular endothelial growth factor production and angiogenesis, along with a reduction in the production of cytokine IL‐2. Sirolimus may be an effective treatment based on both radiologic evaluations and functional impairment scores (Adams 2016).

Surgical excision and debulking

Another intervention for orbital lymphangiomas is surgical debulking and removal of the lesion from the orbit. However, the non‐encapsulated nature of orbital lymphangiomas paired with accompanied vascular tufts, often makes excision a challenge (Saha 2012). Surgery also increases the risk of recurrence, scarring, and damage to adjacent structures (Patel 2017). Surgical removal or debulking is usually accompanied by or follows initial sclerotherapy. A few successful techniques for surgical debulking or removal have been documented. These include the use of TISSEEL, a fibrin glue, which can be injected intraoperatively into the lesion, allowing the surgeon to have a more solid mass to mobilize and excise. The fibrin glue also aids in hemostasis. For a deep orbital lymphangioma lesion in a blind eye and severely painful eye, orbital exenteration may be a reasonable surgical option (Saha 2012).

How the intervention might work

Due to the complicated nature of orbital lymphangiomas, the interventions described focus on reducing size and progression, in order to avoid the exacerbation of pain, proptosis, amblyopia, intralesional hemorrhage, optic neuropathy, and loss of visual acuity.

Sclerotherapy treatments for these lesions utilize numerous agents with different mechanisms of action that are intended to reduce the size (i.e. debulk) of the lesion. When injected into the lesion, sclerosants cause scarring of the lymphatic malformation and lead to cell death and reduction in size (Patel 2017). Compounds such as sodium tetradecyl sulfate, ethanol, and doxycyline are used to enhance death of the endothelial cells of the lesion. Chemotherapeutic agents (e.g. bleomycin and pingyangmycin) are used to inhibit cell proliferation and promote inflammatory responses that lead to cell death. Finally, compounds like OK‐432 (Picibanil) are thought to promote inflammatory responses that lead to cytokine production from circulating lymphocytes.

Systemic sildenafil therapy aims to reduce the size of the lesion, similar to the goals of sclerotherapy, by inhibiting PDE‐5, leading to a vasodilatory effect that may help to collapse the cystic channels of the lymphangioma. Cystic dilation of lymphangiomas is considered to be an effect resulting from the contraction of the vascular channels. Sildenafil therapy is believed to reduce the size of the lesion by relaxing the smooth muscle of these vascular channels, leading to a reduction in size of the lesion (Gandhi 2013).

Systemic sirolimus therapy aims to reduce the size of the lesion through reduction in angiogenesis and cell growth. Sirolimus is a target of the mTOR leading to a disruption in the P13K/AKT pathway. Normally, this pathway is important in governing cell growth along with vascular development and angiogenesis. Disorders in this pathway that cause activation lead to abnormal tissue overgrowth and result in vascular anomalies (Adams 2016). In lymphangiomas, sirolimus is therefore intended to disrupt this pathway, reduce angiogenesis and cell growth, and ultimately lead to a reduction in the size of the lesion.

The goal of surgical interventions is to reduce the size of the lesion or remove it completely in order to reduce harm, pain, and discomfort from the lymphangioma.

Why it is important to do this review

Orbital lymphangiomas can lead to severe visual, cosmetic, and quality of life issues for patients, especially children. There is currently no consensus on the best first‐line intervention to treat this condition in children and adults. Surgical resection is a challenge due to the lesion's un‐encapsulated nature and intimate relationship to orbital contents. The difficulty and danger of total excision is paired with a high recurrence rate of the lesions, occurring up to many years after initial surgery (Russin 2015).

When considering alternative treatments, sclerotherapy and systemic sildenafil and sirolimus are viewed as less invasive methods to reduce the size and severity of these lesions. A recent study that compared surgical therapy to primary sclerotherapy for the treatment of head‐and‐neck lymphatic malformations suggested no difference in effectiveness at one‐year postintervention (Bagrodia 2015). This finding, along with various studies promoting the use of sclerotherapy as a minimally invasive, first‐line treatment for these lesions, suggests the need for further investigation into its effectiveness. Investigation of recent uses of sildenafil and sirolimus are necessary in order to determine which treatment for this condition minimizes risks and maximizes function and other favorable outcomes for patients.

In this review, we aim to parse current literature regarding each of these treatments and analyze the effectiveness, recurrence rate, and side effects of each. Through doing so, we may shed light on the most effective treatment to manage these lesions according to the amelioration of symptoms and improvement in quality of life.

Objectives

To assess the effectiveness of medical and surgical interventions for the reduction/treatment of orbital lymphangiomas in children and adults.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs). We will include all reports published in any language.

