Study review of the effectiveness and safety of drugs used in intra-arterial chemotherapy in the treatment of Retinoblastoma

REVIEW ARTICLE

CANALES, Inácia Maria da Silva ^[1], RIBEIRO, Alessandra Maximiano ^[2], SOARES, Amata dos Santos ^[3], KLINGELBT, Ingrid ^[4], ANDREOLLI, Rafael ^[5], SANTANA, Claudinei Alves ^[6]

CANALES, Inácia Maria da Silva. Et al. Study review of the effectiveness and safety of drugs used in intra-arterial chemotherapy in the treatment of Retinoblastoma. Revista Científica Multidisciplinar Núcleo do Conhecimento. Year 05, Ed. 10, Vol. 04, pp. 35-51. October 2020. ISSN: 2448-0959, Acess Link: https://www.nucleodoconhecimento.com.br/health/pharmacous-safety

SUMMARY

Retinoblastoma is a malignant tumor characteristic of childhood, which was once a sign of enucleation, since 2005 has been applied an innovative treatment with intra-arterial chemotherapy that found to be effective, bringing good tumor control and minimal systemic complications. Studies present results of effectiveness and safety of this therapy used in some countries, as well as the main drugs used and the positive results in the treatment of retinoblastoma. The information was obtained through a review study in the scientific literature, which found that the most used drugs in intra-arterial chemotherapy are melphaline, carboplatin and topotecan. From these results we can conclude that the drug of choice is melphane, which can be used in monotherapy or combined with carboplatin or topotecan. Currently, there are still ongoing studies evaluating the effectiveness and safety of topotecan and carboplatin in pediatrics, whether in monotherapy or combined therapy with other antineoplastic drugs.

Keywords: Retinoblastoma, Intra-arterial chemotherapy, melphane, topotecan, carboplatin.

1. INTRODUCTION

Retinoblastoma is a disease characterized by an intraocular malignant tumor originating from the ectodermal neura membrane of the embryonic retina, which manifests itself in childhood, with signs and symptoms varying according to size and location, the most common being leukococcus, also called the “cat’s eye” reflex, being an important diagnostic criterion, and other manifestations may occur that include blindness , glaucoma, strabismus and conjunctival hyperemia (SELISTRE, 2013; INSTITUTO ONCOGUIA, 2017; DEPARTAMENTO CIENTÍFICO DE ONCOHEMATOLOGIA, 2015).

There are two forms of manifestation of the disease, being unilateral (about 3 cases in 4 children) and bilateral (about 1 case in 4 children), with no predisposition to race and ethnicities, the occurrence is almost equally in boys and girls, and may also affect the right or left eye, but it can be sporadic or hereditary (INSTITUTO ONCOGUIA, 2017).

With the percentage of 30 to 40% of hereditary origin with bilateral or multifocal germline mutation and 60 to 70% are non-hereditary forms, and the somatic, unilateral and unifocal mutation is associated (FABIAN, 2017; PINA, 2012).

The classification currently most used in the staging of localized forms of this type of tumor is according to the International Classification System of Intraocular Retinoblastoma. This classification is based on the size of the lesion, distance from the tumor in relation to the photon and optic disc, and presence of subretinian or vitreous dissemination (Revista da Sociedade Portuguesa de Ophthalmology).

The international classification of intraocular Retinoblastoma is shown in the table below:

Table one. International Classification of Intraocular Retinoblastoma and the Preservation Rate of the Eyeball.

Fonte: Adaptado de Instituto Oncoguia (2017).

The incidence of cases ranges from 1/16,000 to 1/18,000 live births, affecting 8,102 children per year worldwide (NETO, 2016).

In Brazil, the expectation is about 400 new cases per year, commonly occurring in infants and young children, and the average age at diagnosis is 2 years rarely affecting children over 6 years of age (NETO, 2016; AMERICAN CANCER SOCIETY, 2018).

In the United States, every year 200 to 300 children are diagnosed with retinoblastoma (AMERICAN CANCER SOCIETY, 2018).

Twenty years ago, the treatment of retinoblastoma was synonymous with enucleation or external radiotherapy that most often caused enofthalmia and marked facial deformities (RODRIGUES; LATORRE and CAMARGO, 2004; CARDOSO et al., 2011).

