Feature, Report

Inside the clinical speciality of ocular oncology

From a subspeciality that barely existed four decades ago, to one bursting with innovative treatments today, ocular oncology has developed to the extent that success is measured in saving eyes, preserving vision and ultimately saving lives. RHIANNON BOWMAN investigates.

Ocular oncology involves diagnosing and treating tumours that occur in or around the eye – tumours of the eyelid, conjunctiva, intraocular structures and orbit.

Sydney optometrist Dr Russel Lazarus, who has 30 years of clinical and academic experience and is part of an international network providing evidence-based resources to educate the public about visual health, explains that while ocular tumours may cause vision loss or loss of the eye itself, they can also be potentially life-threatening if cancer metastasises.

“Eye cancer survival rates depend on the type of tumour, and its size and location and the stage of the cancer at diagnosis,” he writes on The Optometrists Network website.

“Malignant (cancerous) ocular tumours can be primary, starting within the eye, or secondary, spreading to the eye from another organ. Two types of primary tumours develop within the eye itself – retinoblastoma in children and ocular melanoma in adults.”

Lazarus says both types of tumours are rare; retinoblastoma accounts for 2% of all childhood cancers; ocular melanoma affects one in five million adults, worldwide.

Forty years ago, ocular tumours often required enucleation (removal of the eye). There was little clinical interest in intraocular tumours, and the subspecialty of ocular oncology did not exist.

US-based husband-and-wife leaders in the field, Drs Carol and Jerry Shields, wrote in an Indian Journal of Ophthalmology guest editorial, ‘Trends in the management of intraocular tumors over 40 years’, that at that time “diagnostic challenges were steep, especially in the clinical recognition of various intraocular tumors as many clinicians were not familiar with wide-angle viewing with the indirect ophthalmoscope and fundus photography was in its infancy”.

Today, the Shields’ believe ocular oncology has emerged as a vitally important subspecialty, “bursting with innovative treatments and remarkable success. More than saving vision, we have achieved ultimate goals of saving life and the eye”, they wrote. Some of the advances the Shields’ have witnessed in their careers include:

• New methods of intravenous, intra-arterial, and intravitreal chemotherapy have led to high rates of the globe salvage for retinoblastoma patients

• Vitreous retinoblastoma seeds, a previously-doomed finding, are now reversed with chemotherapy lavage of the vitreous cavity

• Treatment of metastasis with standard radiotherapy or plaque radiotherapy, as well as photodynamic therapy or intravitreal injections, has led to minimally invasive tumour control, often with the return of visual acuity

• Tumour size and genomic status allow a better estimation of ultimate metastatic risk associated with uveal melanoma.

• Uveal melanomas can now be detected at an incredibly small size, under 2 mm in thickness, using OCT as well as documented risk factors

• Melanomas that previously disguised as an innocent nevus can be unmasked by autofluorescence for early detection

• Non-malignant choroidal hemangioma and retinal hemangioblastoma with their hidden threat for vision loss can be more clearly identified on indocyanine green or fluorescein angiography and OCT, with eradication using photodynamic therapy, photocoagulation, or localised radiotherapy.

(Source: Trends in the management of intraocular tumors over 40 yearsIndian Journal of Ophthalmology)

Advances in treatment continue. Last year, a West Australian motherof- three who already lost one eye to ocular melanoma was being treated with an experimental immunotherapy drug, Tebentafusp, as part of a trial at Sydney’s St Vincent’s Hospital.

The therapy has been found to improve overall survival rates for patients with metastatic ocular melanoma in clinical trials overseas, with St Vincent’s being the first Australian trial site.

Ocular oncology specialists are a small community in Australia, comprising 12-15 specially trained surgeons. Insight spoke with three, from Brisbane, Sydney and Adelaide, about their path to becoming a specialist in ocular oncology in Australia, their clinical experience, new treatments currently undergoing clinical trials, and new benchmarks in collecting clinical data.

Ocular oncology registry under development

Sydney-based ocular oncologist Dr Li-Anne Lim – also an experienced general ophthalmologist and cataract surgeon – graduated with a Masters in clinical ophthalmology from the University of Sydney. She then spent 12 months at the Henry C. Witelson Ocular Pathology Laboratory at McGill University in Montreal, Canada, before completing her ophthalmology training at Sydney Eye Hospital.

With scholarship support, Lim pursued further subspecialty fellowship training at Wills Eye Hospital in Philadelphia, US. Training under husband-and-wife leaders in the field, Dr Carol and Dr Jerry Shields, Lim exclusively diagnosed and managed intraocular and periocular malignant and benign tumours, and simulating lesions.