Types of participants

We will include trials in which participants underwent any of the treatments for orbital lymphangioma that we have targeted. We will not apply any restrictions regarding location or demographic factors. We will include trials that enrolled children and adults up to 32 years of age.

Types of interventions

We will include RCTs comparing at least two of the following interventions with each other for the treatment of orbital lymphangiomas:

1. observation;

2. sildenafil therapy;

3. sirolimus therapy;

4. sclerotherapy;

5. surgery (excision or debulking).

The primary comparison of the review will be be surgical versus non‐surgical (sclerotherapy, sildenafil, sirolimus, or observation) therapy. Secondary comparisons, when data are available, will include sclerotherapy versus systemic therapy (sildenafil or sirolimus) and sclerotherapy versus observation.

Types of outcome measures

Primary outcomes

The primary outcome of interest in this review is reduction (mean change) in lymphangioma size up to two years after intervention based on clinical assessment or imaging, or both.

Secondary outcomes

1. Levels of pain post‐therapy (as reported by participants) up to two years after the intervention. Patient‐reported pain may be reported as continuous (mean or mean change) or dichotomous (proportions with improvement, no change, or worsening) measures.

2. Functional impairment related to ptosis and exposure keratopathy up to two years after the intervention. We will define functional impairment as the inability to perform daily activities (as reported by participants) due to the ptosis or exposure keratopathy. Functional impairment may be reported as continuous (mean or mean change) or dichotomous (proportions with improvement, no change, or worsening) measures.

Adverse effects

We will document and tabulate any adverse effect reported in the included studies related to systemic therapy or surgery. Specific adverse effects of interest in this review will include recurrence or increased size of the mass after surgery, infections following treatment, damage to surrounding orbital structures during surgery or sclerosant injection or both, increased pain, lid edema, increased pressure in the orbit due to volume of injections, and any systemic adverse effects.

Economic data

We do not plan to include economic data.

Quality of life data

We will evaluate quality of life scores (mean or mean change) measured with a validated questionnaire whenever this information is available.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist will search the following electronic databases. There will be no language or publication year restrictions.

• Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (latest issue) (Appendix 1)

• MEDLINE Ovid (1946 to present) (Appendix 2)

• Embase.com (1947 to present) (Appendix 3)

• PubMed (1948 to present) (Appendix 4)

• LILACS (Latin American and Caribbean Health Science Information database (1982 to present) (Appendix 5)

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) (Appendix 6)

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp) (Appendix 7)

Searching other resources

We will search the reference lists of trials included in this review for additional trials of interest. We also will use the Science Citation Index to find trials that have cited the identified trials.

Data collection and analysis

Selection of studies

Two review authors will independently review the abstracts and titles of articles identified through the electronic searches, using the criteria for considering studies for this review, and classify the titles and abstracts into three categories: 'definitely use,' 'possibly use,' and 'definitely exclude.' Any disagreements on classification will be resolved through discussion between the two review authors. After all review authors are in agreement, the full‐text reports of studies classified as 'definitely use' and 'possibly use' will be retrieved. Each review author will independently assess these reports for the inclusion criteria and classify them as 'include,' 'unsure,' and 'exclude.' All studies that meet our inclusion criteria will undergo assessment of risk of bias and data will be extracted. Any discrepancies regarding study selection will be resolved through discussion, and reasons for exclusion will be documented.

Data extraction and management

Two review authors will independently view the reports from selected studies and extract data regarding study design, participant characteristics, and interventions and outcomes assessed, using the data extraction forms developed by Cochrane Eyes and Vision (Appendix 8). The review authors will discuss all discrepancies. If any issue arises with a specific study, we will contact the study investigators to request clarification regarding methods or missing information. We will contact study authors by email to obtain information needed to include or exclude the study from the review, allowing them two weeks to respond. If they do not respond, we will contact them a second time and allow another two weeks to respond. After four weeks, we will classify all studies and extract data based on the available information. One review author will enter data into Review Manager 5 (Review Manager 2014), and a second review author will verify these data.

Assessment of risk of bias in included studies

We will use the guidelines provided in in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions to assess the risk of bias in included studies (Higgins 2011). We will consider the following parameters:

• random sequence generation (selection bias);

• allocation concealment; prior to randomization (selection bias);

• masking (blinding) of participants and personnel (performance bias);

• masking (blinding) of outcome assessors (detection bias);

• incomplete outcome data (attrition bias);

• selective outcome reporting (reporting bias);

• other sources of bias.

