Intracameral Chemotherapy for Globe Salvage in Retinoblastoma with Secondary Anterior Chamber Invasion
Authors: Francis L. Munier, Alexandre Moulin, Marie-Claire Gaillard, Massimo Bongiovanni, Sarah Decembrini, Susan Houghton, Maja Beck-Popovic, Christina Stathopoulos
Journal: Ophthalmology (2017)

The presence of anterior chamber seeding (ACS), whether primary (1%) or secondary, is commonly treated by enucleation. Considering the new frontiers of conservative management of very advanced retinoblastoma, the reported incidence of secondary ACS leading to conservative failure has progressed from 6% after chemoreduction to 67% after intra-arterial chemotherapy (IAC).1Pavlidou E. Burris C. Thaung C. et al.Anterior segment seeding in eyes with retinoblastoma failing to respond to intraophthalmic artery chemotherapy.JAMA Ophthalmol. 2015; 133: 1455-1458Crossref PubMed Scopus (14) Google Scholar Anterior chamber seeding is considered an intractable form of retinoblastoma regardless of the treatment used because of the hypoxic radio-resistant nature of the seeds and inability to reach tumoricidal concentrations in the aqueous using known routes of chemotherapy administration. Successful attempts to treat ACS were reported only recently and concerned patients with primary ACS in diffuse anterior retinoblastoma of retinal origin by intracameral chemotherapy (ICC)2Munier F.L. Gaillard M.C. Decembrini S. et al.Intracameral chemotherapy (melphalan) for aqueous seeding in retinoblastoma: bicameral injection technique and related toxicity in a pilot case study.Ocul Oncol Pathol. 2017; 3: 149-155Crossref PubMed Scopus (27) Google Scholar and of extra-retinal origin by brachytherapy.3Shields C.L. Lally S.E. Manjandavida F.P. et al.Diffuse anterior retinoblastoma with globe salvage and visual preservation in 3 consecutive cases.Ophthalmology. 2016; 123: 378-384Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar In this retrospective review approved by the ethical committee of Vaud, Switzerland (authorization no. 2016-00149), 12 consecutive patients with ACS treated with ICC were identified between November 2011 and October 2016. One case was excluded with primary ACS class III (pseudo-hypopion) resulting from anterior diffuse retinoblastoma published previously2Munier F.L. Gaillard M.C. Decembrini S. et al.Intracameral chemotherapy (melphalan) for aqueous seeding in retinoblastoma: bicameral injection technique and related toxicity in a pilot case study.Ocul Oncol Pathol. 2017; 3: 149-155Crossref PubMed Scopus (27) Google Scholar with an event-free follow-up of 5.5 years. The study population consisted of 11 eyes with secondary ACS from 11 heavily pretreated patients for whom advised enucleation was refused by the parents, including 10 patients with relapse referred from other centers. There were 4 eyes with unilateral and 7 eyes with bilateral retinoblastoma, of which 4 were remaining eyes after previous enucleation of the fellow eyes. The demographic characteristics and the treatment received before ICC, as well as ACS classification, relapses, and concomitant ultrasound biomicroscopy features, are shown in Table S1 (available at www.aaojournal.org). Anterior chamber seeding was classified as class I in 5 eyes, class II in 5 eyes, and class III in 1 eye (Fig 1A–F). According to the integrity of anterior hyaloid, 2 distinct mechanisms of tumor progression into the anterior segment could be distinguished: (1) transhyaloid infiltration into the posterior chamber secondary to vitreous seeds attached to the anterior hyaloid in 3 eyes (no peripheral primary or secondary retinal tumors) or to the anterior progression of a peripheral parietal tumor overlying the pars plana in 4 eyes (Fig 1G, I); and (2) invasion via a disrupted anterior hyaloid of iatrogenic origin, that is, pars plana vitrectomy (Fig 1K, L), and clear corneal intracapsular lensectomy in 2 eyes each. Anterior chamber seeding was isolated (9 eyes) or associated with an anterior uveal infiltration (2 eyes) as assessed by ultrasound biomicroscopy. Intracameral chemotherapy with melphalan was administered (concentration of 15 or 20 μg/ml, the lower concentration used initially and the higher concentration used in case of ACS relapse/persistence) as previously described.2Munier F.L. Gaillard M.C. Decembrini S. et al.Intracameral chemotherapy (melphalan) for aqueous seeding in retinoblastoma: bicameral injection technique and related toxicity in a pilot case study.Ocul Oncol Pathol. 