Globe-sparing interventions in the management of intraocular retinoblastoma

RETINOBLASTOMA is the most common malignant intraocular tumor in children; it is also one of the most highly curable pediatric solid tumors if detected early. The conventional treatment of retinoblastoma is primary enucleation. Recent research reported a trend toward decreasing frequency of enucleation in the management of retinoblastoma.1 The trend toward globesparing interventions has been largely attributed to earlier diagnosis and recent success with conservative globe-sparing treatment options. Currently, globesparing interventions include first-line chemotherapy or chemoreduction, subconjunctival chemotherapy, systemic chemotherapy for metastasis, transpupillary thermotherapy (TTT), chemothermotherapy (CTT), laser photocoagulation, cryotherapy, brachytherapy, and external beam radiotherapy (EBRT). Expanded clinical options currently available have markedly decreased the overall enucleation rate for retinoblastoma.2

CLINICAL SCENARIO

A 10-month old boy is brought to an ophthalmologist because of cat’s eye reflex in the left eye. The patient had undergone enucleation of his right eye for glaucomatous stage retinoblastoma 6 months earlier. Examination revealed the presence of a solitary retinal mass of about 12 mm in diameter, located nasal to the disc. There was no evidence of vitreous seeding.

Realizing that this was the only eye of the patient, the ophthalmologist wants to do everything humanly possible to preserve it. He has heard about chemothermotherapy (CTT) but is not sure if this was the best alternative he can offer.

CLINICAL QUESTION

Among patients with retinoblastoma, is chemoreduction combined with adjuvant treatment effective in preserving the globe and vision?

SEARCH METHOD

An electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) on The Cochrane Library (Issue 1 2005) and MEDLINE on PubMed was performed. The literature search was limited to the English language with no date restrictions. The search terms used were retinoblastoma and chemothermotherapy, thermochemotherapy, or chemoreduction. The search yielded 70 articles, 22 were chosen for evaluation and 8 were included in the review. Two reviewers independently assessed the articles for inclusion.

Selection criteria

This review was designed to include clinical trials in which treatment of retinoblastoma with chemoreduction combined with adjuvant therapy was compared with another treatment or no treatment.

CITATION

1. Schiavetti A, Hajistilianou T, Clerico A, et al. Conservative therapy in intraocular retinoblastoma: response/ recurrence rate. J Pediatr Hematol Oncol 2005; 27: 3-6.
2. Shields CL, Mashayekhi A, Cater J, et al. Chemoreduction for retinoblastoma: analysis of tumor control and risk for recurrence in 457 tumors. Am J Ophthalmol 2004: 138: 329-337.
3. Schueler AO, Jurklies C, Heimann H, et al. Thermotherapy in hereditary retinoblastoma. Br J Ophthalmol 2003; 87: 90-95.
4. Lumbroso L, Doz F, Urbieta M, et al. Chemothermotherapy in the management of retinoblastoma. Ophthalmology 2002; 109: 1130-1136.
5. Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 2002; 133: 657-664.
6. Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 2002; 120: 163-1658.
7. Wilson MW, Rodriguez-Galindo C, Haik BG, et al. Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma. Ophthalmology 2001; 108: 2106-2115.
8. Shields CL, Shields JA, Needle M, et al. Combinedchemoreduction and adjuvant treatment for intraocular retinoblastoma. Ophthalmology 1997; 104: 2101-2111.

DISCUSSION

Data collection and analysis

No randomized controlled clinical trials were found. The available literature consists mostly of prospective
nonrandomized clinical trials and interventional case series (Level 4 evidence). The reviewers extracted data
and assessed trial quality of the included studies. Due to the variability in treatment methods and main outcome measures, no statistical summary measure was calculated.

Main results

Eight trials were included in this review (Table 1). The highest rate of globe preservation (98%) was shown in a
study of 193 eyes in 125 children (457 tumors) treated with chemotherapy plus adjuvant therapy, consisting of
either cryotherapy or transpupillary thermotherapy or both. In this study, the rate of recurrence leading to subsequent enucleation or external beam radiation rose with greater tumor thickness and when the tumors were at the macula. Two other trials on chemothermotherapy (CTT), which consisted of intravenous (IV) administration of carboplatin followed shortly by transpupillary thermotherapy (TTT), yielded globe-salvage rates of 92% to 96%. This intervention was particularly effective in small to medium tumors (up to 12 mm). Globe-preservation rates were much lower (58% – 67%) when chemoreduction was combined with other modes of adjuvant or focal

treatments (cr yotherapy, laser therapy, plaque radiotherapy). Chemotherapy alone posted the lowest
globe-preservation rate of 19.5%. In most trials, globepreservation rates were much lower for tumors classified as Reese–Ellsworth (RE) V. Two trials studied the factors that led to treatment with enucleation or external beam radiation. Results were not consistent.

