14.6 Treatment Options

care taken to not perforate or penetrate the globe and to limit the risk of tumor cell spread within the orbital cavity. The optic nerve should then be cut in such a way as to obtain as long a section as possible and minimize the risk of tumor cells distal to the cut margin. Because unilateral disease is often diagnosed late, when the stage is advanced and the potential for vision preservation is poor, enucleation is generally the preferred treatment modality, although in select cases more conservative therapy may be considered.

14.6.3 Chemoreduction

During the past decade, chemoreduction (systemic chemotherapy to reduce tumor volume before focal consolidation) has become the preferred modality for ocular salvage. Multiagent chemotherapy is generally used, and the standard regimen currently consists of combinations of carboplatin and vincristine, with or without etoposide. Systemic chemotherapy may also decrease the risk of development of trilateral retinoblastoma and may be effective against small undetected lesions.

The results of a number of trials have been published using systemic chemotherapy for patients whose intraocular tumors are too large to be treated with focal therapy alone, in situations where local therapy would limit vision and offer little improvement over enucleation. All centers reporting to date have demonstrated that globe and vision salvage is achievable in many cases, especially for tumors that are classified as R–E group IV or lower. Advanced retinoblastoma tumors with diffuse vitreous seeding (group D and higher) have proven extremely difficult to treat, however. Several strategies have been used in an attempt to overcome this problem.

The lack of high eye salvage rates in advanced cases has led to the development of newer adjuvant therapies, including subtenon (subconjunctival) carboplatin (see Section 14.6.4) and use of higher doses of carboplatin or etoposide. There is no absolute agreement between different institutions regarding the best combination of chemotherapy agents and the number of treatment cycles. In comparisons of different studies, similar outcome is seen between two-drug combinations (carboplatin combined with either etoposide or vincristine) and three-drug combinations (vincristine, etoposide or teniposide, and carboplatin or cisplatin, with or without the addition of cyclosporine) (Table 14.3).

Friedman et al. [16] treated 75 eyes with 6 cycles of chemotherapy consisting of carboplatin, etoposide, and vincristine, with a median follow-up of 13 months. Almost half of the treated eyes (30) were group V. The response in R–E groups I and II was excellent, with avoidance of EBRT or enucleation in all of them. For groups IV and V, the success rate was lower, with 33% of 6 eyes and 53% of 30 eyes, respectively, requiring EBRT and/or enucleation. In a prospective study with a medium follow-up of 21 months, Brichard et al. [17] treated 24 eyes (21 were group V), with 2 to 6 cycles of chemotherapy. Chemotherapy was combined with

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Table 14.3 Comparison of outcomes of recent retinoblastoma treatment trials

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thermotherapy plus cryotherapy in 16 eyes and thermotherapy plus cryotherapy plus radioactive iodine 125 plaque radiation therapy in 4 eyes; this strategy made EBRT unnecessary in 60% of the eyes. Enucleation remained the treatment of choice in 70% of the group V eyes. One of the more recent studies with a large number of treated eyes (145, with 74 eyes in group V) was done by Antoneli et al. [18] in 2006. These authors used two to six cycles of vincristine, carboplatin, and etoposide plus focal therapy with cryotherapy, laser photocoagulation, and thermotherapy or plaque radiation therapy during and/or after the chemotherapy. In the group of patients with R–E stages I, II, and III disease, the success rate (ocular salvage) for unilateral and bilateral tumors was 50 and 79% (P = 0.179), respectively. In contrast, in the group with R–E stages IV and V disease, children with bilateral tumors responded significantly better (40.7%) than children with unilateral tumors (0%) (P = 0.012) [18].

These studies indicate that for patients with R–E eye groups I, II, or III, systemic chemotherapy in combination with local ophthalmic therapies can avoid the need for enucleation or EBRT. More aggressive therapy is required for R–E eye groups IV and V.

The efficacy of two-drug chemotherapy regimens has been investigated in recent studies [19–21]. Schiavetti et al. [20] achieved an overall complete response rate of 88% after four to eight courses of carboplatin plus etoposide in conjunction with focal therapy (either laser photocoagulation or cryotherapy). The response rate was 100, 94, and 100% for R–E groups I, II, and III, respectively, and 83 and 70% for groups IV and V, respectively. However, the relapse rate was found to be 57% after a mean of 7 months (range, 2–36 months) and was 100% for group V eyes. St. Jude’s researchers reported better outcomes, with 43 eyes in 25 patients treated with 8 courses of vincristine and carboplatin. Focal treatment was given in 39 of the eyes, only after documentation of progression. EBRT was required in 18 eyes (44.2%), and 13 eyes (30.2%) were enucleated. With this treatment, the ocular salvage rate was 83.3% for R–E group I, II, and III eyes and 52.6% for group IV and V eyes. More recently, Zage et al. [21] at Children’s Memorial Hospital in Chicago, treated 48 eyes in 29 patients with a combination of carboplatin and etoposide and early local therapy. The reported response rate was 85.4%; the vision salvage rate was 82.6% without EBRT for eye groups A and B but only 20% for R–E group V eyes. The evidence suggests that a regimen with only two chemotherapy agents (i.e., carboplatin combined with either etoposide or vincristine) and a total of six to eight cycles is a suitable approach for low-stage tumors, but for R–E groups IV and V a more aggressive regimen is still required.

The presence of extraocular disease, particularly invasion of the central nervous system, has prompted the use of drugs like carboplatin that have better central nervous system penetration [22]. Regimens of chemotherapy that use carboplatin, etoposide, and vincristine have been used to treat patients with extraocular disease. There are emerging data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma. Local tumor recurrence is not uncommon in the first few years after treatment and can often be successfully treated with focal therapy [23]. Among patients with heritable disease,