Dr Li-Anne Lim

Ultra-widefield imaging has improved detection of choroidal melanoma in patients which would otherwise not have been picked up until later.

She says gaining experience at this high volume, tertiary referral centre allowed her to gain expertise in the clinical management of eye cancers, research and new imaging and therapeutic technologies.

Now a clinical senior lecturer at the University of Sydney and practising at Sydney Eye Hospital, The Children’s Hospital Westmead, and Chatswood Eye Specialists, Lim is a member of the International Society of Ocular Oncology (ISOO) and involved in the ocular oncology multidisciplinary team at The Kinghorn Cancer Centre at St Vincent’s Hospital in Sydney.

Together with Dr Michael Giblin, the first ophthalmologist in Australia to undergo fellowship training in ocular oncology, Lim works to provide the highest standard of care for patients with eye cancer.

She says technology is changing when and where patients are diagnosed with eye tumours.

“I’ve noticed recently, with the advance of ultra-widefield imaging and more optometrists using this technology in their practice, more than a handful of patients, who have been diagnosed with a mass but no symptoms, have been found accidentally at their optometrist through routine imaging. Ultra-widefield imaging has improved detection of choroidal melanoma in patients which would otherwise not have been picked up until later,” she says.

“Telehealth has also improved management of ocular oncology patients, with image-sharing and documentation accessible remotely, reducing the burden of travel for patients.”

Technology like OCT is also beneficial in detecting radiation side-effects that require injections, Lim says.

During her fellowship at Wills Eye Hospital in Philadelphia, Lim says she was fortunate to be using technology not widely used in Australia, namely intra-arterial chemotherapy for the treatment of retinoblastoma.

“Cutting-edge treatments like intra-arterial chemotherapy delivers chemotherapy directly to the eye – with less absorption to the rest of the body – with minimal side effects,” she says.

“We performed this treatment for the first time in Sydney last year, with paediatric ophthalmologist Dr Michael Jones. Previously, we couldn’t offer this treatment in Sydney as we didn’t have a neurosurgeon or intraarterial radiologist who could do it.”

As part of the ocular oncology multidisciplinary team at The Kinghorn Cancer Centre at St Vincent’s Hospital in Sydney, Lim takes part in regular online meetings with colleagues across Sydney and New South Wales to provide holistic care for patients. She also collaborates with ocular oncologists and paediatric ophthalmologists across Australia and New Zealand to share and discuss retinoblastoma cases, a rare form of eye cancer that affects children under five years of age.

“In countries like the US, ocular oncologists have a higher case load because they have a larger population. Here, we treat about 20 new cases of retinoblastoma a year, so sharing and discussing these cases can be beneficial,” Lim explains.

“Some types of retinoblastoma are genetically inherited. It has been so wonderful to see the changing face of retinoblastoma when treating families affected by this disease. Where we once only had treatments that were disfiguring, and often resulted in eye removal, it is such a joy to be able to see the children of retinoblastoma survivors being treated with eye sparing treatments like intra-arterial chemotherapy. Furthermore, pre-implantation genetic testing also means that the diagnosis may be avoided altogether, an important part of our ongoing care of children with retinoblastoma who mature to adulthood,” Lim says.

Retinoblastoma – pre-treatment (top) and nine months post intra-arterial chemotherapy. Image courtesy of Dr Li-Anne Lim.

Approximately 150 Australians are diagnosed with uveal melanoma each year, of which approximately 50% of patients develop metastasis (cancer spreading to other parts of the body).

“Unfortunately that statistic hasn’t changed much over the last few decades, but we’re working closely with medical oncologists to address this. The trial at Sydney’s St Vincent’s Hospital of the bispecific protein drug, Tebentafusp, is showing promise.”

Lim says collaborating with other specialists, like paediatric ophthalmologist Dr Michael Jones, head of the department of ophthalmology at the Children’s Hospital at Westmead, is one of the advantages of a career in ocular oncology.

She is also witnessing the infancy of greater support for ocular oncology patients.

“The Kinghorn Cancer Centre at St Vincent’s Hospital in Sydney was recently awarded funding for an ocular nurse. Just as breast cancer awareness has focused on the importance of a breast care nurse to support patients [led by The McGrath Foundation], we’re building similar support for ocular oncology patients,” Lim says.

Looking ahead, Lim says trials for future treatment to save not just an eye, but save vision, are promising.

“I’m excited to see progress on potential treatment that may help to improve vision, such as anti-VEGF treatment used to treat radiation side effects,” she says.

Lim is part of a team of ocular oncologists gathering data in Australia to identify patterns in diagnosis and treatment.

