Periocular Cancer Treatment: From Control to Prevention

An enhanced understanding of the aetiology of common eye cancers is leading to new treatments and diagnostic techniques, according to Dr Michèle Beaconsfield, who delivered the inaugural Richard Collin Lecture at the European Society of Ophthalmology (SOE) meeting in Prague.

“Of course, we’ve known about skin cancer as long as we’ve been alive,” Dr Beaconsfield said. “The first written documentation of skin cancer [was in] Egyptian papyri from around 2500–3000 BC.”

She observed how basal cell carcinoma (BCC), the most common skin cancer, was first described in 1827 by Arthur Jacob—an Irish ophthalmologist who coined the term “rodent ulcer” to illustrate the slow-growing cancer. Jacob had written in the journal Dublin Hospital Reports that a rodent ulcer has characteristic features of “slowness of its progress, the peculiar condition of the edges and surface of the ulcer, the comparatively inconsiderable suffering produced by it, its incurable nature unless by extirpation, and its not contaminating the neighbouring lymphatic glands.”

Noting the current European incidence of nonmelanoma skin cancer approaches 150 per 100,000 annually, she said, “The European incidence of nonmelanoma skin cancer is enormous. The health burden on health systems is enormous. Clinicians like us have warned that this is getting worse.

“Eighty percent of basal cell carcinomas occur on the head and neck, and 20% of those are palpebral, so overall, of the [most common] cancer worldwide, we look after about 16%.”

Surgery remains the gold standard for eradication, Dr Beaconsfield said. Basal cell carcinoma presentations at an advanced stage or in patients unfit for surgery present difficulties—even today. However, alternative treatment approaches, previously limited to radiation therapy or palliation, have recently become available, thanks to progress in the understanding of the dysregulated growth pathways and immune surveillance that may lead to skin cancer development.

One important growth pathway is the Hedgehog signalling pathway (Hh). Experiments with drosophila flies led to an understanding of the importance of this pathway in body segmentation during development. Dr Beaconsfield explained how the Hh pathway in adults regulates growth and repair in response to tissue injury. The Hedgehog pathway can be used in cancer cells to contribute to abnormal cell overgrowth.

This same growth pathway is associated with basal naevus syndrome, also known as Gorlin syndrome, a rare autosomal disorder characterised by the development of multiple basal cell carcinomas from a young age.

“In the majority of cases, it is a defect in this particular gene—chromosome 9q—and does not produce a normal Patched protein,” Dr Beaconsfield said.

The normal inhibitory action of Patched is missing from the Hedgehog pathway, leading to an abnormal overgrowth signal to cells, which she said results in unrestrained growth of basal cell carcinomas. Thus, the pathway presented a potential target for molecular inhibition of basal cell cancer development.

Wildflower and dying lambs

Our understanding of cancer’s molecular basis has not always progressed in a straightforward, stepwise manner. Dr Beaconsfield explained initial scientific interest in the Hedgehog pathway involved targeting it in cancer, which, regrettably, was unsuccessful. Finally, a breakthrough came from a report in veterinary science. Unfortunate freak events were recurring in Idaho, United States, in the 1950s. Lambs were born with severe, often deadly, congenital deformities. The lambs had cyclopia, in addition to other cranial defects, that caused feeding and respiratory problems. In-depth investigation, including by federal authorities, revealed the ewes had consumed Veratrum californicum while pregnant. Analysis of the wildflower found it contained the alkaloid chemical cyclopamine.

Researchers subsequently discovered cyclopamine mediated teratogenic effects in the lambs by downregulating the Hedgehog pathway before finally uncovering a naturally occurring antagonist to the Hh pathway. Unfortunately, it was too toxic for clinical use. Further refinement of cyclopamine ultimately led to the development of vismodegib and sonidegib. These groundbreaking medications reversed basal cell carcinoma growth and caused tumours to shrink, though they carry a significant side effect profile. They are not active against all basal cell carcinomas, as different growth pathways may be active in different tumours.

Dr Beaconsfield emphasised the importance of immunosurveillance in cancer cell inhibition, as cancer cells can escape the immunosurveillance by host immune cells through various means. Augmenting the immune response to cancer has become a major therapeutic target, particularly in deadly melanoma.

She added more and more drugs are coming online “to the extent that in the last five years alone, 2,000 agents have come on the market for investigation.” Combining different drugs can have an additive effect, especially useful in metastatic melanoma.

But ideally patients should not get to the stage of having advanced metastatic disease—rather, diagnosis should be at the earliest asymptomatic stages.

“The Galleri test is about to come on the market now,” Dr Beaconsfield said. “It detects early cancers.”

This intriguing device, predicted to come on the market in 2024, will detect about 50 cancers at their very earliest preclinical stages via liquid biopsy (i.e., a blood draw). The test is not perfect but represents a further progression in cancer management.

Dr Beaconsfield has had a long career in oculoplastic surgery. She set up the eyelid oncology service in Moorfields Eye Hospital, London, where she first took up a consultant oculoplastic surgeon post in 1991. mb@consultantsee.co.uk