**4.2 Intravitreal chemotherapy technique**

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 and affirmation [59].

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

should be carried out concurrently at the injection site while withdrawing the needle. Then, uniform intraocular distribution of the drug is achieved by gentle shaking of the eye using forceps. Examination is usually performed at the end of the procedure to rule out possible acute complications such as retinal detachment and bleeding. The ocular surface is then washed with balanced salt solution to remove any remnant chemotherapeutic agent that could be toxic. The child is usually discharged in the same day and the family is instructed to avoid touching the eye [59]. The procedure may vary minimally between different specialized treatment centers.

#### **4.3 Chemotherapeutic agents**

Melphalan hydrochloride is the principal drug injected into the vitreous cavity in retinoblastoma patients. It is a cytotoxic nitrogen mustard derivative that inhibits the synthesis of DNA and RNA together [59]. Its effective dosage range was studied and set at 20–30 μg per injection as low doses (8 μg) were not adequate to control and eradicate the disease while high doses (50 μg) controlled the disease but resulted in local toxicity (cataract, posterior segment hemorrhage, hypotony and phthisis bulbi) [60]. The number of injections is governed by the response. In general, Shields et al. proposed giving a total of six injections weekly or every 2 weeks [7].

Topotecan, a topoisomerase-1 inhibitor, is another potent intravitreal agent that had been employed in the treatment of retinoblastoma with vitreous seeds. Experimental animal studies showed that topotecan produce high and stable levels in the vitreous [61]. One of the distinguishable advantages of topotecan is its ability to attain a vitreous-to-plasma concentration five times more than melphalan [62]. Previous studies have shown that it is an effective anti-tumor drug with good safety profile and low ocular toxicity [63]. It had been used intravitreally in combination with melphalan in humans with encouraging results where this multi-agent regimen managed to achieve notable vitreous seeds regression with fewer injections [64]. Topotecan can also be used effectively in patients with recurrent or resistant viable vitreous seeds according to a recent study on 17 eyes which demonstrated control of these seeds in all treated eyes (100%) in the absence of ocular or systemic side effects and with a lower number of injections [65].

#### **4.4 Complications**

Extraocular tumor dissemination through the needle track with subsequent metastasis was perhaps the most feared serious event limiting the use of this treatment modality in the past. However, a meta-analysis examining published studies on this matter revealed that the risk of systemic spread is very low (two cases out of 1304 injections, proportion of extraocular spread secondary to injections was 0.007) especially when the appropriate safety enhancing injection techniques are applied. Therefore, IVitC can be utilized unreservedly whenever needed after proper patient selection [66].

Ocular side effects are generally uncommon in patients receiving IVitC. The major factor influencing the risk of complications and local ocular toxicity is the dose of administered medication where toxicity is more likely with melphalan doses higher than 30 μg [67]. Among the most frequent side effects is retinal pigment epithelium changes (salt and pepper retinopathy), which is believed to represent a form of chemical burn to the retinal at the area where the drug is concentrated the most [68, 69]. Retinal function decline due to toxicity, usually highlighted on electroretinography (ERG), is a possible complication of melphalan although the results are conflicting in the literature where one study showed no effect on ERG (dose:

**79**

*Retinoblastoma Management: Advances in Chemotherapy*

20–30 μg) while another reported non-progressive decreased ERG amplitudes of approximately 5 μV (equivalent to 5% retinal response) with every 30 μg melphalan injection [70–72]. ERG can actually be a useful tool to monitor these patients for

Other major ocular complications that were highlighted in a systematic review with a total of 1287 intravitreal injections given to 306 eyes include: iris depigmentation and atrophy, chorioretinal atrophy with vitreous hemorrhage and retinal detachment [67]. Fortunately, there are no reports of endophthalmitis after IVitC; nonetheless, all protective measures should be taken to prevent this possible devas-

With regards to serious systemic side effects, namely significant neutropenia of grade 3 and 4, these were not observed when analyzing 46 blood samples withdrawn from patients receiving IVitC (despite some patients received concurrent IAC) [71]. Again, this accentuates the benefit of local therapies in these young

Treating retinoblastoma with vitreous seeding can be really challenging due to the avascular nature of the vitreous; and therefore, drug delivery through systemic routes may not be sufficient sometimes. Besides this, it tends to be resistant to external radiation and systemic chemotherapy [68, 73]. In the past two decades, a quantum leap forward in the management of advanced retinoblastoma was reached with the help of IVitC. The reported vitreous seeding control rates of IVitC (melphalan with or without topotecan) ranges between 60 and 100% [60, 68, 71, 72, 74]. Additionally, the attained globe salvage rates are also impressive reaching up to 100% as reported in one study on 11 eyes receiving a total of 55 intravitreal melpha-

Periocular chemotherapy (POC) administration was designed to allow delivery of a higher concentration of the tumoricidal drugs locally. This route was firstly tested in retinoblastoma animal models using carboplatin and it had been shown that this route produces vitreous concentrations 8–10 folds more than the intravenous route [75, 76]. These preclinical results led to the conduction of a trial in which children with retinoblastoma were treated using subconjunctival carboplatin and the results were promising [77]. Thereafter, POC grew in popularity and it was consequently incorporated into the multimodal treatment algorithm of retinoblastoma. Currently, it is a part of the prospective multicenter Children's Oncology Group trials for retinoblastoma. In this section, POC will be tackled

POC is used predominantly as an adjunctive therapy to systemic chemotherapy as presently there is no evidence promoting it as a stand-alone therapy [78]. It is indicated principally in patients with recurrent localized tumor and in advanced disease (group D and E) where chemotherapy can be desirably infused in higher concentrations without exposing the patient to increased systemic toxicity [7]. It can also be utilized in patients who are not fit to receive systemic chemotherapy as well as

patients with recurrent or persistent viable non-calcified vitreous seeds [78].

