**2. Intravenous chemotherapy for retinoblastoma**

The era of chemotherapeutic treatment for retinoblastoma began in 1953 when Carl Kupfer reported the successful use of intravenous nitrogen mustard along with irradiation to treat a child with recurrent retinoblastoma [2]. Thereafter, the use of triethylene melamine, a chemotherapeutic alkylating agent, via different routes (oral, intramuscular, intravenous and intra-arterial) became more widespread between clinicians until the late 1960s given that it allowed the reduction of radiotherapy dose which was associated with multiple potential side effects [3–6]. In the following years, the use of systemic chemotherapy fluctuated until the early 1990s when the use of systemic chemotherapy was popularized and strongly advocated by the leading retinoblastoma treatment centers worldwide and the use of external beam radiation was restricted in favor of chemotherapy due to the considerable risk of secondary tumors in patients receiving radiotherapy.

The management of retinoblastoma should be carried out by an experienced team as these children need meticulous bilateral ocular examination, usually under anesthesia, in parallel with systemic evaluation by a pediatric oncologist with experience in ocular oncology and appropriate systemic imaging by magnetic resonance imaging (MRI) must be standardly performed to rule out metastasis. These steps are vital to accurately classify the disease in accordance with the more recent International Classification of Retinoblastoma (ICRB). This will direct the treatment to either systemic chemotherapy or local therapies (thermal, cryotherapy and chemotherapy) or a combination of both.

Understating the effect of systemic chemotherapy on the different forms of retinoblastoma (solid tumor, subretinal tumor and vitreous seeds) is essential as it helps in guiding the treatment. Moreover, the likely complications and systemic toxicities of IVC are important to be looked at carefully before commencement as this will help in individualizing the treatment in this vulnerable subset of patients so as to reduce systemic morbidities without jeopardizing the treatment success [7]. In this section, we will highlight the principal characteristics of this treatment modality.

#### **2.1 Indications**

The use of IVC varies slightly between different treatment centers worldwide; but generally speaking, the umbrella of IVC usage encompasses its use in patients with intraocular disease only and in patients with or at high risk of extraocular disease. When the disease is limited to the eyes, IVC aims at shrinking the size of the tumor to expedite cure and lessen the damage induced by consolidating local therapies to follow, especially when the tumor involves sensitive retinal areas such as the macula. This has been termed chemoreduction and it had been shown to achieve adequate tumor control (alone or along with focal consolidating therapies) and eliminate the need for enucleation or external beam radiation (EBR) in more than 75% of patients in a large series (n = 457, group A–D). The risk of recurrence in this series was 22% and these were usually detected in the first year after starting the treatment; yet; none occurred by 4 years of follow up [8, 9]. This is probably the most important concern arising with the use of chemoreduction; though continuous surveillance of these children partly helps in overcoming this shortcoming.

**73**

*Retinoblastoma Management: Advances in Chemotherapy*

this therapy developed trilateral retinoblastoma [10].

autologous hematopoietic progenitor cell rescue [17].

**2.2 Chemotherapeutic protocol**

ments can follow [7].

**2.3 Complications**

is safe and effective in decreasing the risk of metastasis [12, 13].

Moreover, one study suggested that the administration of chemoreduction might minimize the risk of pineoblastoma where none of the children (n = 147) receiving

IVC is used also as an adjuvant therapy after enucleation in patients with extraocular disease (metastasis) as well as patients with intraocular disease associated with high-risk histopathological features (e.g., optic nerve invasion beyond the lamina cribrosa and choroid invasion >3 mm) demonstrated on histopathological examination of the enucleated eye [11]. It is speculated that patients with high-risk features might presumably have micro-metastasis and administering systemic chemoprophylaxis helps in improving their prognosis. Evidence in the literature supports the use of prophylactic IVC in high-risk patients where it was shown that it

Patients with extraocular disease receiving IVC can be divided into three categories: those with orbital and/or regional spread to the preauricular lymph nodes or optic nerve cut, those with central nervous system (CNS) dissemination and those with distant extracranial metastasis [14]. In patients presenting with orbital retinoblastoma, IVC is a valuable treatment. This holds true when it is predominantly administered in combination with other therapies (multimodal therapy: surgery, radiotherapy and chemotherapy) as its effect is usually inadequate when given alone [15]. Patients who have CNS involvement usually have a very poor prognosis with low survival rate. The usual approach to these patients consists of platinum-based IVC with agents having good CNS penetration along with focal CNS treatments such as radiotherapy. Some studies suggested using high doses of IVC followed by autologous hematopoietic progenitor cell rescue; yet, this technique is controversial [16]. Distant metastasis usually occurs to the bone and a small series (n = 14) on stage 4A patients showed promising results using intense induction chemotherapy followed by high dose consolidating chemotherapy and

Over the past decades, multiple chemotherapeutic agents were used, and multiple chemotherapy protocols were implemented, some of which are now outdated. In the meantime, the most commonly employed IVC therapy is the VEC protocol consisting of three main chemotherapeutic agents (Vincristine, Etoposide, Carboplatin) in standard doses based on the body weight. Higher doses may be used in patients with more advanced disease (bilateral group D or E) [7, 18]. This threedrug regimen is the most popular combination preferred by many experts and this stems from its proven effect on neuronal tumors in the pediatric age group as well as its good penetration into the eye [19]. The patient usually receives 6–9 cycles on a monthly basis and once the tumor shrinks in size, then focal consolidating treat-

