**3. Intra-arterial chemotherapy for retinoblastoma**

Intra-arterial chemotherapy (IAC), also known as ophthalmic artery chemosurgery (OAC), is an important treatment strategy for retinoblastoma that evolved rapidly and gained popularity worldwide. Today, this modality of treatment is being performed in many retinoblastoma treatment centers located in more than 45 countries across the globe [28]. This treatment modality was initially explored by Reese et al. [3] who directly injected the alkylating agent triethylene melamine (TEM) into the internal carotid artery; nevertheless, it was not until 2006 when Abramson and Gobin introduced the novel technique of super-selective ophthalmic artery catheterization via transfemoral artery approach which allowed immediate and effectual delivery of the administered agent (melphalan) into the diseased eye [29]. Thereafter, many oncology centers adopted this technique and started publishing their experience. In this section, we will be shedding the light on the important aspects and most recent results of IAC.

#### **3.1 Indications**

IAC opened the door to a new era in the treatment of retinoblastoma. The key exciting factor behind this local therapy is its ability to achieve adequate therapeutic intraocular concentrations of the delivered chemotherapeutic agents while minimizing the systemic toxicity induced by these infused drugs such as neutropenia and secondary tumors [30]. In view of this, IAC is utilized mainly in treating patients with intraocular disease without local or systemic spread. Previous studies on IAC have shown that it can be used successfully as a primary retinoblastoma treatment in

**75**

**3.2 IAC technique**

**3.3 Chemotherapeutic agents**

systemic side effects [34].

*Retinoblastoma Management: Advances in Chemotherapy*

naïve eyes (no previous therapy employed) or as a secondary treatment in eyes with recurrent or residual tumor after trying other treatment modalities such as systemic chemotherapy, external beam radiotherapy and others [29, 31–37]. Currently, the common indications for IAC in retinoblastoma patients include unilateral retinoblastoma that cannot be halted by local treatments alone (e.g., cryotherapy or laser photocoagulation) and advanced unilateral retinoblastoma (such as group D and E based on the ICRB) [30]. Several studies had previously reported the following advantages of using IAC in patients with group D retinoblastoma: better eye conservation rates and greater visual acuity compared to systemic chemotherapy, shorter treatment period and ability to repeat the therapy several times using multiple agents without endangering the patients' life and vision [28, 38]. It is also noteworthy to mention that IAC can save naïve eyes with advanced retinoblastoma from enucleation particularly when subretinal seeding is present (2 year ocular survival rate of 83%) [39]. Furthermore, IAC has a proven benefit even in patients presenting with advanced disease such as those having retinoblastoma-induced total or partial retinal detachment in which it can successfully achieve retinal re-attachment and thus help

in preserving the eye and the life with the least possible side effects [40, 41].

is probably attributed to their inherent genetic predisposition [42, 43].

available, however, this is out of the scope of this chapter [34].

Simultaneous IAC (tandem therapy) to both eyes consecutively is also a valuable and safe treatment method in patients with bilateral germline retinoblastoma whether used primarily or secondarily. This was demonstrated in two recent studies, which reported excellent globe salvage rates (ocular survival rate > 90%) even in patients with advanced disease. Despite that the safety profile of this simultaneous therapy was considerably high where no treatment-associated deaths occurred, these children were still at risk of secondary tumors such as pineoblastoma and this

The technique of IAC is carried out on patients who are generally anesthetized and is usually coordinated by a specialized and experienced oncology/radiology team. The common femoral artery on the ipsilateral treatment side is usually used to gain access to the internal carotid artery and then the ophthalmic artery (OA) is selectively catheterized under fluoroscopic guidance at its ostium (origin) while heparin is infused intravenously to prevent coagulation. Then, in order to verify the proper placement of the microcatheter, selective angiography is done by contrast infusion to delineate the vascular anatomy and ocular perfusion. Due to the variability of vascular territory anatomy and blood flow patterns, OA catheterization might fail and other routes are

The most commonly used intra-arterial chemotherapeutic agent is melphalan,

a potent alkylating agent. Melphalan is by far the strongest chemotherapeutic drug acting effectually against human retinoblastoma cells [44]. It is very safe when administered locally but very toxic when infused systemically due to the resultant severe myelosuppression [45]. In fact, it is currently considered an ideal agent due to its favorable safety profile, short half-life and ability to be used in combination with other agents to achieve greater tumor control when needed [34, 46]. Topotecan, a topoisomerase inhibitor, and carboplatin, an alkylating agent, are other agents that have been used alone or as a part of a multi-drug regimen in advanced cases that fail to respond to melphalan solitarily or in bilateral tandem therapy where the dose of melphalan is decreased to prevent

*DOI: http://dx.doi.org/10.5772/intechopen.86820*

#### *Retinoblastoma Management: Advances in Chemotherapy DOI: http://dx.doi.org/10.5772/intechopen.86820*

*Retinoblastoma - Past, Present and Future*

vulnerable subset of patients [23].