“We’re in the process of building an ocular oncology registry, funded through the Save Sight Institute. We’re making progress; the registry is being built but is not yet live.”

More research is required

Brisbane’s Dr Lindsay McGrath hopes the imminent ocular oncology registry described by Lim fills a gap in the current landscape, helping provide real world, long-term data that could be difficult to obtain in randomised controlled trials.

“We see about 30-40 new cases of choroidal melanoma a year in Queensland. A registry would be beneficial, because, at the moment, we don’t have an effective method or means to compare individual cases,” she says.

McGrath graduated from optometry with honours from Queensland University of Technology in 2005. She then went on to medical school at the University of Queensland and completed a Masters of Philosophy in ophthalmology in 2013.

She undertook her specialty ophthalmology training in her home state of Queensland and completed her training at The Royal Victorian Eye and Ear Hospital, with an acting fellow role in the orbital, lacrimal and plastics team. She completed a further year of subspecialty training in ocular oncology, oculoplastics and the orbit at the Royal Hallamshire Hospital in Sheffield, UK.

Dr Lindsay McGrath

We have three priorities when treating our patients; one, save their life; two, save their eye; three, save their vision.

McGrath is a member of the Australian and New Zealand Society of Ophthalmic Plastic Surgeons, British Oculoplastics Surgeons Society and International Society of Ocular Oncologists. She is also a member of RANZCO’s special interest group in ocular oncology.

She joined Terrace Eye Centre in Brisbane in 2019. The centre holds a weekly ocular oncology clinic, which draws patients from the entire Queensland state, plus Northern NSW and the Northern Territory, referred by optometrists, ophthalmologists and GPs.

“The bulk of cases are choroidal melanoma. Retinoblastoma management is done at the Queensland Children’s Hospital due to the expertise of the paediatric ophthalmology team there, as well as links with paediatric oncologists,” McGrath explains.

“I specialise in surgical and medical management of intraocular and extraocular tumours, squamous and melanocytic tumours of the conjunctiva, diseases of the eyelids, lacrimal system and orbit. We have three priorities when treating our patients; one, save their life; two, save their eye; three, save their vision. We’re able to save eyes more often now than 30 years ago,” she says.

McGrath says two main treatments – plaque radiation (or brachytherapy), and photodynamic therapy for small tumours and lesions – help save eyes.

“But if a patient presents late and the tumour is larger than if it had been detected earlier – which has happened as a result of COVID – we may need to remove eyes. We still remove about 10 eyes a year for melanoma, which affects predominantly Caucasian patients between 40 to 80 years of age,” McGrath says.

Although diagnostic equipment hasn’t changed a lot in the last 10 years, McGrath agrees with Lim that the advantage now, compared to 10 years ago, is better imaging equipment.

“We’ve seen an increase in referrals because of improved imaging – and that also means we’ve seen an increase in the number of cases that are, in fact, not melanomas – the patient may actually have a retinal tear, pre-curser lesions, or moles – but these all need investigating in their own right,” she says.

“From our point of view in clinic, these conditions all require critical examination and monitoring.”

Fundus images of a left choroidal melanoma. Image courtesy of Dr Lindsay McGrath.

While radiation is still the main treatment for eye cancer, McGrath says during her fellowship at the Royal Hallamshire Hospital in Sheffield she had access to equipment on the frontier of radiation treatment.

“In the UK, they have access to a different type of radiation – a proton beam, which is a newer type of particle. The machine costs millions and takes up a whole room, but it is used not just for treating eyes. A prototype is currently being built in Adelaide, at Australian Bragg Centre for Proton Therapy and Research, but it’s potentially years away from completion. When it is complete, it will allow us to treat larger tumours, and potentially save more lives,” McGrath says.

Other leaders in the field are pushing the envelope in the treatment space.

The Australasian Ocular Melanoma Alliance (AOMA) is a research group that aims to further the care and treatment of patients with ocular melanoma across Australia and the world.

“The AOMA is run by medical oncologist Dr Anthony Joshua from NSW, who has his finger in international trials (Tebentafusp). Local drug companies don’t have a large eye cancer population to feed into here, in terms of trials, but international trials attract more patients, and newer drugs, aimed at helping save eyes, and promoting longer survival with metastases.”

One of those newer drug trials is belzupacap sarotalocan (previously known as AU-011). This drug is in Phase 2 development, and not on the market.

A virus-like drug conjugate (described as ‘essentially inactivated human papillomaviruses’), AU-011 is a potential first in cancer molecule used to treat tumours and preserve vision.