Two review authors will independently conduct bias assessments using the Cochrane 'Risk of bias' tool. We will categorize each study for each potential source of bias as at high, low, or unclear risk of bias. Any disagreements will be resolved by discussion. We will contact study investigators when methods are reported unclearly or incomplete.

Measures of treatment effect

We will categorize outcomes as either dichotomous or continuous. For continuous outcomes, such as reduction in lymphangioma size and changes in quality of life scores, we will calculate mean differences (MDs) and 95% confidence intervals (95% CIs) to estimate treatment effects. For dichotomous outcomes, such as the proportion of participants with adverse effects, we will calculate risk ratios (RRs) with 95% CIs to estimate treatment effects. Secondary outcomes of patient‐reported pain and functional impairment may be reported as continuous (mean or mean change) or dichotomous (proportions with improvement, no change, or worsening) measures.

Unit of analysis issues

The primary unit of analysis will be one eye per participant, with the unit of analysis being the participant. For any trials that included both eyes, we will assess whether appropriate analysis was used for correlated outcomes in pairs of eyes. We will record details of the study design with respect to the treatment modality and treatment of either one or both eyes.

Dealing with missing data

We will contact study authors whenever study reports are missing outcome data or regarding unclear study methods, outcome data, or any other information that could hinder our classification of the study for inclusion or exclusion in our review. We will contact the report authors by email and allow two weeks for a response with the requested information. If we are unable to retrieve missing information for an included study, we will classify the study as containing missing data when discussing the results.

Assessment of heterogeneity

We will assess clinical and methodological heterogeneity through comparison among the included studies of inclusion/exclusion criteria, characteristics of study participants, and assessments of primary and secondary outcomes. We will use the I² statistic (percentage) to judge statistical heterogeneity among studies included in any meta‐analysis. This statistic estimates the proportion of variation in outcome estimates due to statistical heterogeneity that cannot be attributed to random error. An I² value over 50% will be considered to indicate substantial statistical heterogeneity (Deeks 2011). We also will generate forest plots and assess them for consistency of direction and size of the effect among studies. We will consider the degree of overlap in CIs among individual studies, with poor overlap of CIs indicating the presence of heterogeneity.

Assessment of reporting biases

In order to assess reporting bias, we will compare outcomes reported in each included study to the outcomes listed in the original study protocol, design report, or registry record to judge whether selective outcome reporting occurred. If a sufficient number of studies are included in our review (more than 10) for individual outcomes, we will examine funnel plots for evidence of asymmetry, which may imply possible publication bias.

Data synthesis

After taking into account the assessment of heterogeneity and the number of included trials, we will perform a meta‐analysis for each outcome using either a random‐effects or fixed‐effect model. If substantial clinical or methodological heterogeneity is observed, according to the criteria detailed above, we will not combine outcome data from individual studies in a meta‐analysis, but instead will narratively describe the findings. When there is no evidence of clinical, statistical, or methodological heterogeneity and three or more trials are included in a meta‐analysis, we will use a random‐effects model. When there is no evidence of clinical, statistical, or methodological heterogeneity and fewer than three trials are included in a meta‐analysis, we will use a fixed‐effect model.

Subgroup analysis and investigation of heterogeneity

We do not plan to conduct any subgroup analysis.

Sensitivity analysis

When sufficient data are available, we will conduct sensitivity analysis to evaluate the effects of excluding studies deemed as at overall high risk of bias. We will report these findings in a tabular format.

Summary of findings

We will prepare a table to summarize findings with respect to estimates of our primary and secondary outcomes and adverse effects of treatments. We also will summarize the strengths and limitations of estimates of both primary and secondary outcomes. We will assess the certainty of the evidence to support each estimate using the GRADE approach (GRADEpro 2015).

We will report the following outcomes in 'Summary of findings' tables.

1. Reduction in lymphangioma size (assessed up to a period of two years after the intervention)

2. Self reported pain (post‐therapy, assessed up to a period of two years after the intervention)

3. Functional impairment related to ptosis and exposure keratopathy (assessed up to two years after the intervention)

4. Quality of life (assessed up to two years after the intervention)

5. Adverse effects (assessed up to two years after the intervention)

Potential pair‐wise comparisons will include:

• surgical excision/debulking versus observation;

• surgical excision/debulking versus sildenafil;

• surgical excision/debulking versus sirolimus;

• surgical excision/debulking versus sclerotherapy;

• sildenafil therapy versus observation;

• sildenafil therapy versus sirolimus;

• sildenafil therapy versus sclerotherapy;

• sirolimus therapy versus observation;

• sirolimus therapy versus sclerotherapy;

