Trilateral retinoblastoma (TRB) occurs in 3% of patients with unilateral or bilateral germline retinoblastoma.1 This midline malignant neuroectodermal tumor arises commonly in the pineal gland (77%-83% of patients) and less frequently in the parasellar region (17%-23% of patients).2,3
Trilateral retinoblastoma is difficult to treat and usually fatal.3 Complete resection is seldom possible for tumors in the pineal or parasellar locations.4 Craniospinal irradiation is too damaging to the growth, intellectual, cognitive, and endocrine functions, particularly for children younger than 3 years of age.5- 7 Chemotherapy alone rarely cures young children with other intracranial neuroectodermal tumors, such as medulloblastoma.8 Trilateral retinoblastoma often presents with dissemination in the cerebrospinal fluid (CSF) (leptomeningeal TRB or neoplastic meningitis) and is extremely difficult to cure because most intrathecal drugs are ineffective for solid-tumor CSF metastases.9
We designed a multifaceted chemotherapy regimen for TRB. For induction, we used our Toronto Protocol, which consists of high-dose cyclosporine A (CSA), an inhibitor of the multidrug resistance P-glycoprotein (p170), to modulate a high dose of carboplatin, etoposide, and vincristine sulfate (hereafter referred to as CEV), which is described in Chan et al10 for treatment of children with intraocular retinoblastoma. Intraventricular topotecan hydrochloride11 combined with cytarabine12 was given via an Ommaya reservoir, and this method of treatment was previously shown to be effective for treating CSF metastases.13 To avoid craniospinal irradiation, we used supralethal-dose chemotherapy as consolidation therapy, with rescue of the bone marrow by autologous peripheral stem cell transplant. To the best of our knowledge, this multifaceted treatment regimen led to tumor response and to survival beyond that ever reported for a patient with leptomeningeal TRB in any study.4 The significant extension of survival among the patients reported suggests that this protocol may in some instances offer the potential for cure for leptomeningeal TRB.
This study reports all cases of TRB from 2000 to 2008 treated at The Hospital for Sick Children (Toronto, Ontario, Canada). All patients were treated during a prospective clinical trial that was approved by The Hospital for Sick Children research ethics board and that conforms to the principles of the Declaration of Helsinki.
A 4-month-old girl had hypothalamic overgrowth syndrome and central blindness from a large suprasellar tumor observed on computed tomographic (CT) and magnetic resonance imaging (MRI) scans (Figure, A). Her bilateral retinal tumors were initially diagnosed as astrocytic hamartoma.14 Craniopharyngioma or germ cell tumor was suspected, but CSF α-fetoprotein and β-human chorionic gonadotropin levels were normal. Needle biopsy of the suprasellar region showed necrotic tumor, but open biopsy confirmed the diagnosis of TRB, with bilateral group B (T1b) eyes, staged according to the International Intraocular Retinoblastoma Classification (IIRC).15 Postoperative CSF sample was positive for tumor cells (M1e on TMN staging),16 but samples obtained prior to and during the needle biopsy were negative. There were no bone marrow or bone metastases. Her germline RB1 mutation was a deletion (g.59444 del196) affecting splicing of exon 8.
Radiological imaging of cases 1, 2, and 3. Case 1 shows a postgadolinium axial T1-weighted magnetic resonance imaging (MRI) scan of a suprasellar tumor at diagnosis (A) (arrow indicates tumor at back of eye) and an axial MRI scan of the same suprasellar tumor before transplant (B). Case 2 shows a postgadolinium axial spectral presaturation with inversion recovery T1-weighted MRI scan of a suprasellar tumor at diagnosis (C) and a postgadolinium axial MRI scan of the same suprasellar tumor before transplant (D). Case 3 shows an axial MRI scan of a suprasellar tumor at diagnosis (E) and an axial MRI scan of the same suprasellar tumor before transplant (F).
She responded to 6-cycle systemic CEV-CSA and to intraventricular cytarabine-topotecan given via an Ommaya reservoir,14 with clearing of the CSF metastases, shrinkage of the suprasellar (Figure, B) and retinal tumors, and restoration of vision. She received a supralethal dosage of carboplatin, etoposide, and cyclophosphamide as consolidation with autologous peripheral stem cells for bone marrow rescue. However, 19 months after diagnosis and 11 months after transplant, the tumor recurred along the needle biopsy track, and she died 32 months after the diagnosis was given.
Autopsy revealed multiple subdural and subarachnoid nodular growths and widespread leptomeningeal and ventricular metastases, especially around the needle biopsy tract (data not shown). The suprasellar mass was calcified and nonviable. The eyes showed calcified tumor and retinal scarring, with one tiny focus of viable tumor in the right eye.
A 6-month-old boy presented with leukocoria of the left eye, which was classified as IIRC group D (T3a) and enucleated. Two months later, he developed central blindness, and a large suprasellar tumor was found on CT and MRI scans (Figure, C); a small tumor in the right eye was classified as IIRC group A (T1a). He had CSF metastases (M1e stage) but no bone marrow or bone metastases. To avoid risk of tumor dissemination as observed in case 1, the suprasellar tumor was not biopsied. His germline RB1 mutation was a 1–base pair deletion (c.1951delT) in exon 19 causing a premature stop codon and nonfunctional pRB protein.
