**3.3 Chemotherapeutic agents**

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 systemic side effects [34].

### **3.4 Complications**

Despite being a less invasive therapeutic intervention, IAC does carry some risk of complications, as it would be expected with any medical interventional procedure. Complications occurring after IAC are attributed either to the procedure itself or to the chemotherapeutic agent/agents or both. Complications developing from the procedure include endovascular complications occurring intraoperative, allergy to iodine and hematoma at the site of entry into the femoral artery. Systemic thromboembolic and hemorrhagic events (stroke, limb ischemia) are possible but their current reported overall occurrence is extremely scarce [30, 44]. Up to date, no procedure-related deaths had been reported. Theoretically speaking, since IAC targets chiefly the intraocular pathology, the risk of metastasis and secondary neoplasms remains unchanged or even might be increased, as this treatment is not intended to reach the systemic circulation in high concentrations. Experts studied the incidence of death due to retinoblastoma-associated metastasis in a cohort of patients treated over a 10-year period by IAC primarily or secondarily and found it to be negligible (<1%) [47]. Likewise, IAC was not associated with an increased rate of second primary malignancies (SPM) in a group of patients with germline retinoblastoma from one treatment center studied over a 10-year period (2006–2016) [48]. However, IAC is relatively a recent therapy; therefore, it is still premature to derive definite conclusions regarding the potential risk and studies with longer follow up periods are required.

Neutropenia is another important complication that should be recognized and managed early to prevent devastating complications. The local distribution of the drug has helped in limiting its occurrence to <15% [34, 49]. On the other hand, minor ocular side effects are common and these include: lids edema, blepharoptosis, temporary loss of the eyelashes and forehead hyperemia along the distribution of the supratrochlear artery [50]. Ocular vascular complications are among the universally feared local side effects. A recent review of 16 published studies reported that <2.5% had ophthalmic artery obstruction or occlusion, choroidal ischemia or atrophy and vasospasm [49]. These vascular events should be interpreted in the context of the clinical case given that these are usually sick eyes that might have received other local treatments that might contribute to the occurrence of such events. A recently published study looked at the incidence of vascular events and the variability of their occurrence when IAC is given primarily or secondarily and reported the following: overall vascular complications occur in 5% of eyes per infusion and no difference was observed when IAC is used as a primary or secondary therapy [51].

#### **3.5 Outcomes and success rate**

The body of evidence in the literature supporting the use of IAC has been growing persistently in the past decade. Impressively, the reported globe salvage rate is currently exceeding 90% without compromising patient's survival and the enucleation rate dropped to <10% [35, 52–54]. Even the rate of orbital recurrence was significantly higher in patients with advanced disease treated with enucleation compared to IAC and this further emphasizes the gainful outcome of IAC [55].

A major concern about the risk of recurrence after IAC treatment remains in spite of the success achieved by this treatment modality. A recent study from one of the pioneering centers utilizing IAC with 10 years experience reported that around 25% of eyes treated primarily with IAC might develop recurrence. The recurrence of the disease was observed to occur mainly in the first 12 months post-treatment; and therefore, close follow up with serial meticulous examination is recommended during this period. Surprisingly, the rate of recurrence was higher in eyes that

**77**

*Retinoblastoma Management: Advances in Chemotherapy*

remaining disease free in the first year after IAC [52].

**4. Intravitreal chemotherapy for retinoblastoma**

received the drug through routes other than OA and in eyes with widely spaced treatments more than 4 weeks. The risk of recurrence was <10% by 2 years in eyes

Intravitreal chemotherapy (IVitC) is another well-established targeted therapy accounting for one of the important current treatment modalities for retinoblastoma manifesting vitreous seeds. Initial reports on IVitC date back to the 1960s where thiotepa was injected into the vitreous cavity of six eyes with retinoblastoma; yet the results were inconclusive due to the limited number of treated eyes [56]. Later, this method was revived by Kaneko and Suzuki who injected melphalan intravitreally in 41 eyes along with ocular hyperthermia to cure vitreous seeding with a notable resultant eye preservation rate of 51.3% [57]. The choice of melphalan was essentially based on in-vitro testing of 12 anti-neoplastic drugs, and melphalan proved to be the most effective against retinoblastoma cells [45]. Implementing this technique into current practice took several years and perhaps the major limiting factor was the fear of disseminating the cancer cells during injection with the risk of subsequent extraocular spread causing metastasis and death. This section will elaborate on the key qualities of this relatively new therapy.