Through the Queensland Ocular Oncology Service, McGrath has had the privilege of working closely with Professor Nicholas Hayward who runs a melanoma research group at QIMR Berghofer Medical Research Institute in Brisbane.

“He is exceptionally highly regarded in cutaneous melanoma research circles worldwide, and we are lucky enough that Nick has put funding aside for rare melanoma subtypes like ocular melanoma, to help establish a research database, collecting patient’s tumour samples, and blood samples.”

Although ocular tumours are relatively rare compared to conditions like cataract or diabetic retinopathy, McGrath says ocular melanoma is a poorly understood tumour, and more research is required.

She is contributing to the literature; a paper she co-authored on ocular melanoma, titled ‘Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours’, was published in peer-reviewed journal Nature Communications in 2020.

“This is the first time that ultraviolet light has been implicated in iris melanoma, and further highlights the importance of shielding the eyes from ultraviolet radiation – particularly in Australia,” McGrath says.

Treating cancer has an ‘urgency and value’

Dr David Sia is a dual-fellowship vitreoretinal specialist and ocular oncologist based in Adelaide.

He obtained his medical degree from the University of Otago, New Zealand, in 2009 and went on to undertake ophthalmology registrar training in Adelaide and Alice Springs.

Following completion of registrar training, Sia then pursued overseas fellowship training and completed a 13-month ocular oncology fellowship in London, UK at the prestigious Moorfields Eye Hospital, St Bartholomew’s Hospital and Royal London Hospital. This was followed by a two-year vitreoretinal fellowship in Edmonton, Canada, at Alberta Retina Consultants.

Dr David Sia

The field has come a long way, and the rate of enucleations have significantly dropped.

Upon returning to Adelaide in 2020, Sia was appointed as a vitreoretinal specialist and ocular oncologist at the Royal Adelaide Hospital, Flinders Medical Centre and Women’s and Children’s Hospital. In addition, he holds a position as clinical associate lecturer at the University of Adelaide, is widely published and actively engaged in clinical research.

“I feel the biology of cancer is extremely interesting. The treatment of cancer has an urgency and value for saving life that is highly impactful. Patients diagnosed with cancer are extremely worried and being involved in helping them is a great privilege,” he says.

Sia sees roughly 15-20 oncology patients a week, mostly uveal melanoma and ocular surface squamous neoplasia.

“I also receive referrals for conditions such as choroidal haemangiomas, choroidal metastasis, choroidal osteoma, conjunctival melanoma and vitreoretinal lymphoma. As I do retina work as well, I often get referrals for all sorts of weird and wonderful fundus lesions of uncertain diagnosis. This is part of what makes this specialty so interesting and challenging,” Sia says.

Optos colour reconstruction photograph of the left eye showing a large inferior choroidal melanoma with exudative retinal detachment. Image courtesy of Dr David Sia.

He says there have been exciting advances in the diagnosis and management of intraocular tumours in the past decades – but some limitations linger.

“The field has come a long way, and the rate of enucleations have significantly dropped. Quite a lot of enucleations performed can potentially be avoided if given the necessary resources and access to treatment. South Australia is still limited in the range of treatment options but I hope this will change in the coming years,” he says.

“Some of the most significant advances include molecular prognostication techniques for uveal melanoma such as gene expression profiling and other biomarkers. These allow a more accurate prediction, and classification of uveal melanoma into more aggressive and likely to metastasise or less likely to.”

He continues: “These have not only provided information to direct screening for patients, but also paving the way for identifying candidates for future adjuvant treatment to reduce risk of metastasis.”

But treatment for uveal melanoma has not changed much over the last decade, Sia says.

“Radiation by brachytherapy is still the mainstay. Computerised radiation planning and conformal loading of plaques is an exciting way of improving the accuracy and delivery of plaque brachytherapy.

“Several trials on using photodynamic therapy to treat uveal melanoma were released in the last decade, which showed a suboptimal response rate. It is still offered as a second or third line treatment option. There is strong data that intravitreal anti-VEGF injections following plaque brachytherapy is significant in preserving vision,” he says.

New methods for more targeted uveal melanoma treatment in order to preserve more vision are on the horizon, and immunotherapy for metastatic uveal melanoma has had a recent breakthrough, Sia says.

“I am excited about better treatments for uveal melanoma and metastatic uveal melanoma. More focused treatment for small uveal melanoma is on the horizon. A viral-like drug conjugate that specifically binds to uveal melanoma cells is injected into the eye and subsequently activated with laser to cause tumour cell destruction,” he explains.

“I am also excited for new immunotherapy drugs for uveal melanoma/ metastatic uveal melanoma, and the role of these as adjuvant or neo adjuvant therapy.”

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