PEER REVIEWED

New Hope for Retinoblastoma Patients

Recent developments provide better prognoses.

APARNA RAMASUBRAMANIAN, MD • CAROL L. SHIELDS, MD

Retinoblastoma is the most common pediatric intraocular malignant tumor.¹ The last century has seen a paradigm shift in the management of retinoblastoma. A study from London showed that the five-year survival rate for children with unilateral retinoblastoma increased from 85% for those diagnosed between 1963 and 1967 to 97% for those diagnosed between 1998 and 2002.² This significant improvement in mortality cannot be extrapolated to all parts of the world, as reports from Africa predict a disease-free survival of around 20%.³ Kivela wrote an illuminating editorial describing the advancement in the medical field since the early description of retinoblastoma by Dr. James Wardrop in 1809. He concluded the editorial by hoping it would not take another 200 years for the benefit to spread worldwide.⁴

This review focuses on the major revolutions in retinoblastoma management providing new hope to patients with this disease. We have reviewed the key publications in the last five years that have had an impact on our understanding and management of retinoblastoma.

EPIDEMIOLOGY AND ETIO-PATHOGENESIS

Kivela summarized recent epidemiological publications in retinoblastoma and estimated that 7,202 to 8,102 children develop retinoblastoma annually throughout the world. Of these, an estimated 3,001 to 3,376 die of retinoblastoma annually, with most deaths coming from Asia and Africa.⁵

The etiology and pathogenesis of retinoblastoma are still unclear, with recent evidence showing the role of aneuploidy and chromosome instability.⁶ Also, recent data have suggested that retinomas may represent premalignant lesions and not regressed tumors.⁷

DIAGNOSIS AND TUMOR CLASSIFICATION

Detection of intraocular calcification is critical for the diagnosis of retinoblastoma, and often computed tomography (CT) scans, which carry radiation exposure to radiosensitive retinoblastoma patients, are used. Galluzzi et al. inferred from a retrospective analysis that ophthalmoscopic evaluation, ultrasonography and magnetic resonance imaging (MRI) put together are equivalent to CT imaging for detection of calcium.⁸ Ramasubramanian and coworkers described autofluorescence imaging in patients with retinoblastoma and found that calcification appears strikingly hyperautofluorescent, concluding that this technique may potentially be used to detect subtle calcification in the eye.⁹

The International Classification of Retinoblastoma was created in 2003 to make tumor classification easier and better suited for the chemotherapy era (Table 1).¹⁰

TREATMENT
Systemic Chemotherapy

The advent of chemotherapy transformed the treatment of retinoblastoma, decreasing the number of enucleations and the use of external-beam radiotherapy. Shields and coworkers provided a retrospective analysis of 249 eyes and reported that, based on the ICRB, success with chemoreduction for retinoblastoma (defined as avoidance of external-beam radiation and enucleation) was 100% for group A, 93% for group B, 90% for group C and 47% for group D.¹¹

In another retrospective analysis, group E retinoblastoma treated with systemic chemotherapy was analyzed (Figure 1). A comparison of the results of chemotherapy alone vs chemotherapy with prophylactic external-beam radiation (defined as low-dose radiation delivered prior to onset of tumor or seed recurrence) was performed. The authors concluded that chemotherapy alone was successful in 25% of eyes with group E retinoblastoma, but with the addition of prophylactic external-beam radiation, the globe salvage rate increased to 83%.¹²

Figure 1. Advanced Group E retinoblastoma (A) treated with systemic chemotherapy showing compete tumor regression (B). Retinoblastoma with extensive vitreous seeds (C) treated with intra-arterial chemotherapy showing regressed tumor and calcified vitreous seeds. (D)

The current systemic regimen (six cycles of etoposide, carboplatin, and vincristine) can cause transient bone marrow suppression, nephrotoxicity and a risk of infection. Lambert and coworkers evaluated 248 children receiving chemotherapy to quantify the risk of carboplatin-induced ototoxicity and found no chemotherapy-induced hearing deficit.¹³ The potential risk for induction of secondary cancers is not known but is predicted to be minimal due to the low-dose, short-term treatment.

Tumor regression patterns in retinoblastoma include: type 0, in which the tumor completely disappears, leaving no retinal scar; type 1, with a completely calcified mass; type 2, with a completely noncalcified mass; type 3, with a partially calcified mass; and type 4, with a flat atrophic scar.¹⁴ In an analysis of 557 retinoblastomas treated with chemoreduction, the regression patterns following treatment revealed that most small retinoblastomas resulted in a flat scar, intermediate tumors in a flat or partially calcified remnant, and large tumors in a more completely calcified scar. In this analysis, the authors did not find any correlation between regression types and tumor recurrence rates.¹⁵

Intra-arterial Chemotherapy

A unique method of chemotherapy delivery is the intraarterial technique (Figure 2), whereby medication is delivered directly to the affected organ by intra-arterial catheter. This concept was popularized in the 1990s and used to treat head and neck tumors, pancreatic tumors, liver tumors and other malignancies. The technique allows for concentrated, high-dose administration of chemotherapy to a focal site with limited systemic side effects. It is especially useful for small vessels such as the ophthalmic artery and was explored by Japanese researchers for use in retinoblastoma.¹⁶ Abramson et al. in 2008 published preliminary reports on nine patients treated with intra-arterial chemotherapy and demonstrated good tumor regression with minimal systemic and local toxicity.¹⁷

Figure 2. Angiography during the intra-arterial procedure demonstrating the microcatheter in the internal carotid artery (A) about to make the turn into the ophthalmic artery. Angiography done after the catheter enters the ophthalmic artery and before injection of chemotherapy shows the vasculature of the globe (B).

