Patients with isolated orbital retinoblastoma had fared poorly when treated with surgery +/− radiation therapy [2], but their prognosis improved considerably when conventional chemotherapy was added to the treatment regimen, with 1-year event-free survival of 40 % following treatment with a variety of chemotherapy agents [3, 4]. The management of orbital retinoblastoma is discussed in detail elsewhere (Chap.​ 17).

More recent publications confirm that patients with regional extraocular disease (orbital and/or preauricular disease, optic nerve margin positivity) may be cured with conventional chemotherapy and external beam radiation therapy. Investigators in Argentina treated 15 patients with orbital or preauricular nodal disease on 2 consecutive protocols. Chemotherapy included vincristine, doxorubicin, and cyclophosphamide (local protocol 87) or vincristine, idarubicin, cyclophosphamide, carboplatin, and etoposide (local protocol 94). The external beam radiation therapy dose was 4,500 cGy, administered up to the chiasm for patients with orbital disease and to the involved nodes in patients with preauricular adenopathy. The group achieved a 5-year event-free survival of 84 % [5]. The Argentine and New York groups also reported the results of 12 patients with optic nerve margin positivity treated with the chemotherapy regimens above and orbital radiation therapy (4,000–4,500 cGy). All 12 were event-free survivors [6].

Similarly, investigators in Brazil reported the results of 2 consecutive protocols. Chemotherapy included vincristine, doxorubicin, cyclophosphamide, cisplatin, and teniposide (1987–1991) or ifosfamide, etoposide, cisplatin, and teniposide (1992–2000). The external beam radiation therapy dose was 4,000–5,000 cGy to the orbit. Triple intrathecal therapy was also administered. Their therapy was successful in 20 of 32 patients (63 %) with orbital disease and 22 of 29 (76 %) with optic nerve margin positivity [7].

Older publications from several centers reported the results of trials utilizing conventional dose chemotherapy and radiation therapy for metastatic extraocular disease, most using vincristine, doxorubicin, cyclophosphamide, cisplatin, and etoposide. Despite occasional reports of long-term event-free survival [9, 10], the bulk of the evidence suggested that the prognosis remained grim with such an approach [11–13]. More recent publications confirm the dismal prognosis. The Argentine investigators (using the regimens discussed above) noted that all 26 patients with distant metastases died [5]. Similarly, the Brazilian investigators noted that treatment with their regimens (discussed above) led to survival of only 1 of 14 patients (7 %) with distant metastases [7].

Individual case reports had suggested that the use of high-dose chemotherapy with ASCR might be beneficial for patients with metastatic retinoblastoma [14, 15], and subsequently Institut Curie investigators reported the results of 25 patients with high-risk retinoblastoma treated with high-dose carboplatin, etoposide, and cyclophosphamide followed by ASCR [16]. Five of eight patients with stage 4a disease were event-free survivors 11–70 months after high-dose chemotherapy. Three had central nervous system relapses and died of disease 10–20 months after high-dose chemotherapy. Three other patients had disease that progressed during induction with conventional induction chemotherapy and never received high-dose chemotherapy. In total, then, five of 11 patients (45 %) with stage 4a metastatic disease were event-free survivors.