In general, eyes with group A tumors are treated with local therapy alone. Combination of systemic chemotherapy with CEV and local therapy has been successful in treating group B eyes (R-E stage I–III) [15]. Six courses of low-dose CEV or three courses of high-dose CEV have been used (Table 11.1). Ocular salvage rates of nearly 100 % can be achieved with CEV regimen and local therapy. With this success, attempts were made to minimize morbidity by eliminating etoposide. Investigators at St. Jude Children’s Research Hospital achieved an ocular salvage rate of 83 % in R-E group I–III eyes using eight cycles of vincristine and carboplatin [7]. Subsequently, the Children’s Oncology Group conducted a study of two-drug regimen (vincristine and carboplatin) in group B tumors. This study was closed early due to more-than-expected number of failures.

In spite of initial response with low-dose CEV regimen in eyes with subretinal or vitreous seeds, only 53 % of R-E group 4 and 5 eyes (group C, D, or E) were treated successfully without requiring EBRT and/or enucleation [15, 16]. Gallie et al. reported relapse-free rates of up to 89 % with the addition of cyclosporine to chemotherapy to reverse drug resistance [8]. Other groups were not able to reproduce the results of this pilot study. Subsequently, doses of the chemotherapy agents were increased in an attempt to achieve increased intraocular drug levels. This resulted in 66 % eye salvage at 5 years in one study, but nearly half the eyes required low-dose EBRT at recurrence [17]. In addition, subtenon or periocular carboplatin has been used to increase drug delivery to the vitreous where blood supply is poor. Preliminary studies using subtenon carboplatin and high-dose CEV showed improved ocular salvage rates [18]. Toxicities observed using this modality included periorbital fat atrophy resulting in mild to moderate cosmetic changes and restriction of extraocular movements [19]. Rare cases of optic atrophy have also been reported [18]. To further evaluate this strategy, the Children’s Oncology Group opened a single-arm trial of systemic and subtenon chemotherapy for group C and D eyes. Unfortunately, this study was closed early due to poor accrual, and study results are awaited.

Traditionally, patients with orbital disease have been treated with surgery with or without irradiation and have fared poorly. The addition of conventional-dose chemotherapy to the treatment regimen has improved survival considerably. Recent reports confirm that conventional chemotherapy and external beam irradiation can cure patients with regional extraocular disease (orbital and/or preauricular disease or optic nerve margin positivity). Investigators in Argentina treated 15 patients with orbital or periauricular nodal disease with chemotherapy (cyclophosphamide, doxorubicin and vincristine or vincristine, idarubicin, cyclophosphamide, carboplatin, and etoposide) [11]. This was followed by external beam irradiation (45 Gy) up to the chiasm in patients with orbital disease and to the involved nodes in patients with preauricular lymphadenopathy. They reported a 5-year event-free survival of 84 %. Chantada et al. reported event-free survival of 70 % at 5 years in 26 patients with optic nerve involvement treated with the above chemotherapy regimens and orbital irradiation. Events included CNS relapse in 3, second malignancy in 3, and death in remission in 2 patients [28]. Investigators in Brazil treated 61 patients with regional extraocular disease using chemotherapy and an external beam radiation therapy dose of 40–50 Gy to the orbit. Triple intrathecal chemotherapy was also administered. Therapy was successful in 20/32 patients with orbital disease and 22/29 with optic nerve margin positivity [12].

Historically, patients with metastatic retinoblastoma were treated with conventional doses of chemotherapy and radiation therapy, and despite some reports of long-term survival, the majority of the evidence pointed to a grim prognosis. This was confirmed by the Argentine and Brazilian investigators referenced above with reports of 0/26 and 1/14 survivors with distant metastatic disease, respectively [11, 12]. Namouni et al. reported the results of 25 patients with metastatic retinoblastoma treated with high-dose carboplatin, etoposide, and cyclophosphamide followed by autologous stem cell rescue (ASCR) [29]. Five of 11 patients (45 %) without CNS metastasis at diagnosis were event-free survivors at 11–70 months after high-dose chemotherapy. Dunkel et al. reported on four patients with metastatic retinoblastoma without CNS involvement treated with high-dose carboplatin, thiotepa, and etoposide with ASCR after complete response to conventional doses of chemotherapy. All four were event-free survivors from 46 to 80 months following diagnosis [30]. Matsubara et al. from Japan reported on five patients with metastatic retinoblastoma treated with conventional-dose chemotherapy and irradiation to bulky sites followed by high-dose chemotherapy with a variety of chemotherapy combinations and ASCR [31]. The three patients without CNS involvement are long-term survivors with no evidence of disease at 113, 107, and 38 months from the time of transplant.

Evidence suggests that high-dose chemotherapy with ASCR is associated with improved survival for patients with metastatic retinoblastoma not involving the CNS. The optimal high-dose chemotherapy combination remains to be determined; however, the inclusion of thiotepa may decrease the risk of CNS recurrence due to the excellent penetration of this agent into the CNS.

There are fewer data on survivors of retinoblastoma with CNS metastatic disease or patients with pineal involvement (trilateral retinoblastoma). Antoneli et al. described seven patients with CNS disease at the time of diagnosis, none of whom survived despite treatment with chemotherapy and irradiation of the whole brain and spine to 36 Gy [12]. Chantada et al. reported on 21 patients with CNS metastatic disease who were treated with conventional-dose chemotherapy and irradiation: 24 Gy to the brain and 18 Gy to the spine [11]. None of those patients survived. Recently, two survivors were reported in a multi-institutional retrospective series of eight patients, following high-dose chemotherapy with ASCR [32].

Trilateral retinoblastoma occurs in 3 % of patients and is diagnosed more commonly in patients with bilateral disease who are less than 1 year of age (Chap.​ 20) [33]. Amoaku et al. reported no cure in five patients with trilateral retinoblastoma, including three patients treated with chemotherapy ± radiation therapy [34]. Jubran et al. described three patients with trilateral disease. One patient survived following a complete resection of the pineal tumor followed by induction chemotherapy, high-dose chemotherapy, and ASCR [26]. Dunkel et al. reported 13 patients with trilateral retinoblastoma treated with two cycles of induction chemotherapy consisting of vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide, followed by high-dose chemotherapy and ASCR [35]. Five patients survived event free at a median of 77 months of follow-up.