The annual incidence of ocular melanoma (OM) and retinoblastoma (RB) in Denmark is around 50 and 5 respectively. RB is mainly diagnosed in children below the age of 2 years. Radiotherapy represents a mainstay in the efforts to cure the cancer while preserving vision. In the proposed project, we will use the notion-wide eye tumor databases to identify clinical and treatment related factors that affect the outcome after radiotherapy in terms of tumor control as well treatment related toxicity with emphasis on vision impairment. Based on a cohort of 150-200 patients treated for eye tumors with plaque brachyterapy, we will establish dose-response relationships for tumor control as well as vision impairment. This information can be used to further optimize current radiotherapy techniques as well as provide the framework for selection of patients for particle therapy. Furthermore, it can be used to optimize particle (proton) therapy techniques for treatment of eye tumors.
There are around 50 new cases a year of ocular melanoma in Denmark. Small tumors are often treated with plaque brachytherapy whereas larger tumors often require enuclation. Local tumor control rates are around 70%. Around 40% of patients treated with eye preserving therapy develop severe vision impairment on the treated eye. Around 50% of the patients develop distant failure (mainly liver metastases). In selected cases, particle therapy with protons can be considered for larger tumors. In fact, OM is the cancer diagnosis for which the largest number of patients have been given proton therapy so far.
There are around 5 new cases of RB annually in Denmark. Most tumors are diagnosed before the age of 2. Occasionally, the tumor is present at birth. Around 60% of the cases are sporadic whereas 40% are hereditary due to a germline mutation in the retinoblastoma (Rb) gene. Hereditary cases are often diagnosed shortly after birth and often affect both eyes. Carriers of Rb mutations has an overall increased risk of numerous malignancies with an approximately 90% risk of getting a second cancer before the age of 50. Unilateral (non-hereditary) tumors are usually treated with enuclation. Bilateral cases represent a particular challenge. Historically, external beam radiotherapy has been the preferred strategy (sometimes combined with enuclation of the most affected eye). Nevertheless, more recently systemic or local intra-arterial chemotherapy has been increasingly used. Due to the low incidence of RB, this change in strategy has not been subjected to randomized trials and is only to a limited extent supported by evidence.
The aim of the project is to analyze patient and treatment related factors that affect outcome after treatment for malignant eye tumors in terms of tumor control as well as treatment induced toxicity.
For OM, we will establish dose-response models for tumor control as well as vision impairment. This information can be used to optimize current radiotherapy techniques, to select patients for particle therapy as well as to develop particle therapy techniques specifically dedicated to treatment of eye tumors. Thus, the study may lead to an improved therapeutic ratio for OM.
For RB, we will use our database to evaluate the treatment outcome in terms of survival, tumor control, eye preservation and vision preservation according to the utilized therapeutic strategy. Other toxicity endpoints (e.g. cosmesis and QoL) may be included as well. In particular, we wish to elucidate the consequences of the recent shift in treatment strategy. Furthermore, we will analyze the occurrence of second malignancies with the intention to address the question of possible radiation-induced cancers.
Finally, we can use the data obtained for OM to optimize the radiotherapy technique for RB including proton therapy.
All cases of ocular melanoma and retinoblastoma since 1943 are registered in a nation-wide database. The database includes 3,542 patients with OM and 369 patients with RB. The database is unique and represents a valuable resource for research in these rare malignancies. Approximately 40 patients with OM are given plaque radiotherapy in Denmark. Treatment of RB in Denmark is centralized in Aarhus.
We will identify approximately 150-200 patients with OM that are given plaque brachytherapy in recent years. These patients will be evaluated concerning vision impairment and other treatment-related toxicities (e.g. cataract, glaucoma, field of view, retinal detachment and dry eye). Based on recordings of tumor and treatment characteristics, we will simulate (in silico) the dose distribution in the patients including the dose to the tumor and various ‘structures at risk’. Based on this, we will establish dose-response relationships for tumor control and normal tissue toxicity.
Based on the RB patients from the database, we will analyze the outcome according to various treatment strategies. The patients will be analyzed with regard to survival, tumor control, eye preservation and vision. Other endpoints like QoL, skull deformation, cataract and dry eye may also be investigated. The pattern of second tumors will be analyzed as well.
As described above, we intend to provide data that can be used to optimize the treatment strategy for patients with eye tumors. As such our project is likely to have consequences for future Danish patients with eye tumors.
Impact / relevance / etics
The project is expected to make a substantial contribution to the field. The study addresses clinically relevant questions. The results of the study are likely to affect clinical practice and improve the outcome of treatment for malignant eye tumors. In our view, the study does not pose any ethical problems.
The study will be conducted in cooperation between Department of Oncology, Department of Ophthalmology, Department of Pediatrics, Department of Medical Physics and Department of Oncology, Aarhus University Hospital. The project will involve DOOG (Dansk Oftalmo-Onkologisk Gruppe) that has representation from Aarhus University Hospital as well as Rigshospitalet. The study may also involve data from a European retinoblastoma database and a Nordic retinoblastoma network.