**4.1 Indications and contraindications for intravitreal chemotherapy**

This local therapeutic technique is intended essentially to achieve the highest concentration of the delivered tumoricidal drug into the confined intraocular space adjacent to the tumor. IVitC is used as an adjunctive therapy to chemoreduction with systemic chemotherapy and IAC. The main indications for this treatment modality are the presence of active vitreous seeds that are either refractory to standard therapy or recurrent after pervious standard therapy [7]. The use of IVitC had also expanded lately to include patients with retinal and subretinal tumors where it had been shown to be successful in salvaging the globe of such patients [58]. On the other hands, contraindications preventing the execution of this procedure include tumors involving the ciliary body or extending up to the anterior segment, tumors filling the globe, retinal detachment and vitreous hemorrhage.

Before proceeding with this treatment, it is critical to meticulously evaluate the pars plana clinically in all quadrants 360° looking for any tumor foci as that could pose a threat to safety if present due to the risk of spread while injecting. If visualization is difficult, then ultrasound biomicroscopy can be used to help in detection

The procedure is usually carried out in the operating room under sterile conditions while the child is under general anesthesia. The anti-cancerous drug, typically melphalan, is injected through the pars plana 3–3.5 mm from the limbus into the vitreous cavity using a small needle, preferably a 32 gauge-needle. This creates the smallest needle track that helps in reducing the risk of dissemination. The injection is rather done in a seed-free quadrant, 2 o'clock hours away from vitreous seeds to prevent the undesirable exteriorization of tumor cells. Furthermore, some experts advocate reducing the pressure inside the eye by paracentesis before inserting the needle to prevent the possible risk of microscopic tumor seeding. After injecting the drug and before exiting the tumor-harboring globe, triple freeze-thaw cryotherapy

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

**4.2 Intravitreal chemotherapy technique**

and affirmation [59].

*Retinoblastoma - Past, Present and Future*

follow up periods are required.

**3.5 Outcomes and success rate**

Despite being a less invasive therapeutic intervention, IAC does carry some risk of complications, as it would be expected with any medical interventional procedure. Complications occurring after IAC are attributed either to the procedure itself or to the chemotherapeutic agent/agents or both. Complications developing from the procedure include endovascular complications occurring intraoperative, allergy to iodine and hematoma at the site of entry into the femoral artery. Systemic thromboembolic and hemorrhagic events (stroke, limb ischemia) are possible but their current reported overall occurrence is extremely scarce [30, 44]. Up to date, no procedure-related deaths had been reported. Theoretically speaking, since IAC targets chiefly the intraocular pathology, the risk of metastasis and secondary neoplasms remains unchanged or even might be increased, as this treatment is not intended to reach the systemic circulation in high concentrations. Experts studied the incidence of death due to retinoblastoma-associated metastasis in a cohort of patients treated over a 10-year period by IAC primarily or secondarily and found it to be negligible (<1%) [47]. Likewise, IAC was not associated with an increased rate of second primary malignancies (SPM) in a group of patients with germline retinoblastoma from one treatment center studied over a 10-year period (2006–2016) [48]. However, IAC is relatively a recent therapy; therefore, it is still premature to derive definite conclusions regarding the potential risk and studies with longer

Neutropenia is another important complication that should be recognized and managed early to prevent devastating complications. The local distribution of the drug has helped in limiting its occurrence to <15% [34, 49]. On the other hand, minor ocular side effects are common and these include: lids edema, blepharoptosis, temporary loss of the eyelashes and forehead hyperemia along the distribution of the supratrochlear artery [50]. Ocular vascular complications are among the universally feared local side effects. A recent review of 16 published studies reported that <2.5% had ophthalmic artery obstruction or occlusion, choroidal ischemia or atrophy and vasospasm [49]. These vascular events should be interpreted in the context of the clinical case given that these are usually sick eyes that might have received other local treatments that might contribute to the occurrence of such events. A recently published study looked at the incidence of vascular events and the variability of their occurrence when IAC is given primarily or secondarily and reported the following: overall vascular complications occur in 5% of eyes per infusion and no difference was observed when IAC is used as a primary or secondary therapy [51].

The body of evidence in the literature supporting the use of IAC has been growing persistently in the past decade. Impressively, the reported globe salvage rate is currently exceeding 90% without compromising patient's survival and the enucleation rate dropped to <10% [35, 52–54]. Even the rate of orbital recurrence was significantly higher in patients with advanced disease treated with enucleation compared to IAC and this further emphasizes the gainful outcome of IAC [55]. A major concern about the risk of recurrence after IAC treatment remains in spite of the success achieved by this treatment modality. A recent study from one of the pioneering centers utilizing IAC with 10 years experience reported that around 25% of eyes treated primarily with IAC might develop recurrence. The recurrence of the disease was observed to occur mainly in the first 12 months post-treatment; and therefore, close follow up with serial meticulous examination is recommended during this period. Surprisingly, the rate of recurrence was higher in eyes that

**3.4 Complications**

**76**

received the drug through routes other than OA and in eyes with widely spaced treatments more than 4 weeks. The risk of recurrence was <10% by 2 years in eyes remaining disease free in the first year after IAC [52].