2017; 3: 149-155Crossref PubMed Scopus (27) Google Scholar All but 3 eyes (vitrectomized with silicone oil or postintracapsular lensectomy, see Table S1, available at www.aaojournal.org) received concomitant intravitreal chemotherapy at least once via the pars plana with 20 to 30 μg of melphalan at a concentration of 200 μg/ml to treat the underlying vitreous disease or, if absent, to prevent cross-contamination between the aqueous and the vitreous. Tumor control was monitored clinically by slit-lamp examination as well as in the iterative aqueous taps by cytopathology and by cell culture when available.2Munier F.L. Gaillard M.C. Decembrini S. et al.Intracameral chemotherapy (melphalan) for aqueous seeding in retinoblastoma: bicameral injection technique and related toxicity in a pilot case study.Ocul Oncol Pathol. 2017; 3: 149-155Crossref PubMed Scopus (27) Google Scholar Intracameral chemotherapy was continued as long as the cytopathology or cell culture remained positive and at least 1 additional injection was given after a negative result. Complete aqueous seeding regression was initially obtained in all eyes after a mean of 0.7 months (range, 0.2–1.3) as assessed clinically and by negative cytopathology and cell culture, after a mean number of 4.3 injections (range, 2–7) with a mean dose of 6.3 μg (range, 2.9–15) per injection. Higher doses corresponded to a greater quantity of aqueous humor withdrawn in cases with disrupted hyaloid (mean 0.46 ml compared with 0.24 ml with the hyaloid intact), indirectly confirming disruption of the hyaloid. Anterior chamber seeding class I required notably less mean 3.2 injections compared with 5.2 injections in classes II and III. Treatment during or after ICC, ICC-related complications, globe preservation, functional results, and histopathology of the enucleated eyes are summarized in Table S2 (available at www.aaojournal.org). Eye preservation was achieved in only 25% (1/4) of cases with disrupted anterior hyaloid versus 71% (5/7) with intact anterior hyaloid, including all 4 remaining eyes after previous enucleation of the fellow eyes. The absence of anterior hyaloid in the former group of 4 eyes could have influenced negatively the outcome by 2 mechanisms: (1) by preventing the achievement of a tumoricidal concentration in the anterior segment through dilution of the ICC in the posterior segment or (2) by favoring or maintaining cross-contamination between the posterior and anterior segment. In the latter group of 7 eyes with apparently intact anterior hyaloid, 2 eyes (cases 5 and 10) underwent enucleation for progressive disease after a retention time of 2.8 and 1.0 months, respectively, after the first ICC. Failure in case 5 was likely related to the extreme aggressiveness of the N-myc amplification genotype, whereas in case 10, secondary enucleation was decided on the basis of disease progression in an eye devoid of visual potential and with an obscured optic disk. In total, enucleation was performed in 5 cases after a mean retention time of 8.8 months (range, 1.0–20.7). In 1 eye (case 5), histopathology revealed higher risk factors, supporting the indication for systemic adjuvant chemotherapy (Table S2, available at www.aaojournal.org) and remained event-free over a follow-up of 24 months. Patient number 1 received 2 courses of carboplatin-etoposide intravenous chemotherapy, considering that transconjunctival pars plana vitrectomy had been performed in the context of unsuspected diffuse infiltrating retinoblastoma before his referral. Conservative treatment was attempted given that visual function was preserved (20/30) with fovea and optic nerve intact. No adjuvant systemic chemotherapy was given to any of the other patients, considering that the prognostic value of aqueous seeding or anterior uveal invasion such as iris or corpus ciliaris involvement is no longer considered a high risk for metastasis.4Baroni L.V. Sampor C. Fandiño A. et al.Anterior segment invasion in retinoblastoma: is it a risk factor for extraocular relapse?.J Pediatr Hematol Oncol. 2014; 36: e509-e512Crossref PubMed Scopus (17) Google Scholar, 5Sreelakshmi K.V. Chandra A. Krishnakumar S. et al.Anterior chamber invasion in retinoblastoma: not an indication for adjuvant chemotherapy.Invest Ophthalmol Vis Sci. 2017; 58: 4654-4661Crossref PubMed Scopus (19) Google Scholar Salvaged eyes have a mean event-free follow-up of 17 months (range, 4–36). All patients are alive without metastasis at a mean follow-up of 24 months (range, 12–54). In conclusion, ICC concomitant with other treatments, offers an alternative to enucleation in selected cases of retinoblastoma with secondary ACS. Although these are encouraging results, further studies with longer follow-up are necessary to assess the safety and long-term efficacy of this new targeted modality. Download .docx (.02 MB) Help with docx files Table S1 Download .docx (.02 MB) Help with docx files Table S2