He responded to 6-cycle systemic CEV-CSA and to intraventricular cytarabine-topotecan,14 with clearing of the CSF metastases, shrinkage of the suprasellar (Figure, D) and retinal tumors, and restoration of vision. He received the autologous peripheral stem cell transplant regimen described for case 1 as consolidation. He remains in remission 3.4 years after diagnosis and 3 years after transplant.
A 9-week-old girl presented with central blindness and diabetes insipidus. Computed tomographic and MRI scans revealed a large suprasellar tumor and hydrocephalus (Figure, E). She had a large macular tumor with impending vitreous seeding in the left eye, classified as IIRC group B (T1b). She had CSF metastases (M1e stage) but no bone marrow or bone metastases. Biopsy of the suprasellar tumor was not performed. Her germline RB1 mutation was a substitution in the intron 17 splice acceptor site (c.1696−2A>G), causing mis-splicing of exon 18.
She responded to 6-cycle systemic CEV-CSA and to intraventricular cytarabine-topotecan,14 with clearing of CSF metastases, shrinkage of the suprasellar (Figure, F) and retinal tumors, and restoration of some vision. She received the autologous peripheral stem cell transplant regimen described for case 1 as consolidation. However, 10 months after diagnosis and 5 months after transplant, the suprasellar tumor recurred, and she died 14 months after diagnosis.
Our multifaceted chemotherapy regimen, which combines systemic CEV-CSA chemotherapy and intraventricular topotecan-cytarabine for induction and supralethal-dosage chemotherapy consolidation with autologous peripheral stem cell bone marrow rescue, offers hope of a cure for leptomeningeal TRB. In a 1977-1997 retrospective study of 94 patients with TRB, the overall median duration of survival from TRB was 1 month without treatment and 8 months with treatment.3 More recently, a 1997-2005 retrospective study of 7 patients with localized TRB (1 suprasellar and 6 pineal) and 6 patients with leptomeningeal TRB (1 suprasellar and 5 pineal) reported an overall median duration of survival of 19 months (range, 3-104 months).4 However, of the 6 patients with leptomeningeal TRB, 2 received radiation therapy (no survivors) and 1 received radioimmunotherapy (the only survivor), with a median duration of survival of 15 months (range, 5-36 months).4 The sole survivor of leptomeningeal TRB had a pineal primary tumor and remained relapse free at 36 months after induction chemotherapy, supralethal chemotherapy/stem cell transplant, intrathecal chemotherapy, and radioimmunotherapy.4 In contrast, our multifaceted chemotherapeutic approach avoided both radiation therapy and surgery in 3 patients with leptomeningeal TRB with suprasellar tumors, with 1 remaining relapse free for 3.4 years after diagnosis and the remaining 2 surviving for 14 and 32 months, respectively.
A possible advantage of our chemotherapy regime that may have contributed to the prolonged survival of patients with TRB may have been the addition of CSA, which not only reverses multidrug resistance in retinoblastoma tumor cells but also inhibits the p170-rich vascular endothelial cells that form the blood-brain barrier limiting the entry of chemotherapeutic drugs into the central nervous system.12,17 Toxicity has always been the dose-limiting factor for multidrug-resistance–reversal chemotherapy.18 Published studies have used 5- to 7-day continuous CSA infusions to reverse tumor-cell p170, but prolonged exposure to CSA also circumvents normal-cell p170. This leads to increased toxicity to p170-expressing bone marrow, liver, kidney, gut, and other tissues and delays liver and renal excretion and metabolism of chemotherapy, thereby further increasing drug exposure to normal tissues.18 We have shown that 3-hour high-dose CSA infusions avoid enhancement of high-dose CEV toxicity (so our patients tolerate chemotherapy well) and are efficacious in modulating retinoblastoma chemotherapy.17
Cytarabine, a pyrimidine antimetabolite antileukemic agent, generally has little anti–solid tumor activity but is not a substrate of p170 and can kill retinoblastoma cell lines in vitro.12 Used together with topotecan (a topoisomerase I inhibitor),11 which is less susceptible to multidrug resistance, we have successfully cleared CSF metastases,13 the most difficult type of retinoblastoma metastases to cure.
High-dose craniospinal radiation therapy is not an option for young children because it causes devastating long-term neuropsychological effects (cognitive and learning problems)7,19 and hormonal complications (growth, thyroid, corticosteroid, and sex hormone deficiencies).6,19 Radiation therapy greatly increases the lifelong risk of secondary malignant neoplasms (glioblastoma multiforme, malignant astrocytoma, meningioma, bone and soft-tissue sarcoma, and malignant melanoma) in children with TRB who are already predisposed to secondary cancers owing to their germline RB1 mutations.20
Treatment of TRB using the Toronto Protocol and intrathecal topotecan combined with cytarabine, followed by consolidation with autologous peripheral stem cell transplant after supralethal chemotherapy avoids the need for radiation therapy and, in some instances, extends survival.
Financial Disclosure: None reported.
Correspondence: Dr Chan, Division of Hematology and Oncology, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (email@example.com).
Funding/Support: This study was supported in part by grants to Dr Chan from The Ontario Institute for Cancer Research and to Dr Gallie from the Canadian Retinoblastoma Society and the Royal Arch Masons of Canada.
Dimaras H, Héon E, Doyle J, Strahlendorf C, Paton KE, Halliday W, Babyn P, Gallie BL, Chan HSL. Multifaceted Chemotherapy for Trilateral Retinoblastoma. Arch Ophthalmol. 2011;129(3):360-371. doi:10.1001/archophthalmol.2011.17