However, the new techniques have shown efficiency in tumor regression or at least control, with aesthetic and functional advantages from techniques such as laser photocoagulation, intra-arterial chemotherapy, cryotherapy, intravitreal chemotherapy, brachiteria, proton-laden particle irradiation or helium and enucleation ions (ERWENNE, 1998; AMERICAN CANCER SOCIETY, 2018; ONCOGUIA INSTITUTE, 2018; LIANG, 2020).

One currently applied form is Intra-Arterial Chemotherapy developed in the United States in mid-2005, affecting all over the world, with Brazil being one of the countries with the most experience in this technique, presenting itself as an effective alternative in the treatment of advanced infant retinoblastoma, minimizing the need for enucleation (INCA, 2019).

For this technique, drugs belonging to classical chemotherapy are used, characterized by three therapeutic classes: Alkylating agents, Platinum and Topoisomerase inhibitor. Melphaline is an antineoplastic agent that acts as an alkylating agent/ nitrogen mustard derived from mecloretamine, interfering with the crossing of DNA chains, preventing replication and leading to cell death, a non-specific phase agent of the cell cycle (MOC BRASIL, 2020).

Carboplatin belonging to a second generation of platinum analogues acts similarly to alkylating agents and has biochemical properties similar to cisplatin, predominantly produces interchain cross-links in DNA, altering its structure and inhibiting its synthesis, a non-specific phase agent of the cell cycle (MOC BRASIL, 2020).

Topotecan has antitumor activity involving inhibition of topoisomerase-I, an enzyme closely involved in DNA replication, relieving tortion stress introduced in front of the moving replication fork, stabilizing the covalent enzyme complex with the dna cleave chain that is an intermediate of the catalytic mechanism, causing protein induction associated with simple DNA chain breaks (EMA , 2009).

The procedure is based on the introduction of a microcatheter in the femoral artery being slowly inserted through the blood vessels to the ophthalmic artery, thus the drugs are injected directly into the blood vessel that irrigates the eye, increasing the accuracy of reach of the desired target providing a high concentration of chemotherapy at the tumor site, and the presence of a specialized professional is necessary (PETERSON et al. , 2011).

The provision of care to cancer patients includes several integrated specialties, of which the pharmaceutical professional plays an important role due to the high complexity of treatment, being fundamental specific technical knowledge, skills and competencies aimed at promoting the effectiveness and safety of treatment (ANDRADE, 2009; MATILE, 2008; GEUM, 2016; INCA; REDE CÂNCER, 2019).

2. METHODOLOGY

This is a review article of the scientific literature with search in databases (PubMed, SciELO, Clinical Trials and Cochrane Library) and government websites (INCA, SBOC, Oncoguia, GRAAC, American Cancer Society and Minas Gerais Society of Pediatrics).

The key words for research were in Portuguese and English: Retinoblastoma. Intra-arterial chemotherapy, melphalan, topotecan, carboplatin and their respective English correspondents, “retinoblastoma”, “intraarterial chemotherapy”, “melphalan”, “topotecan”, “carboplatin”.

The search period was from May/2019 to February/2020.

3. DISCUSSION

Retinoblastoma is considered a serious cancer in which treatment requires the use of specific techniques and antineoplastic drugs (such as melphane, carboplatin and topotecan) in relation to intra-arterial chemotherapy in which safety and effectiveness require evaluation (INSTITUTO ONCOGUIA, 2018).

3.1 MELPHALINE

The most used chemotherapy agent in this technique is melphaline, due to its safety and minimal systemic toxicity. The injectable form contains 50 mg of lyophilized substance, with 10 mL of diluent solution. Derived from mecloretamine, melphaline interferes with the crossing of DNA chains, preventing replication and leading to cell death, a non-specific phase agent of the cell cycle (ABRAMSON, 2008; ANVISA, 2018).

Although there is no protocol as a dosage reference, the effective and safe ophthalmological dose is less than 0.5 mg / kg; its systemic absorption is minimal and toxicity presented as negligible neutropenia. It is recommended before the procedure to filter melphane, as there may be small particles that embolize the ocular vessels causing complications in the procedure (MOC BRASIL, 2020).

An analysis conducted in the international clinical trials database pointed out that there is ongoing research to prove the safety of the drug melphaline in intra-arterial therapy. Three studies were found in the test phase and one finalized study (ABRAMSON, 2008; NIH US, 2013; NIH US, 2017; DUANGNATE et al., 2019).

