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Advanced unilateral retinoblastoma: a case of sparing enucleation treatment failure

      Over the last few years, intra-arterial chemotherapy (IAC) has become an effective alternative for treatment of intraocular retinoblastomas (RB), allowing improved globe salvage and reducing systemic chemotherapy toxicities.
      • Shields C.L.
      • Mashayekhi A.
      • Cater J.
      • Shelil A.
      • Meadows A.T.
      • Shields J.A.
      Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors.
      • Shields C.L.
      • Fulco E.M.
      • Arias J.D.
      • et al.
      Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy.
      • Muen W.J.
      • Kingston J.E.
      • Robertson F.
      • Brew S.
      • Sagoo M.S.
      • Reddy M.A.
      Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma.
      IAC may occult extraocular tumour cells and this risk represents the main criticism concerning its use.
      • Wilson M.W.
      • Haik B.G.
      • Dyer M.A.
      Superselective intraophthalmic artery chemotherapy: what we do not know.
      We report a case of a child with unilateral heavily pretreated RB who developed a relatively small intraocular recurrence with a massive postlaminar optic nerve invasion after IAC.
      A 30-month-old male was admitted for left eye (LE) leukocoria. The patient was examined under anaesthesia with clinical evaluation, indirect ophthalmoscopy, fundus photography, ultrasonography, and fluorescein angiography. The right eye was normal. A large tumour overhanging the optic disc and macula with diffuse vitreous seeding and moderate subretinal seeding was detected in LE and classified as group D (Fig. 1A), according to the International Intraocular Retinoblastoma Classification (IIRC).
      • Linn Murphree A.
      Intraocular retinoblastoma: the case for a new group classification.
      Magnetic resonance imaging (MRI) confirmed an LE intraocular tumour without extraocular involvement. Cerebrospinal fluid cytology was negative for tumour cells, and family history was also negative. Molecular analysis of RB1 using Next-Generation Sequencing and Multiple Ligation-dependent Probe Assay (MLPA) combined approach revealed nither point mutation nor intragenic rearrangement on blood sample.
      Figure thumbnail gr1
      Fig. 1Fundus appearance of the patient’s left eye before and after treatment. (A) Fundus photograph showing large tumour overhanging the optic disc and macula with multiple vitreous seeds and moderate subretinal seeds on presentation. (B) Fundus photograph after 6 monthly cycles of intravenous chemoreduction combined with focal treatments. The tumour and vitreous seeds regressed, showing partial response with residual viable vitreous and subretinal seeds. (C) Fundus photograph after 5 intravitreal melphalan injections and 3 sessions of intra-arterial chemotherapy (IAC) with melphalan, followed by 3 sessions of IAC with melphalan and topotecan. Tumour showed a calcified regression with vitreous and subretinal response. (D) Fundus photograph of the relapse occurred 1 month after IAC, with melphalan and topotecan showing viable tumour in papillary area.
      The patient underwent 4 cycles of etoposide (300 mg/m2) and carboplatin (560 mg/m2), and 2 carboplatin courses combined with focal treatments (chemothermotherapy and thermotherapy). Partial response at the main posterior pole mass with incomplete remission of vitreous seeding and subretinal fluid was achieved (Fig. 1B). MRI routinely performed after intravenous chemoreduction (IVC) and focal therapies confirmed the absence of tumour involvement in optic nerve, orbit, and brain. The patient received 5 intravitreal injections of melphalan (30 μg/0.1 mL dose) every 7 to 10 days and 3 IAC administrations of melphalan (4 mg) at monthly intervals, achieving a regression of both vitreous seeding and solid tumour. Four months later, a relapse with solid tumour at posterior pole was diagnosed and the patient received 3 further IAC treatments with melphalan (4 mg) and topotecan (1 mg), achieving complete tumour response (Fig. 1C).
      After 1 month, recurrent tumour localized in the papillary area was detected (Fig. 1D). MRI showed an enhancement area of 8 mm in length of the optic nerve behind the lamina cribrosa. Enucleation was performed with inclusion of the optic nerve stump as long as possible. Histopathological findings confirmed postlaminar optic nerve invasion involving the surgical cut end (Fig. 2A, B). According to the International Retinoblastoma Staging System,
      • Chantada G.
      • Doz F.
      • Antoneli C.B.
      • et al.
      A proposal for an international retinoblastoma staging system.
      the patient was classified to have stage II:N3,C0,S0 and received adjuvant chemotherapy with ifosfamide 9 g/m2, etoposide 450 mg/m2, and carboplatin 750 mg/m2 for 2 courses and 2 high-dose chemotherapy cycles based on thiotepa 900 mg/m2 followed by autologous peripheral hematopoietic stem cell rescue; local orbital radiotherapy was then performed. The patient is alive without evidence of disease 11 months from relapse.
      Figure thumbnail gr2
      Fig. 2Retinoblastoma of the left eye with postlaminar optic nerve invasion. (A) The histopathological specimen demonstrates postlaminar optic nerve invasion by retinoblastoma cells (haematoxylin–eosin, original magnification ×5). (B) The histopathological specimen showing invasion of the cut section of optic nerve (haematoxylin–eosin, original magnification ×5).
      For over a decade, IVC has been used as first-line treatment for retinoblastoma, improving ocular prognosis. Nevertheless, IVC systemic toxicities are well known as the limited efficacy in patients with advanced retinoblastoma and in cases of vitreous seeds recurrence.
      • Shields C.L.
      • Fulco E.M.
      • Arias J.D.
      • et al.
      Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy.
      IAC seems to be useful as primary treatment in both advanced and less advanced (groups C and D) disease, and it can also be indicated in cases of failure of standard treatments.
      • Shields C.L.
      • Fulco E.M.
