Extraocular Retinoblastoma Treatment

Standard Treatment Options
        Orbital and loco-regional retinoblastoma
        Central nervous system disease
        Trilateral retinoblastoma
        Extracranial metastatic retinoblastoma
Treatment Options Under Clinical Evaluation
        Current Clinical Trials

In developed countries, few patients with retinoblastoma present with extraocular disease. Extraocular disease may be localized to the soft tissues surrounding the eye or to the optic nerve beyond the margin of resection. However, further extension may occur into the brain and meninges with subsequent seeding of the spinal fluid, as well as distant metastatic disease involving the lungs, bones, and bone marrow.

Orbital retinoblastoma occurs as a result of progression of the tumor through the emissary vessels and sclera. For this reason, transscleral disease is considered to be extraocular and should be treated as such. Orbital retinoblastoma is isolated in 60% to 70% of cases; lymphatic, hematogenous, and central nervous system (CNS) metastases occur in the remaining patients. Treatment should include systemic chemotherapy and radiation therapy; with this approach, 60% to 85% of patients can be cured. Since most recurrences occur in the CNS, regimens using drugs with well-documented CNS penetration are recommended. Different chemotherapy regimens have proven to be effective, including vincristine, cyclophosphamide, and doxorubicin and platinum- and epipodophyllotoxin-based regimens, or a combination of both.[1-3] For patients with macroscopic orbital disease, it is recommended that surgery is delayed until response to chemotherapy has been obtained (usually two or three courses of treatment). Enucleation should then be performed and an additional four to six courses of chemotherapy administered. Local control should then be consolidated with orbital irradiation (40 Gy to 45 Gy). Using this approach, orbital exenteration is not indicated.[3] Patients with isolated involvement of the optic nerve at the transsection level should also receive similar systemic treatment, and irradiation should include the entire orbit (36 Gy) with 10 Gy boost to the chiasm (total 46 Gy).[2]

Intracranial dissemination occurs by direct extension through the optic nerve and its prognosis is dismal. Treatment for these patients should include platinum-based intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been traditionally used, there is no preclinical or clinical evidence to support its use. Although the use of irradiation in these patients is controversial, responses have been observed with craniospinal irradiation, using 25 Gy to 35 Gy to the entire craniospinal axis and a boost (10 Gy) to sites of measurable disease. Therapeutic intensification with high-dose marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue has been explored, but its role is not yet clear.[4][Level of evidence: 3iiA]

Trilateral retinoblastoma is usually associated with a pineal or, less commonly, a suprasellar lesion. In patients with the hereditary form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than a primary intracranial focus, such as a pineal tumor. The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months. While pineoblastomas occurring in older patients are sensitive to radiation therapy, current strategies are directed towards avoiding irradiation by using intensive chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue, an approach similar to those being used in the treatment of brain tumors in infants.[5]

Because of the poor prognosis of trilateral retinoblastoma, screening neuroimaging is a common practice. While it is not clear whether early diagnosis can impact survival, the frequency of screening with magnetic resonance imaging for those suspected of having hereditary disease or those with unilateral disease and a positive family history has been recommended as often as every 6 months for up to 5 years. Given the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral retinoblastoma, routine screening might detect the majority of cases within 2 years. However, it is not clear that screening by neuroimaging improves survival.[6] Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.

Hematogenous metastases may develop in the bones, bone marrow, and less frequently, in the liver. Although long-term survivors have been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In recent years, however, studies of small series of patients have shown that metastatic retinoblastoma can be cured using high-dose marrow-ablative chemotherapy and autologous hematopoietic stem cell rescue.[7-13]; [14][Level of evidence: 3iiA]

There is no clearly proven effective or standard therapy for the treatment of extraocular retinoblastoma, although orbital irradiation and chemotherapy have been used. In the past, palliative therapy with radiation therapy (including craniospinal irradiation when there is meningeal involvement) and/or intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone, plus supportive care has been used.[15] A retrospective study showed that extraocular disease, manifested by gadolinium enhancement on magnetic resonance imaging of the proximal optic nerve, might respond to treatment with neoadjuvant chemotherapy prior to enucleation.[16][Level of evidence: 3iiDi]

Two reports suggest that there may be a role for intensive multimodality therapy with autologous stem cell rescue for patients with metastatic retinoblastoma.[4,14][Level of evidence: 3iiA] A few responses were noted in both CNS (including trilateral) and systemic metastases. However, these strategies remain under clinical investigation.

