Argentine scientists, pioneers in the implementation of superselective intraocular chemotherapy

An interdisciplinary team of scientists from different institutions and specializations managed to develop and apply in Argentina a superselective infusion technique of intraocular chemotherapy for treatment of advanced retinoblastoma. The availability of this therapy at the J.P. Garrahan Pediatric Hospital makes it the third institute worldwide in terms of the number of treated patients and a pioneer in the implementation of this technique in Latin America.

The investigation was led by Guillermo Chantada, senior doctor at the Hematology-Oncology Service of that hospital, in collaboration with Paula Schaiquevich, CONICET associate researcher at the Clinical Pharmacokinetic Unit of the Garrahan Hospital. The results were published at the IOVS, Pediatric Blood & Cancer and Ophthalmology.

“Retinoblastoma is the main intraocular neoplasm in Pediatrics. Generally, it affects children under three years and it is the most frequent malignant solid tumour at the Hematology-Oncology Service of the hospital. Although the survival rate in Argentina is about 95%, in the cases where the tumour spreads from the retina to the vitreous humor, the conventional therapy indicated the enucleation- of the eyeball – that it is to say its removal”, Chantada comments.

Furthermore, 60% of the patients have the retinoblastoma in one eye. However, in the case of the remaining 40 per cent it affects both eyes, what would make enucleation cause permanent blindness.

The aim of the researchers was to develop and implement in Argentina the superselective infusion treatment in the ophthalmic artery, a technique improved by a team of Northamerican doctors (from the United States) conducted by David Abramson at the Memorial Sloan-Kettering Cancer Center of New York. For more than a decade both teams have kept a close collaboration.

“This superselective therapy consists of the administration of a chemotherapy drug or a combination of several drugs directly in the bloodstream of the eye through a micro catheter”, Schaiquevich explains and adds: “It is a tumour highly sensitive to different chemotherapies. Nevertheless, when it is in the vitreous humor it becomes resistant for there are no blood vessels. With this treatment, we are able to reach higher concentrations of the drug in the vitreous humour and thus reduce the tumour”, adds Schaiquevich.

Pioneers

The superselective infusión technique has quickly proved effective and showed a significant decrease of the side effects, that is why it became very popular in the main retinoblastoma treatment centers of the world. However, Chantada and Schaiquevich warn that “there are no preclinical and clinical studies that evaluate the pharmacokinetics of the drugs administered by this route”.

This is the reason why the Garrahan team developed a methodological research strategy based on a translational research model, for which they were awarded by the Study Centre for the Development of the Chemical-Pharmaceutical Industry of Argentina (CEDIQUIFA).

“We follow the most traditional steps, such as beginning with animal testing, in vitro studies in retinoblastoma cells, and in thus trying to reach the most active and less toxic combination for patients”, Chantada comments.

With this objective, they developed the administration technique in non-tumour animal models of pigs and rabbits and analyzed the pharmacokinetic, that is to say, they studied the movements and the quantity of the drug in the organism over time. Besides, they evaluated if this therapy actually manages to reach the vitreous humor, where most conventional therapies fail.

“We observed these variations in two chemotherapy drugs: melphalan and topotecan not only in the animals’ eyes but also in a systemic level. Our goal is to make the most part of the drug reach the eyeball and the least reach the rest of the body. In animal models we proved that the amount in the vitreous humor increased thirtyfold compared to the concentration in systemic circulation, demonstrating the selectivity of that administration route”, Schaiquevich explains.

Furthermore, thanks to the team work of all the services of the hospital, the researchers managed not only to conduct the preclinical and clinical tests, but also to determine the maximum dose for melphalan and a specific combination between this drug and topotecan, used in advanced cases.

This advance allowed the clinical group to implement the technique in pediatric patients.

For the researchers, the main advantages of this superselective therapy are associated with the reduction of both the adverse effects, linked to the general chemotherapy, and the hospitalization time of the patients. Besides, it improves the response to the oncologic treatment apart from providing higher ocular survival and an increase in the quality of life of the patients.

Historically the retinoblastomas, and specially the most advanced ones, were treated with external radiation that, in spite of being effective, increased the risk of developing secondary tumours caused for radiation. “Patients cured from retinoblastoma and preserved the eye, but by the age of 20 or 30 they had greater risk of developing a second neoplasm”, Chantada comments.

Considering these complications, physicians started treating retinoblastoma with systemic chemotherapy, that is to say general. In this case, the difficulties continued because despite the fact that the eye represented only 1% of the body volume, the remaining 99% also received the drug, although not needed, and thus increasing the risk of secondary tumours.

For this reason, the aim of the subsequent advances was to increase the rate of ocular preservation without risking the survival of the patient. “Tolerance to this treatment is excellent: children do not experience hair loss, they are not hospitalized and their body defences are not affected. Actually, it is markedly different from conventional chemotherapy for it causes less harm and the patient is not exposed to the long term effect of therapies”, Chantada comments.

Currently, with this treatment, more than 300 infusions were carried out successfully. The researchers are working on finding more selective methods and new drugs. Furthermore, in collaboration with Osvaldo Podhajcer, CONICET senior researcher at the Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA, CONICET-FIL), they plan the development of tumour animal models with retinoblastoma and to sequence these tumours during their most aggressive phase.