• sclerotherapy versus observation.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Orbital Neoplasms] explode all trees #2 MeSH descriptor: [Eyelid Neoplasms] explode all trees #3 MeSH descriptor: [Conjunctival Neoplasms] explode all trees #4 MeSH descriptor: [Lymphatic Abnormalities] explode all trees #5 MeSH descriptor: [Lymphangioma] explode all trees #6 lymphangioma* or lymphangioendothelioma* #7 "cystic hygroma" or "cystic hygromas" #8 (lymphatic* or lymphic*) near/3 (malformation* or abnormal* or anomal*) #9 (orbit* or periorbit* or ocular* or oculo* or eyelid* or conjunctiv*) near/3 (lymphatic* or neoplas* or malformation* or tumor*) #10 {or #1‐#9}

Appendix 2. MEDLINE (Ovid) search strategy

1. Randomized Controlled Trial.pt. 2. Controlled Clinical Trial.pt. 3. (randomized or randomised).ab,ti. 4. placebo.ab,ti. 5. drug therapy.fs. 6. randomly.ab,ti. 7. trial.ab,ti. 8. groups.ab,ti. 9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10. exp animals/ not humans.sh. 11. 9 not 10 12. exp Orbital Neoplasms/ 13. exp Eyelid Neoplasms/ 14. exp Conjunctival Neoplasms/ 15. exp Lymphatic Abnormalities/ 16. exp Lymphangioma/ 17. (lymphangioma* or lymphangioendothelioma*).tw. 18. cystic hygroma*.tw. 19. ((lymphatic* or lymphic*) adj3 (malformation* or abnormal* or anomal*)).tw. 20. ((orbit* or periorbit* or ocular* or oculo* or eyelid* or conjunctiv*) adj3 (lymphatic* or neoplas* or malformation* or tumor*)).tw. 21. or/12‐20 22. 11 and 21

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville 2006.

Appendix 3. Embase.com search strategy

#1 'randomized controlled trial'/exp #2 'randomization'/exp #3 'double blind procedure'/exp #4 'single blind procedure'/exp #5 random*:ab,ti #6 #1 OR #2 OR #3 OR #4 OR #5 #7 'animal'/exp OR 'animal experiment'/exp #8 'human'/exp #9 #7 AND #8 #10 #7 NOT #9 #11 #6 NOT #10 #12 'clinical trial'/exp #13 (clin* NEAR/3 trial*):ab,ti #14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti #15 'placebo'/exp #16 placebo*:ab,ti #17 random*:ab,ti #18 'experimental design'/exp #19 'crossover procedure'/exp #20 'control group'/exp #21 'latin square design'/exp #22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 #23 #22 NOT #10 #24 #23 NOT #11 #25 'comparative study'/exp #26 'evaluation'/exp #27 'prospective study'/exp #28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti #29 #25 OR #26 OR #27 OR #28 #30 #29 NOT #10 #31 #30 NOT (#11 OR #23) #32 #11 OR #24 OR #31 #33 'orbit tumor'/exp #34 'eyelid tumor'/exp #35 'conjunctiva tumor'/exp #36 'lymphatic malformation'/exp #37 'lymphangioma'/exp #38 (lymphangioma* OR lymphangioendothelioma*):ab,ti #39 "cystic hygroma*":ab,ti #40 ((lymphatic* OR lymphic*) NEAR/3 (malformation* OR abnormal* OR anomal*)):ab,ti #41 ((orbit* OR periorbit* OR ocular* OR oculo* OR eyelid* OR conjunctiv*) NEAR/3 (lymphatic* OR neoplas* OR malformation* OR tumor*)):ab,ti #42 #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 #43 #32 AND #42

Appendix 4. PubMed search strategy

1. ((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomised[tiab] OR randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh]) 2. lymphangioma*[tw] OR lymphangioendothelioma*[tw] 3. cystic hygroma*[tw] #4 (lymphatic*[tw] OR lymphic*[tw]) AND (malformation*[tw] OR abnormal*[tw] OR anomal*[tw]) #5 (orbit*[tw] OR periorbit*[tw] OR ocular*[tw] OR oculo*[tw] OR eyelid*[tw] OR conjunctiv*[tw]) AND (lymphatic*[tw] OR neoplas*[tw] OR malformation*[tw] OR tumor*[tw]) 6. #2 OR #3 OR #4 OR #5 7. #1 AND #6 8. Medline[sb] 9. #7 NOT #8