In November 2017, a study conducted in Maryland – USA was published in order to point out the safety of the intra-arterial technique when melphane was used, aiming to find the tolerable dose of the drug. Melphaline was used through the femoral artery, infused for 30 minutes in 10 children with advanced retinoblastoma (phase V), already with indication of enucleation.  The results showed that the technique presents minimal systemic and local side effects (grade 3 neutropenia). Of the 10 eyes, 7 were recovered, 1 was unsuccessful due to vascular anomaly in the artery, 1 developed retinal ischemia and 1 developed radiation-like retinopathy after brachytherapy. This technique was first described by David H. Abramson in the phase I/II clinical trial conducted at the Memorial Sloan-Kettering Cancer Center Hospital in New York, with the use of melphane in intra-arterial chemotherapy in the ophthalmic artery for the treatment of intraocular retinoblastoma (ABRAMSON, 2008).

Further studies are still ongoing. In Spain, a non-randomized phase II clinical trial aims to preserve the visual acuity of patients using melphaline in intra-arterial therapy in 5 patients (NIH US, 2013).

The U.S. children’s oncology group directs a clinical trial with 14 participants to estimate the rate of eye recovery after treatment with intra-arterial melphaline in children with newly diagnosed unilateral retinoblastoma with group D disease. , has as members children’s hospitals, universities and cancer centers in North America (NIH US, 2017).

In California, San Francisco, a study is underway to test the safety of the combination of standard, alternating chemotherapeutic therapy and intra-arterial chemotherapy using melphane in combination with other antineoplastic drugs (carboplatin, etoposide, and vincristine) in different interval regimens. The study used 6 patients with advanced and newly diagnosed intraocular retinoblastoma (NIH US, 2017).

Studies have proven the efficacy of the intra-arterial therapy procedure. A survey conducted in Thailand, conducted from January 2009 to November 2017, showed positive results, where melphane is used as the main drug. Of the 27 eyes of 26 patients with retinoblastoma, 7 (26%) intra-arterial chemotherapy as primary treatment and 20 (74%) had IAC (intra arterial chemotherapy) as secondary treatment. The eyes were categorized through the International Classification of Retinoblastoma (ICRB) as group B (n = 3.11%), group C (n = 1.4%), group D (n = 12.44%) and group E (n = 11, 41%). The average number of IAC sessions was 3 (range 1 to 7). In a mean follow-up of 32 months (range 3 to 95 months), the overall recovery rate of the globe was 52%, with 100% in groups B and C, 75% in group D and 9% in group E. Complications of ASD included occlusive vasculopathy (n = 4.15%), vitreous hemorrhage (n = 3.11%), precipitation of the retinal artery (n = 2.7%), strabismus (n = 2.7%) and transient ischemic attack (n = 1.4%).  (n = 25) (DUANGNATE, 2019).

3.2 CARBOPLATIN

Carboplatin is widely distributed without protein bindings, with hepatic metabolism and renal excretion. Administration and dilution occur intravenously (EV) in 30 to 120 minutes, intraperitoneal. Dilution is in SF or SG 5% (preferably) at a concentration of 0.5 to 2 mg/mL, requiring no adjustment for liver function and, for renal function, the AUC formula (area under the curve) automatically corrects the dose (MOC BRASIL, 2020).

Through research recorded on the Clinical Trials website, only one study was found for the treatment of retinoblastoma with the use of carboplatin through intra-arterial chemotherapy. This study began on March 6, 2019, at Memorial Sloan Kettering Cancer Center, New York, Usa, and was in the volunteer recruitment phase (NIH US, 2019).

The aim of this study is to determine whether treatment with intra-arterial carboplatin causes hearing loss in children. For the study, the observational cohort method was established, with the estimated participation of 50 volunteers of both sexes, with the disease, aged 3 months to 18 years. The results will have an intra-arterial post-auditory evaluation (AI) with carboplatin allowed only after 9 months or approximately one year from the beginning of treatment. The study is expected to be completed in March 2021 (NIH US, 2019).

According to the study conducted in Japan by specialists in intra-arterial chemotherapy, the use of the drug carboplatin, which is a derivative of platinum, has fewer side effects than its precursor cisplatin, that is, lower renal, neurological and gastrointestinal toxicity (MANJANDAVIDA et al., 2019).