**2.4 Outcomes and success rate**

in patients receiving it [26].

does not seem that IVC increases the risk ominously. A long term follow-up study demonstrated that the rate of secondary tumors in germline retinoblastoma patients treated with systemic chemotherapy was 4%, which is less than expected for this

The introduction of systemic chemotherapy resulted in an improved eye salvage rate, not to mention the enhanced visual outcome. Chemoreduction success can be predicted in patients with retinoblastoma following the ICRB classification as following: 100% in group A, 93% in group B, 90% in group C and <50% in group D and E [24]. The success rate in the advanced stages can be augmented when combining IVC with other modalities of treatment such as IAC or IVitC. Long-term studies have shown that chemotherapy with or without adjunctive therapies maintains ambulatory vision of ≥6/60 in almost two-thirds of the patients, particularly those with multiple tumors and/or no foveolar tumors [25]. Furthermore, IVC seems to exert a protective effect against pineoblastoma as its occurrence is usually very low

The effect of systemic chemotherapy as a monotherapy appears to be satisfactory especially in patients with less advanced disease whereas in patients with advanced disease, its remedial action is complementary to the selective recent therapies. A recently published meta-analysis comparing IVC to the more selective IAC revealed that both methods are equivalent in terms of tumor recurrence and metastasis. IAC evidently had a higher total success rate and ocular sparing effect in group D patients compared to IVC [27]. Despite this, we believe that IVC will continue to be an integral part of the treatment regimen of retinoblastoma.

Intra-arterial chemotherapy (IAC), also known as ophthalmic artery chemosurgery (OAC), is an important treatment strategy for retinoblastoma that evolved rapidly and gained popularity worldwide. Today, this modality of treatment is being performed in many retinoblastoma treatment centers located in more than 45 countries across the globe [28]. This treatment modality was initially explored by Reese et al. [3] who directly injected the alkylating agent triethylene melamine (TEM) into the internal carotid artery; nevertheless, it was not until 2006 when Abramson and Gobin introduced the novel technique of super-selective ophthalmic artery catheterization via transfemoral artery approach which allowed immediate and effectual delivery of the administered agent (melphalan) into the diseased eye [29]. Thereafter, many oncology centers adopted this technique and started publishing their experience. In this section, we will be shedding the light on the important

IAC opened the door to a new era in the treatment of retinoblastoma. The key exciting factor behind this local therapy is its ability to achieve adequate therapeutic intraocular concentrations of the delivered chemotherapeutic agents while minimizing the systemic toxicity induced by these infused drugs such as neutropenia and secondary tumors [30]. In view of this, IAC is utilized mainly in treating patients with intraocular disease without local or systemic spread. Previous studies on IAC have shown that it can be used successfully as a primary retinoblastoma treatment in

**3. Intra-arterial chemotherapy for retinoblastoma**

aspects and most recent results of IAC.

**74**

**3.1 Indications**

naïve eyes (no previous therapy employed) or as a secondary treatment in eyes with recurrent or residual tumor after trying other treatment modalities such as systemic chemotherapy, external beam radiotherapy and others [29, 31–37]. Currently, the common indications for IAC in retinoblastoma patients include unilateral retinoblastoma that cannot be halted by local treatments alone (e.g., cryotherapy or laser photocoagulation) and advanced unilateral retinoblastoma (such as group D and E based on the ICRB) [30]. Several studies had previously reported the following advantages of using IAC in patients with group D retinoblastoma: better eye conservation rates and greater visual acuity compared to systemic chemotherapy, shorter treatment period and ability to repeat the therapy several times using multiple agents without endangering the patients' life and vision [28, 38]. It is also noteworthy to mention that IAC can save naïve eyes with advanced retinoblastoma from enucleation particularly when subretinal seeding is present (2 year ocular survival rate of 83%) [39]. Furthermore, IAC has a proven benefit even in patients presenting with advanced disease such as those having retinoblastoma-induced total or partial retinal detachment in which it can successfully achieve retinal re-attachment and thus help in preserving the eye and the life with the least possible side effects [40, 41].

Simultaneous IAC (tandem therapy) to both eyes consecutively is also a valuable and safe treatment method in patients with bilateral germline retinoblastoma whether used primarily or secondarily. This was demonstrated in two recent studies, which reported excellent globe salvage rates (ocular survival rate > 90%) even in patients with advanced disease. Despite that the safety profile of this simultaneous therapy was considerably high where no treatment-associated deaths occurred, these children were still at risk of secondary tumors such as pineoblastoma and this is probably attributed to their inherent genetic predisposition [42, 43].

## **3.2 IAC technique**

The technique of IAC is carried out on patients who are generally anesthetized and is usually coordinated by a specialized and experienced oncology/radiology team. The common femoral artery on the ipsilateral treatment side is usually used to gain access to the internal carotid artery and then the ophthalmic artery (OA) is selectively catheterized under fluoroscopic guidance at its ostium (origin) while heparin is infused intravenously to prevent coagulation. Then, in order to verify the proper placement of the microcatheter, selective angiography is done by contrast infusion to delineate the vascular anatomy and ocular perfusion. Due to the variability of vascular territory anatomy and blood flow patterns, OA catheterization might fail and other routes are available, however, this is out of the scope of this chapter [34].