Appendix 5. LILACS search strategy

(MH:C04.588.149.721.656$ OR MH:C04.588.364.659$ OR MH:C05.116.231.754.659$ OR MH:C11.319.457$ OR MH:C11.675.659$ OR MH:C04.588.443.392.500$ OR MH:C11.319.421$ OR MH:C11.338.526$ OR MH: C04.588.364.235$ OR MH:C11.187.169$ OR MH:C11.319.217$ OR MH: C15.604.451$ OR MH:C16.131.482$ OR MH:C04.557.375.450$ OR lymphangioma$ OR lymphangioendothelioma$ OR "cystic hygroma" OR ((lymphatic$ OR lymphic$) AND (malformation$ OR abnormal$ OR anomal$)) OR ((orbit$ OR periorbit$ OR ocular$ OR oculo$ OR eyelid$ OR conjunctiv$) AND (lymphatic$ OR neoplas$ OR malformation$ OR tumor$))) AND ((PT:"randomized controlled trial" OR PT:"controlled clinical trial" OR PT:"multicenter study" OR MH:"randomized controlled trials as topic" OR MH:"controlled clinical trials as topic" OR MH:"multicenter studies as topic" OR MH:"random allocation" OR MH:"double‐blind method" OR MH:"single‐blind method") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animals OR MH:rabbits OR MH:rats OR MH:primates OR MH:dogs OR MH:cats OR MH:swine OR PT:"in vitro")

Appendix 6. ClinicalTrials.gov search strategy

Lymphangioma OR lymphangioendothelioma OR "cystic hygroma" OR ((orbit OR orbital OR periorbital OR eyelid OR conjunctival) AND (lymphatic OR neoplasm OR malformation OR tumor))

Appendix 7. WHO ICTRP search strategy

Lymphangioma OR lymphangioendothelioma OR cystic hygroma OR orbit AND lymphatic OR orbit AND neoplasm OR orbit AND malformation OR orbit AND tumor OR orbital AND lymphatic OR orbital AND neoplasm OR orbital AND malformation OR orbital AND tumor OR ocular AND lymphatic OR ocular AND neoplasm OR periorbital AND lymphatic OR periorbital AND neoplasm OR periorbital AND malformation OR periorbital AND tumor OR ocular AND lymphatic OR ocular AND neoplasm OR ocular AND malformation OR ocular AND tumor OR eyelid AND lymphatic OR eyelid AND neoplasm OR eyelid AND malformation OR eyelid AND tumor OR conjunctival AND lymphatic OR conjunctival AND neoplasm OR conjunctival AND malformation OR conjunctival AND tumor

Appendix 8. Data on study characteristics

Mandatory items		Optional items
Methods
Study design	Parallel‐group RCTi.e. people randomized to treatment Within‐person RCTi.e. eyes randomized to treatment Cluster RCTi.e. communities randomized to treatment Cross‐over RCT Other, specify	Exclusions after randomization Losses to follow‐up Number randomized/analyzed How were missing data handled? e.g. available‐case analysis, imputation methods Reported power calculation (Y/N), if yes, sample size and power Unusual study design/issues
Eyes or Unit of randomization/ unit of analysis	One eye included in study, specify how eye selected Two eyes included in study, both eyes received same treatment, briefly specify how analyzed(best/worst/average/both and adjusted for within‐person correlation/both and not adjusted for within‐person correlation) and specify if mixture one eye and two eyes Two eyes included in study, eyes received different treatments,specify if correct pair‐matched analysis done
Participants
Country		Setting Ethnic group/ancestry Equivalence of baseline characteristics (Y/N)
Total number of participants	This information should be collected for total study population recruited into the study. If these data are reported only for the people who were followed up, please indicate.
Number (%) of men and women
Average age and age range
Inclusion criteria
Exclusion criteria
Interventions
Intervention (n = ) Comparator (n = ) See MECIR 65 and 70	Number of people randomized to this group Drug (or intervention) name Dose Frequency Route of administration
Outcomes
Primary and secondary outcomes as defined in study reports See MECIR R70	List outcomes Adverse events reported (Y/N) Length of follow‐up and intervals at which outcomes assessed	Planned/actual length of follow‐up

Contributions of authors

Each author of the protocol has contributed to the following tasks:

• Conception and design of the protocol: AB, JR, SP

• Drafting the protocol or commenting on it critically for intellectual content: AB, JR, SP

• Final approval of the document to be published: AB, JR, SP

Sources of support

Internal sources

• No sources of support supplied

External sources

• Cochrane Eyes and Vision US Project, supported by grant 1 UG1 EY020522, National Eye Institute, National Institutes of Health, USA.

• National Institute for Health Research (NIHR), UK.

  • Richard Wormald, Co‐ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.
  • This protocol was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the CEV UK editorial base.

  The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS, or the Department of Health.

Declarations of interest

Sheel R Patel: None known. Jamie B Rosenberg: None known. Anne Barmettler: None known.

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