Common side effects, which are usually observed with any systemic chemotherapy, include transient pancytopenia owing to bone marrow suppression, fever and alopecia. The occurrence of these side effects is usually limited to the treatment period. Although carboplatin, a platinum based agent, had been linked to ototoxicity and nephrotoxicity, these serious side effects are rare as they are dose-dependent [20, 21]. There was an underlying concern that etoposide may induce acute myelogenous leukemia especially with high multiple doses; yet, the results of several studies on this topic were reassuring [7, 22]. With regards to secondary tumors, it

*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*

sections.

lower due to the limited healthcare resources [1]. The different chemotherapy treatment strategies outlined above will be discussed thoroughly in the upcoming

The era of chemotherapeutic treatment for retinoblastoma began in 1953 when Carl Kupfer reported the successful use of intravenous nitrogen mustard along with irradiation to treat a child with recurrent retinoblastoma [2]. Thereafter, the use of triethylene melamine, a chemotherapeutic alkylating agent, via different routes (oral, intramuscular, intravenous and intra-arterial) became more widespread between clinicians until the late 1960s given that it allowed the reduction of radiotherapy dose which was associated with multiple potential side effects [3–6]. In the following years, the use of systemic chemotherapy fluctuated until the early 1990s when the use of systemic chemotherapy was popularized and strongly advocated by the leading retinoblastoma treatment centers worldwide and the use of external beam radiation was restricted in favor of chemotherapy due to the considerable risk

The management of retinoblastoma should be carried out by an experienced team as these children need meticulous bilateral ocular examination, usually under anesthesia, in parallel with systemic evaluation by a pediatric oncologist with experience in ocular oncology and appropriate systemic imaging by magnetic resonance imaging (MRI) must be standardly performed to rule out metastasis. These steps are vital to accurately classify the disease in accordance with the more recent International Classification of Retinoblastoma (ICRB). This will direct the treatment to either systemic chemotherapy or local therapies (thermal, cryotherapy

Understating the effect of systemic chemotherapy on the different forms of retinoblastoma (solid tumor, subretinal tumor and vitreous seeds) is essential as it helps in guiding the treatment. Moreover, the likely complications and systemic toxicities of IVC are important to be looked at carefully before commencement as this will help in individualizing the treatment in this vulnerable subset of patients so as to reduce systemic morbidities without jeopardizing the treatment success [7]. In this section, we will highlight the principal characteristics of this treatment

The use of IVC varies slightly between different treatment centers worldwide; but generally speaking, the umbrella of IVC usage encompasses its use in patients with intraocular disease only and in patients with or at high risk of extraocular disease. When the disease is limited to the eyes, IVC aims at shrinking the size of the tumor to expedite cure and lessen the damage induced by consolidating local therapies to follow, especially when the tumor involves sensitive retinal areas such as the macula. This has been termed chemoreduction and it had been shown to achieve adequate tumor control (alone or along with focal consolidating therapies) and eliminate the need for enucleation or external beam radiation (EBR) in more than 75% of patients in a large series (n = 457, group A–D). The risk of recurrence in this series was 22% and these were usually detected in the first year after starting the treatment; yet; none occurred by 4 years of follow up [8, 9]. This is probably the most important concern arising with the use of chemoreduction; though continuous surveillance of these children partly helps in overcoming this shortcoming.

**2. Intravenous chemotherapy for retinoblastoma**

of secondary tumors in patients receiving radiotherapy.

and chemotherapy) or a combination of both.

**72**

modality.

**2.1 Indications**

Moreover, one study suggested that the administration of chemoreduction might minimize the risk of pineoblastoma where none of the children (n = 147) receiving this therapy developed trilateral retinoblastoma [10].

IVC is used also as an adjuvant therapy after enucleation in patients with extraocular disease (metastasis) as well as patients with intraocular disease associated with high-risk histopathological features (e.g., optic nerve invasion beyond the lamina cribrosa and choroid invasion >3 mm) demonstrated on histopathological examination of the enucleated eye [11]. It is speculated that patients with high-risk features might presumably have micro-metastasis and administering systemic chemoprophylaxis helps in improving their prognosis. Evidence in the literature supports the use of prophylactic IVC in high-risk patients where it was shown that it is safe and effective in decreasing the risk of metastasis [12, 13].

Patients with extraocular disease receiving IVC can be divided into three categories: those with orbital and/or regional spread to the preauricular lymph nodes or optic nerve cut, those with central nervous system (CNS) dissemination and those with distant extracranial metastasis [14]. In patients presenting with orbital retinoblastoma, IVC is a valuable treatment. This holds true when it is predominantly administered in combination with other therapies (multimodal therapy: surgery, radiotherapy and chemotherapy) as its effect is usually inadequate when given alone [15]. Patients who have CNS involvement usually have a very poor prognosis with low survival rate. The usual approach to these patients consists of platinum-based IVC with agents having good CNS penetration along with focal CNS treatments such as radiotherapy. Some studies suggested using high doses of IVC followed by autologous hematopoietic progenitor cell rescue; yet, this technique is controversial [16]. Distant metastasis usually occurs to the bone and a small series (n = 14) on stage 4A patients showed promising results using intense induction chemotherapy followed by high dose consolidating chemotherapy and autologous hematopoietic progenitor cell rescue [17].