Advantages of Intra-arterial Chemotherapy

Intra-arterial chemotherapy allows selective delivery of chemotherapy to the eye with minimal systemic absorption. In our experience, some patients have a slight decrease in white blood cell count at two weeks following treatment, but no patients to date have needed transfusion. No other side effects of chemotherapy, such as fever, vomiting, loss o f scalp hair or infection, have been witnessed by our team so far.^18,19

The dose delivered to the eye is 10 times that achieved with systemic chemotherapy. This high dose delivered to the eye accelerates regression of tumor and seeds.²⁰ The long-term outcome of these patients and their recurrence rates after intra-arterial chemotherapy are still unknown.

Drawbacks of Intra-arterial Chemotherapy

We believe that there are many considerations when deciding on intra-arterial chemotherapy. In 3% to 5% of patients, the ophthalmic artery arises from the middle meningeal artery, instead of the internal carotid artery.²¹ In these instances, it is not possible to cannulate the ophthalmic artery and the procedure has to be abandoned. Structural brain anomalies can impose significant risk with the procedure and hence preoperative MRI is performed. The chemotherapy infusion has to be repeated every three to four weeks for up to three to six injections for complete regression of tumor.

Cannulation of the ophthalmic artery is difficult in children — particularly in infants less than six months old — and requires surgical expertise and precision. As it is a neuroinvasive procedure, the risk of stroke and other severe neurological complications have to be considered. Kaneko et al. reported experience with 187 patients and 563 cannulations with a technical success rate of 98% and no cannulationrelated complications, such as hemorrhage, stroke or death.¹⁶ So far, we have not en countered any serious neurological side effects.

Most patients experience self-limiting lid edema and chemosis, which persist for two to four weeks following chemotherapy. Shields et al. noted from their experience that the major concerns with intra-arterial chemotherapy have been recurrence of vitreous seeds and ischemia due to ophthalmic artery occlusion.¹⁸

PATHOLOGY

The International Retinoblastoma Staging Working Group reached consensus on tissue handling after enucleation, definitions of histopathological risk features, and reporting in retinoblastoma.22 The consensus definitions are:

• Massive Choroidal Invasion — maximum diameter of invasive tumor focus of 3 mm or more that may reach the scleral tissue.
• Focal Choroidal Invasion — tumor focus of less than 3 mm and not reaching the sclera.
• Optic Nerve Invasion — classified as prelaminar, laminar, retrolaminar or tumor at surgical margin.

Eagle described the high-risk features in 19% of all retinoblastoma, with optic nerve invasion in 10% and massive uveal invasion in 8%. Of 297 eyes, 20% of the retinoblastomas contained foci of photoreceptor differentiation. He postulated that retinomas may be precursors to retinoblastoma lesions in view of the poor correlation between photoreceptor differentiation and age at enucleation.²³ This pathological hypothesis has also been proved by genetic analysis,⁷ dispelling the earlier concept that retinomas are benign variants.

GENETICS

Parsam et al. reported a less time-consuming and more economical approach to detect gene mutation in retinoblastoma patients. The strategy was to detect large deletions/duplications by fluorescent quantitative multiplex PCR; small deletions/insertions by fluorescent genotyping of RB1 alleles; and point mutations by PCR-restriction fragment length polymorphism and sequencing.²⁴

Zhang and coworkers studied the mis-splicing in RB1 gene and found that few bases are effective for oncogenic mutation in view of the frequency of their detection. They also noted that the location of mutation relative to the splice sequence had a strong and consistent influence on phenotypic expression. Further validation in the near future of the genomic sequence and its phenotypic expression would aid in prognosis and management of retinoblastoma patients.²⁵

SECONDARY TUMORS

MacCarthy and coworkers analyzed the National Tumor Registry from 1951 to 2004 to estimate the occurrence of nonocular tumors in retinoblastoma. The cumulative risk of developing nonocular tumor at 50-year follow-up is 48% for heritable cases and 5% for nonheritable cases. Soft-tissue sarcomas were the most commonly encountered tumor, followed by osteosarcoma, carcinoma, central nervous system tumors, melanoma and leukemia.²⁶

FUTURE DIRECTIONS

VEGF. Arean et al. investigated the immunohistochemical expression of vascular endothelial growth factor in retinoblastoma tumors. They observed a correlation between VEGF-staining intensity and time of progression and mitotic and apoptotic activity, suggesting that therapeutic targeting of VEGF may retard retinoblastoma tumor progression.²⁷

Photodynamic therapy. Stephan et al. investigated the effectiveness of PDT on retinoblastoma cell lines. They found that PDT/verteporfin (Visudyne, Novartis) effectively killed chemotherapy-resistant and primary retinoblastoma cell lines — an interesting observation that requires clinical testing and evaluation.²⁸

CONCLUSION

Extensive clinical and basic science research has significantly altered the management of retinoblastoma, providing new hope to the afflicted patients. Ongoing efforts are required to broaden the treatment benefit to retinoblastoma patients in other parts of the world. RP

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