STUDY AUTHORS’ CONCLUSIONS

Classifications of retinoblastoma based on disease severity have been developed to aid in the prediction of
globe salvage. The Reese–Ellsworth classification, which correlates the likelihood of globe salvage with tumor extent, is widely used in most research studies (Table 2). The available treatment methods for retinoblastoma
for globe salvage in the management of retinoblastoma include intravenous chemoreduction, thermotherapy, cryotherapy, laser photocoagulation, plaque radiotherapy, external beam radiotherapy, and systemic chemotherapy for metastatic disease.3 Chemoreduction with or without adjunctive focal measures and thermotherapy alone have been the most promising of the globe-sparing modalities described. Chemoreduction Chemoreduction is a method of reducing tumor volume by means of chemotherapeutic agents. This allows the use of adjunctive therapeutic measures that are more focused and less damaging, increasing the likelihood of globe salvage. The chemotherapeutic agents employed are varied and depend on the preference of the pediatric oncologist, but consist mainly of a combination of the following agents: carboplatin, etoposide, and vincristine. The chemotherapy regimen is generally given in 6 cycles for adequate tumor reduction. Adjunctive focal therapy if given is delivered at cycle 2 after achieving adequate tumor reduction. Chemoreduction allows for a reduction in tumor size that permits focal treatments to be applied to a smaller area, preserving more vision and delaying or possibly avoiding enucleation.4 Schiavetti, et al. J Pediatr Hematol Oncol 2005 Although all groups of patients with intraocular retinoblastoma responded to carboplatin/etoposide chemotherapy associated with focal therapy, all the cases in RE group V relapsed. This approach is questionable in RE group V, where delaying aggressive treatment in a very young child may be justified. Shields, et al. Am J Ophthalmol 2004 Chemoreduction alone or combined with cryotherapy or thermotherapy is effective for treatment of retinoblastoma, but tumor recurrence rate is highest when the tumor is thicker (risk ratio of 1.13 per 1 mm increase) or located in the macula (risk ratio 3.58). Shields, et al. Am J Ophthalmol 2002 Chemoreduction offers satisfactory retinoblastoma control for RE groups I-IV, with treatment failure necessitating additional external beam radiotherapy in only 10% of eyes and enucleation in 15% of eyes at fiveyear follow-up. RE group V requires external beam radiotherapy in 47% and enucleation in 53% at 5 years.

Shields, et al. Arch Ophthalmol 2002
Chemoreduction is an option for selected eyes with unilateral retinoblastoma. Those with advanced RE group
V retinoblastoma showed poorest results, while those with less advanced groups I through IV disease showed best results, maintaining the globe in 71% of eyes, occasionally with satisfactory functional visual acuity.
Wilson, et al. Ophthalmology 2001 Multiagent chemotherapy alone does not ensure a cure for multifocal intraocular retinoblastoma. Supplemental focal therapy is needed to control disease progression.

Shields, et al. Ophthalmology 1997
Chemoreduction and adjuvant treatment of intraocular retinoblastoma with seeding provide good retinal tumor control, even in eyes with advanced disease. Chemoreduction alone generally is not adequate to achieve complete tumor seed control. Cautious follow-up of affected patients is recommended because the risk for recurrent vitreous and subretinal seeds is substantial and proper treatment is critical for salvaging the eye.

Thermochemotherapy

Thermotherapy is a focal or adjunctive treatment modality that applies focused heat to tissue at subphotocoagulation levels to induce tumor necrosis in the treatment of intraocular masses. A transpupillary diode-laser system is used to selectively increase temperature in the tumor. The goal is to attain a focal temperature rise of 42o to 60o Celsius, which is below the coagulative threshold sparing the surrounding retinal tissues.5 The thermal action has been found to have a synergistic effect by increasing the cytotoxic effects of platinum analogues in the treatment of retinoblastoma.6 The combination of heat and chemotherapy is called chemothermotherapy (CTT).

Schueler, et al. Br J Ophthalmol 2003
Chemothermotherapy using an indirect laser ophthalmoscope with a spot size of about 400 µm was efficient for retinoblastoma with a tumor height less than 4 mm. In larger tumors, the recurrence rate was unacceptably high (risk ratio 1.36). Fish flesh regression after TCT correlates with a higher rate of local tumor recurrence (risk ratio 4.88). Treatment-related complications occurred in less than 9% of the treated eyes.

Lumbroso, et al. Ophthalmology 2002
Chemothermotherapy is an effective technique to treat small- to medium-sized retinoblastomas in children,
avoiding external beam irradiation.

REVIEWERS’ CONCLUSIONS
The evidence as to the effectiveness of chemoreduction combined with adjuvant or focal therapy comes mainly from nonrandomized, interventional case series (Level 4 evidence). There is evidence that chemothermotherapy provides the best chance for ocular (globe) preservation. Chemoreduction combined with other forms of adjuvant or focal therapy showed poorer outcomes compared with CTT, but is still better than chemotherapy alone. There is no evidence that chemoreduction with adjuvant therapy leads to preservation of vision. If at all possible, further large well-conducted randomized controlled trials, with longer follow-up, are advisable.

RESOLUTION OF THE CLINICAL SCENARIO
For intraocular tumors ≤10 mm, with no evidence of vitreous and/or retinal seeding (RE I-IV), chemothermotherapy offers the best chance for globe preservation (Grade C recommendation).

References
1. Shields CL, Mashayekhi A, Demirci H, et al. Practical approach to management of retinoblastoma. Arch Ophthalmol 2004; 122: 729-735.
2. Lee V, Hungerford JL, Bunce C, et al. Globe conserving treatment of the only eye in bilateral retinoblastoma. Br J Ophthalmol 2003;87:1374-1380.
3. Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Ped Ophthalmol Strab 1999; 36: 8-18.
4. Shields CL, Shields JA. Chemotherapy for retinoblastoma (editorial). Med Pediatr Oncol 2002;38: 377-378.
5. Schueler AO, Jurklies C, Heimann H, et al. Thermotherapy in hereditary retinoblastoma. Br J Ophthalmol 2003; 87: 90-95.
6. Murphree AL, Villablanca JG, Deegan WF III, et al. Chemotherapy plus focal treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 1996, 114: 1348-1356.

Keywords: Retinoblastoma, Globe, Intraocular tumor, Chemotherapy, Enucleation