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

cumulative retinal toxicity.

tating complication.

lan injections [69].

comprehensively.

**4.5 Outcomes and success rate**

**5. Periocular chemotherapy for retinoblastoma**

**5.1 Indications for periocular chemotherapy**

children.

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

*Retinoblastoma - Past, Present and Future*

**4.3 Chemotherapeutic agents**

2 weeks [7].

**4.4 Complications**

proper patient selection [66].

should be carried out concurrently at the injection site while withdrawing the needle. Then, uniform intraocular distribution of the drug is achieved by gentle shaking of the eye using forceps. Examination is usually performed at the end of the procedure to rule out possible acute complications such as retinal detachment and bleeding. The ocular surface is then washed with balanced salt solution to remove any remnant chemotherapeutic agent that could be toxic. The child is usually discharged in the same day and the family is instructed to avoid touching the eye [59]. The procedure may vary minimally between different specialized treatment centers.

Melphalan hydrochloride is the principal drug injected into the vitreous cavity in retinoblastoma patients. It is a cytotoxic nitrogen mustard derivative that inhibits the synthesis of DNA and RNA together [59]. Its effective dosage range was studied and set at 20–30 μg per injection as low doses (8 μg) were not adequate to control and eradicate the disease while high doses (50 μg) controlled the disease but resulted in local toxicity (cataract, posterior segment hemorrhage, hypotony and phthisis bulbi) [60]. The number of injections is governed by the response. In general, Shields et al. proposed giving a total of six injections weekly or every

Topotecan, a topoisomerase-1 inhibitor, is another potent intravitreal agent that had been employed in the treatment of retinoblastoma with vitreous seeds. Experimental animal studies showed that topotecan produce high and stable levels in the vitreous [61]. One of the distinguishable advantages of topotecan is its ability to attain a vitreous-to-plasma concentration five times more than melphalan [62]. Previous studies have shown that it is an effective anti-tumor drug with good safety profile and low ocular toxicity [63]. It had been used intravitreally in combination with melphalan in humans with encouraging results where this multi-agent regimen managed to achieve notable vitreous seeds regression with fewer injections [64]. Topotecan can also be used effectively in patients with recurrent or resistant viable vitreous seeds according to a recent study on 17 eyes which demonstrated control of these seeds in all treated eyes (100%) in the absence of ocular or systemic side

Extraocular tumor dissemination through the needle track with subsequent metastasis was perhaps the most feared serious event limiting the use of this treatment modality in the past. However, a meta-analysis examining published studies on this matter revealed that the risk of systemic spread is very low (two cases out of 1304 injections, proportion of extraocular spread secondary to injections was 0.007) especially when the appropriate safety enhancing injection techniques are applied. Therefore, IVitC can be utilized unreservedly whenever needed after

Ocular side effects are generally uncommon in patients receiving IVitC. The major factor influencing the risk of complications and local ocular toxicity is the dose of administered medication where toxicity is more likely with melphalan doses higher than 30 μg [67]. Among the most frequent side effects is retinal pigment epithelium changes (salt and pepper retinopathy), which is believed to represent a form of chemical burn to the retinal at the area where the drug is concentrated the most [68, 69]. Retinal function decline due to toxicity, usually highlighted on electroretinography (ERG), is a possible complication of melphalan although the results are conflicting in the literature where one study showed no effect on ERG (dose:

effects and with a lower number of injections [65].

**78**

20–30 μg) while another reported non-progressive decreased ERG amplitudes of approximately 5 μV (equivalent to 5% retinal response) with every 30 μg melphalan injection [70–72]. ERG can actually be a useful tool to monitor these patients for cumulative retinal toxicity.

Other major ocular complications that were highlighted in a systematic review with a total of 1287 intravitreal injections given to 306 eyes include: iris depigmentation and atrophy, chorioretinal atrophy with vitreous hemorrhage and retinal detachment [67]. Fortunately, there are no reports of endophthalmitis after IVitC; nonetheless, all protective measures should be taken to prevent this possible devastating complication.

With regards to serious systemic side effects, namely significant neutropenia of grade 3 and 4, these were not observed when analyzing 46 blood samples withdrawn from patients receiving IVitC (despite some patients received concurrent IAC) [71]. Again, this accentuates the benefit of local therapies in these young children.

### **4.5 Outcomes and success rate**

Treating retinoblastoma with vitreous seeding can be really challenging due to the avascular nature of the vitreous; and therefore, drug delivery through systemic routes may not be sufficient sometimes. Besides this, it tends to be resistant to external radiation and systemic chemotherapy [68, 73]. In the past two decades, a quantum leap forward in the management of advanced retinoblastoma was reached with the help of IVitC. The reported vitreous seeding control rates of IVitC (melphalan with or without topotecan) ranges between 60 and 100% [60, 68, 71, 72, 74]. Additionally, the attained globe salvage rates are also impressive reaching up to 100% as reported in one study on 11 eyes receiving a total of 55 intravitreal melphalan injections [69].
