**2.2 Chemotherapeutic protocol**

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multiple chemotherapeutic agents were used, and multiple chemotherapy protocols were implemented, some of which are now outdated.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 treatments can follow [7].

#### **2.3 Complications**

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

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 vulnerable subset of patients [23].

#### **2.4 Outcomes and success rate**

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 in patients receiving it [26].

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.