      • Arias J.D.
      • et al.
      Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy.
      • Grigorovski N.
      • Lucena E.
      • Mattosinho C.
      • et al.
      Use of intra-arterial chemotherapy for retinoblastoma: results of a survey.
      Melphalan is the most widely used drug, even with its combination with other agents such as topotecan, mainly in cases of extensive vitreous seeding and advanced tumour stage and as secondary treatment in case of systemic chemotherapy failure.
      • Gobin Y.P.
      • Dunkel I.J.
      • Marr B.P.
      • Brodie S.E.
      • Abramson D.H.
      Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.
      Shields et al. reported that IAC as primary therapy achieved globe salvage in 100% of group C, 100% of group D, and 33% of group E RB, whereas, when employed as secondary treatment, globe salvage was achieved in 50% of cases.
      • Shields C.L.
      • Bianciotto C.G.
      • Jabbour P.
      • et al.
      Intra-arterial chemotherapy for retinoblastoma: report No. 1, Control of retinal tumors, subretinal seed, vitreous seeds.
      In case of advanced RB, the recent use of intravitreal chemotherapy combined with IAC can increase the rate of ocular salvage, providing control of vitreous seeding in up to 100% of cases.
      • Shields C.L.
      • Kaliki S.
      • Rojanaporn D.
      • Al-Dahmash S.
      • Bianciotto C.G.
      • Shields J.A.
      Intravenous and intra-arterial chemotherapy for retinoblastoma: what have we learned?.
      Despite excellent results in terms of globe salvage rate, IAC has some limitations. The low systemic drug exposure could potentially lead to inadequate control of micrometastases with an increased risk of dissemination.
      • Wilson M.W.
      • Haik B.G.
      • Dyer M.A.
      Superselective intraophthalmic artery chemotherapy: what we do not know.
      • Jabbour P.
      • Chalouhi N.
      • Tjoumakaris S.
      • et al.
      Pearls and pitfalls of intraarterial chemotherapy for retinoblastoma.
      Gobin et al. reported a 2.5% incidence of metastatic disease after IAC.
      • Gobin Y.P.
      • Dunkel I.J.
      • Marr B.P.
      • Brodie S.E.
      • Abramson D.H.
      Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.
      Eagle et al. analyzed 8 enucleated eyes after IAC and observed optic nerve invasion in 3 eyes, laminar invasion in 1 eye, and choroidal invasion in 1 eye.
      • Eagle Jr, R.C.
      • Shields C.L.
      • Bianciotto C.
      • Jabbour P.
      • Shields J.A.
      Histopathologic observations after intra-arterial chemotherapy for retinoblastoma.
      We report a case of advanced, unilateral RB with partial response after IVC, treated with intravitreous chemotherapy and IAC with excellent control of vitreous seeding. We decided to treat this advanced pretreated unilateral RB with IAC on the basis of reported results of up to 50% of globe salvage in refractory/relapse RB receiving secondary IAC.
      • Shields C.L.
      • Bianciotto C.G.
      • Jabbour P.
      • et al.
      Intra-arterial chemotherapy for retinoblastoma: report No. 1, Control of retinal tumors, subretinal seed, vitreous seeds.
      • Suzuki S.
      • Yamane T.
      • Mohri M.
      • Kaneko A.
      Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis.
      Finally, the patient showed a solid tumour recurrence after combined melphalan and topotecan IAC. The intraocular recurrence in papillary zone was not extensive but was associated with massive postlaminar optic nerve tumour involvement. The MRI, routinely performed during the follow-up, allowed us to detect the postlaminar optic nerve tumour growth, with the consequent decision to submit the patient to enucleation. It is conceivable that IAC drug concentration within the optic nerve should be lower than that in the retina and in the choroid, resulting in a less effective control of extraocular tumour cells.
      According to our experience, the enucleation-sparing strategy did not represent the best choice in unilateral and advanced/relapsed retinoblastoma as in this case. Reasonably, an early enucleation treatment would have been the optimal option avoiding systemic chemotherapy and its toxicities and reducing metastatic spread risk. Furthermore, as reported by Levin et al., chemotherapy strategy masks histopathologic features and promotes extraocular dissemination by resistant cells.
      • Levin M.H.
      • Gombos D.S.
      • O’Brien J.M.
      Intra-arterial chemotherapy for advanced retinoblastoma: is the time right for a prospective clinical trial?.
      On the basis of histopathologic findings, the patient received adjuvant systemic chemotherapy to reduce metastatic risk and increase survival chances. To avoid both tumour extent underestimation and surgery delay, we preferred to promptly perform enucleation without neoadjuvant chemotherapy. Moreover, in cases with postlaminar optic nerve involvement at MRI, enucleation, by means of a combined anterior (ophthalmological) and subfrontal (neurosurgical) approach, is recommended to minimize the risk of residual tumour at the surgical margin of the optic nerve.
      • Bellaton E.
      • Bertozzi A.I.
      • Behar C.
      • et al.
      Neoadjuvant chemotherapy for extensive unilateral retinoblastoma.
      According to our experience, in children with advanced and resistant unilateral RB, we suggest performing IAC with caution, always considering enucleation as the best strategy to prevent metastatic disease. A strict follow-up with MRI every 3 to 4 months during IAC treatment is then recommended for early detection of both local and metastatic spread.
      Advanced and refractory RB management still represents a challenge. IAC is an effective therapy in terms of tumour control and globe salvage rate. However, in patients with advanced or recurrent RB, IAC needs to be used cautiously for its possible lack of metastatic disease control.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

      Acknowledgement

      The authors would like to thank Prof. Franco Locatelli for critical review of the paper.

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