However, carboplatin through a protocol is used with two drugs for unilateral intra-arterial chemotherapy (IAC), along with melphaline and topotecan. In bilateral IAC, to avoid the cumulative toxicity of melphane that leads to myelosuppression, the dose of melphaline is reduced with the addition of carboplatin without compromising the effect of IAC. The recommended dosage is 15 to 30 mg (MANJANDAVIDA et al., 2019).

3.3 TOPOTECAN

Preclinical data on the ocular pharmacology of superselective intra-arterial topotecan (SSOAI) were based on experiments in a swine model. After administering 1 mg of SSOAI topotecan for 30 minutes, topotecan reached vitreous concentrations above ic50 calculated up to 4 hours, a proportion five times higher in vitreous plasma compared to Melphane, the most commonly used agent for SSOAI. In addition to being found in vitreous humor up to 16 hours after infusion, in contrast to the rapid deterioration of Melphane in the same applied technique (SOUZA et al., 2019).

The optimal dose of topotecan by this route remains to be established, but all indications are that the dose will be between 0.5 mg to 4 mg. Therefore, topotecan is an interesting candidate drug for SSOAI based on penetration and favorable residence in the vitreous (SOUZA et al., 2019).

Due to the high rate of vitreous exposure to plasma of the topotecan such a situation can promote a favorable penetration of the drug through the blood-retinian barrier, and thus reach deeper layers of the optical region. Preliminary studies suggest that in this internal structure of the eye topotecan clearance is limited to the vitreous and its elimination through the tear, with this, it is related to the lower toxicity of the drug in systemic regions (SCHAIQUEVICH et al., 2014).

Issues favorable to ophthalmologic use are related to stability in dilution solutions, avoiding the formation of precipitates that can be harmful to the patient. And the plasma pharmacokinetics that concomitantly associated intra-arterial topotecan and Melphaline, where there was no clinical impairment to treatment (SCHAIQUEVICH et al., 2014).

Since November 2011, there has been an ongoing study, recorded in the Clinical Trials database, with 36 patients of both sexes aged up to 15 years, with a history of recurrent and/or refractory bilateral retinoblastoma, who had intra-arterial ophthalmic topotecan administration in order to verify efficacy and safety. The intervention was due to topotecan infusion for 30 minutes, every 21 days, for a period of up to 18 weeks. The results will have as parameters visual acuity, electroretinogram, visual evoked potential and functional magnetic resonance imaging (NIH US, 2017).

As stated earlier, this is an ongoing study, and for this reason, no conclusive data are available, as the latest update since the study dates from March 1, 2017. Therefore, it is difficult to establish the role of topotecan as a single agent for the treatment of retinoblastoma. But due to its low ocular toxicity, through all routes of administration, it is likely that its place in the therapeutic arsenal against retinoblastoma, is found in combined multiagent chemotherapy regimens (NIH US, 2017).

4. CONCLUSION

The safety and effectiveness of the drugs studied proved that Melphaline is the main drug used and that it meets these characteristics. Melphane can be used individually or together at doses below 0.5mg/kg, varying according to the size and severity of the intraocular tumor, and its adverse effects have been proven in research as mild neutropenia.

As seen, there are currently studies in several phases that assess the effectiveness and safety of other drugs, such as Carboplatin and Topotecan, to be applied individually or in an associated chemotherapy regimen in pediatric patients.

Because recent studies are not available so far conclusive results, but everything indicates that in the future these drugs will be part of the therapeutic arsenal, either individually or being part of combined multiagent chemotherapy regimens.

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^[1] Pharmaceutical. Specialist in Clinical and Hospital Pharmacy (Senac), Graduation in Pharmacy and Biochemistry (UNINOVE).

^[2] Pharmaceutical. Specialist in Clinical and Hospital Pharmacy (Senac), Graduation in Pharmacy (UNIP).

^[3] Pharmaceutical. Specialist in Clinical and Hospital Pharmacy (Senac), Graduation in Pharmacy (ANHANGUERA).

^[4] Pharmaceutical. Specialist in Clinical and Hospital Pharmacy (Senac), Graduation in Pharmacy (FOC).

^[5] Pharmacist. Specialist in Clinical and Hospital Pharmacy (Senac), Graduation in Pharmacy (UNIP).

^[6] Advisor. Pharmacist. Master in Medical Sciences, FMUSP. Multiprofessional Oncology Specialist (HSL), Specialist in Hospital Pharmacy (FOC), Graduation in Biochemical Pharmacy (USJT).

Submitted: August, 2020.

Approved: October, 2020.