The following is an example of national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ARET0321 (Combination Chemotherapy, Autologous Stem Cell Transplant [SCT], and/or Radiation Therapy in Treating Young Patients With Extraocular Retinoblastoma): Patients with metastatic or recurrent retinoblastoma that is beyond the globe are eligible for treatment with combined conventional chemotherapy, high-dose chemotherapy, and SCT with conventional radiation.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with extraocular retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

1. Antoneli CB, Ribeiro KB, Rodriguez-Galindo C, et al.: The addition of ifosfamide/etoposide to cisplatin/teniposide improves the survival of children with retinoblastoma and orbital involvement. J Pediatr Hematol Oncol 29 (10): 700-4, 2007.  [PUBMED Abstract]
   
   
2. Aerts I, Sastre-Garau X, Savignoni A, et al.: Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol 31 (11): 1458-63, 2013.  [PUBMED Abstract]
   
   
3. Radhakrishnan V, Kashyap S, Pushker N, et al.: Outcome, pathologic findings, and compliance in orbital retinoblastoma (International Retinoblastoma Staging System stage III) treated with neoadjuvant chemotherapy: a prospective study. Ophthalmology 119 (7): 1470-7, 2012.  [PUBMED Abstract]
   
   
4. Dunkel IJ, Chan HS, Jubran R, et al.: High-dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma. Pediatr Blood Cancer 55 (1): 149-52, 2010.  [PUBMED Abstract]
   
   
5. Dunkel IJ, Jubran RF, Gururangan S, et al.: Trilateral retinoblastoma: potentially curable with intensive chemotherapy. Pediatr Blood Cancer 54 (3): 384-7, 2010.  [PUBMED Abstract]
   
   
6. Kivelä T: Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17 (6): 1829-37, 1999.  [PUBMED Abstract]
   
   
7. Namouni F, Doz F, Tanguy ML, et al.: High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer 33 (14): 2368-75, 1997.  [PUBMED Abstract]
   
   
8. Kremens B, Wieland R, Reinhard H, et al.: High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 31 (4): 281-4, 2003.  [PUBMED Abstract]
   
   
9. Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003.  [PUBMED Abstract]
   
   
10. Dunkel IJ, Aledo A, Kernan NA, et al.: Successful treatment of metastatic retinoblastoma. Cancer 89 (10): 2117-21, 2000.  [PUBMED Abstract]
    
    
11. Matsubara H, Makimoto A, Higa T, et al.: A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant 35 (8): 763-6, 2005.  [PUBMED Abstract]
    
    
12. Jubran RF, Erdreich-Epstein A, Butturini A, et al.: Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience. J Pediatr Hematol Oncol 26 (1): 31-4, 2004.  [PUBMED Abstract]
    
    
13. Palma J, Sasso DF, Dufort G, et al.: Successful treatment of metastatic retinoblastoma with high-dose chemotherapy and autologous stem cell rescue in South America. Bone Marrow Transplant 47 (4): 522-7, 2012.  [PUBMED Abstract]
    
    
14. Dunkel IJ, Khakoo Y, Kernan NA, et al.: Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer 55 (1): 55-9, 2010.  [PUBMED Abstract]
    
    
15. Rootman J, Hofbauer J, Ellsworth RM, et al.: Invasion of the optic nerve by retinoblastoma: a clinicopathological study. Can J Ophthalmol 11 (2): 106-14, 1976.  [PUBMED Abstract]
    
    
16. Armenian SH, Panigrahy A, Murphree AL, et al.: Management of retinoblastoma with proximal optic nerve enhancement on MRI at diagnosis. Pediatr Blood Cancer 51 (4): 479-84, 2008.  [PUBMED Abstract]