Risk factor in TTT provokes doubts concerning long-term efficacy

Residual open choroidal vessels in the deeper layers of the tumor may carry live malignant cells.

ROME – Transpupillary thermotherapy in the treatment of choroidal melanoma may be associated with a higher risk of recurrence than expected, according to Edoardo Midena, MD, of Padua University.

“If (the procedure) doesn’t prove more successful than radiotherapy, we may have to restrict its indications even further,” he said here at the meeting of the Italian Ophthalmologic Society.

Transpupillary thermotherapy (TTT) uses the infrared wavelength (810 nm) to raise temperature above 42°C to 44°C, attacking deep tumor cells. A series of large, 3-mm spots (six times larger than those used in photocoagulation) are delivered, each for at least 60 seconds, under retrobulbar anesthesia and maximum pupil dilation. Dr. Midena uses an Iris Medical Oculight SLx laser (Iridex).

How it works

“These slow, large spots penetrate deep into the tumor, causing cellular necrosis,” Prof. Midena explained.

The mechanisms of this thermal treatment are complex and not yet well known. There is a direct necrotic effect of the heat on the cells, which is partly linked to vessel occlusion (tumor cells are not well fed by blood vessels and easily become hypoxic). TTT also seems to increase cell apoptosis incrementally and modify immunogenesis in the tumor.

“The quantity of energy delivered is calculated to produce a whitening of the tissue, which appears towards the end of each 60-second spot,” Prof. Midena continued. “If this aspect appears too soon, before the treatment has reached at least 45 seconds, [the surgeon should] reduce the energy, as this is a sign that you are doing photocoagulation rather than thermotherapy — attacking the surface, but not the deeper layers of the tumor.”

Two to three sessions are necessary for a standard treatment.

Parapapillary choroidal melanoma before (left) and 1 year after treatment by TTT (right). A flat chorioretinal scar is visible in the area previously containing the melanoma.

A mid-peripheral choroidal melanoma before (left) and 2 years after successful treatment with TTT (right).

Restricted indications

Thermotherapy has several advantages. It preserves vision, and it is a quick, nonsurgical treatment that is accepted by the patient. It is also inexpensive. However, problems are not negligible, and after several years of clinical experience they appear to be more serious than expected.

“In the literature on the subject, we don’t have follow-up beyond 3 to 4 years and a total of about 500 cases — too little data to evaluate the real efficacy of the treatment. We shouldn’t forget that we are dealing with a very malignant tumor, which has a 50% survival rate at 10 years,” Prof. Midena said.

He explained that some of the first studies of TTT reported a 22% recurrence rate, which was far too high, taking into account that survival after recurrence is limited. Indications for primary treatment were therefore restricted to small choroidal melanomas of maximum 3.5-mm thickness and 10-mm diameter, sufficiently distant from the optic nerve and the fovea to preserve vision.

“TTT is also indicated in the treatment of recurrences, where radiotherapy cannot be used a second time, and in ‘sandwich’ therapy, where it is combined with brachytherapy to treat thicker tumors or tumors that are near the optic nerve,” Prof. Midena said. “In the treatment of retinoblastoma, TTT can be used in combination with chemotherapy. Thermal energy allows better penetration of the drugs.”

Risk factor

Prof. Midena pointed out that complications of TTT are not rare.

“Several cases of complications such as vessel occlusion or retinal traction have been reported. In such cases vision cannot be preserved, so there is no point in doing TTT rather than radiotherapy,” he said.

Moreover, a recent investigation has revealed a new risk factor, present in 45 of the 80 patients treated with TTT by Prof. Midena and colleagues.

“These patients had a minimum follow-up of 12 months. Recurrence rate was around 10%, and retinal complications as documented in the literature. Angiographic examination with indocyanine green revealed that the choriocapillaris was closed in all eyes, but 76% of the cases had open choroidal vessels in the deeper layers of the tumor.”

He explained that live malignant cells might survive the rise in temperature around these vessels, as the blood flow cools the surrounding tissue.

“These cells are live and active and may cause intraocular recurrence of the melanoma, or even a posterior growth of it. This means that we could see a dead, flat tumor inside, which might however have grown posteriorly, behind the sclera.”

Ultrasonography twice a year for at least 5 years is therefore mandatory, as it is the only way to detect posterior growth of melanoma.

“We may have to resign ourselves to the fact that radiotherapy, which produces a complete occlusion of choroidal vessels, is safer and more effective after all,” Prof. Midena concluded.

For Your Information:

Edoardo Midena, MD, can be reached at Clinica Oculistica, Università di Padova, Via Giustiniani 2, 35128 Padua, Italy; (39) 049-821-2121; fax: (39) 049-821-2129; e-mail: edoardo.midena@unipd.it. Dr. Midena has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Iris Medical Instruments can be reached at 1212 Terra Bella Ave., Mountain View, CA 94043; (650) 940-4700; fax: (650) 940-4710; e-mail: info@iridex.com; Web site: www.iridex.com.