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© 2000 American Society for Clinical Oncology First-Line Chemotherapy With Local Treatment Can Prevent External-Beam Irradiation and Enucleation in Low-Stage Intraocular RetinoblastomaFrom the Pediatric Department, Hematology-Oncology Unit, and Department of Radiooncology, Centre Hospitalier Universitaire Vaudois, and Jules Gonin Eye Hospital, Lausanne, Switzerland. Address reprint requests to Maja Nenadov Beck, MD, Pediatric Department, Hematology-Oncology Unit, University Hospital CHUV, 1011 Lausanne, Switzerland; email mnenadov{at}hola.hospvd.ch
PURPOSE: To evaluate the efficacy of first-line chemotherapy (CT) in preventing external-beam radiotherapy (EBR) and/or enucleation in patients with retinoblastoma (Rbl). PATIENTS AND METHODS: Twenty-four patients with newly diagnosed unilateral or bilateral Rbl received CT associated with local treatment (LT). Two to five courses of etoposide and carboplatin were administered at 3- to 4-week intervals, depending on tumor response, and were completed each time by LT. RESULTS: Tumor response was observed in all eyes. Twenty-one of 24 patients showed a complete response (CR) that persisted at a median follow-up (FU) of 31 months (range, 4 to 41 months). Among the three patients who relapsed, two were lost to FU and one died of progressive disease. CR was achieved by CT and LT alone in 15 (71.4%) of 21 patients with less advanced disease (groups I to III). Six other patients with advanced disease (groups IV and V) experienced treatment failure and needed salvage treatment by EBR and/or enucleation. The difference between the two patient groups with regard to disease stage was statistically significant (P < .0001). EBR could be avoided in 13 (68.4%) of 19 patients, who presented with groups I to III (15 eyes) and group V (one eye) disease, whereas enucleation could be avoided in only two (40%) of five. CONCLUSION: CT combined with intensive LT is effective in patients with groups I to III Rbl, permitting the avoidance of EBR in the majority of these young children and, thus, reducing the risk of long-term sequelae. This is in contrast with the disappointing results for patients with groups IV and V Rbl, in whom EBR and/or enucleation was needed.
RETINOBLASTOMA (Rbl) has become one of the most highly curable pediatric solid tumors. With a combination of enucleation and external-beam radiation (EBR), plaque radiotherapy, laser photocoagulation, and cryotherapy, an overall survival rate of 90% to 95% can be achieved.1,2 These results, however, are dimmed by long-term morbidity related, especially, to EBR, such as radiation-induced chronic dry eye, retinopathy, optic neuropathy, cataract, and midfacial dysmorphism secondary to poor orbital development.3,4 Furthermore, there is evidence of a 30% cumulative risk of mortality that results from a second cancer by 40 years of age in children with bilateral Rbl treated with EBR.5 Tumor reduction by first-line chemotherapy (CT) followed by local measures, such as surgery, is a frequently used concept in pediatric oncology in chemosensitive tumors, for instance, in neuroblastoma, bone, and soft tissue sarcomas. Effectiveness of CT in Rbl was first demonstrated in extraocular6-9 and metastatic disease.10 Recently, this also has been strongly suggested for intraocular Rbl in studies performed by different groups,11-16 which thus opens new ways to a more conservative approach with the aim to avoid EBR and/or enucleation in patients (pts) for whom this would have been the ordinary treatment. Mainly, two chemotherapeutic drugs, etoposide and carboplatin, which are usually used in other neuroectodermal tumors, were chosen for their proven efficacy and passage through the brain-blood barrier.17,18 Based on this evidence, we changed our treatment policy in May 1995. We report here on our preliminary results.
Newly diagnosed pts with unilateral or bilateral Rbl first underwent an ophthalmologic examination under general anesthesia for confirmation of the diagnosis and precise staging according to the Reese-Ellsworth classification.19 All disease groups were considered for CT if they had no absolute indication for enucleation and if they would have otherwise required EBR according to published criteria.1,2,20 Pts were excluded whose tumors were accessible to local treatment (LT) solely, such as cryotherapy, photocoagulation, plaque radiotherapy, and thermochemotherapy (TCT). The risks and benefits of the chemoreduction protocol was explained to the families, and informed consent was obtained. The work-up before CT consisted of an orbital and cerebral computed tomography scan, a lumbar puncture for those pts with possible optic nerve involvement, a hearing control by auditive evoked potentials, and a complete blood cell count and blood chemistry assessment, including renal and hepatic function parameters. CT was given every 3 weeks or at an absolute neutrophil count of  1,000 x 106/L and thrombocyte count of 100 x 109/L after the nadir as follows: etoposide 150 mg/m2/d diluted in 125 to 250 mL of NaCl 0.9% intravenously over 1 hour on days 1 to 3 and carboplatin 200 mg/m2/d diluted in 125 to 250 mL of glucose 5% intravenously over 1 hour on days 1 to 3. In children younger than 1 year or weighing less than 10 kg, the doses were adapted to weight (5 mg/kg for etoposide and 6.7 mg/kg for carboplatin). CT was started within 24 to 48 hours after the ophthalmologic examination to take advantage of the local cryotherapy (two separate single-freeze procedures) performed by the ophthalmologist to improve drug penetration into the vitreous and/or subretinal fluid.21 A minimum of two and a maximum of five CT courses were given depending on tumor response, which was evaluated before each new course by the ophthalmologist. During this control, LT was applied according to the concept of sequential intensive LT for the treatment of every suspicious lesion that was not flat or calcified.13,14 Tumor response was determined as follows: complete response (CR) was defined as complete tumor regression or absence of residual tumor activity, and treatment failure (TF) was defined as local relapse that required a change of treatment strategy. CT was stopped either when only LT could be applied or in the case of TF. All pts were observed during the whole treatment period by only two ophthalmologists, who specialized in Rbl at our center. LT consisted mostly of cryotherapy, argon and xenon photocoagulation, and ruthenium disc. For small residual tumors at the posterior pole in some pts, TCT was chosen, with administration of a single dose of carboplatin (540 mg/m2 or 18 mg/kg) at day 1 followed by transpupillary diode-laser heat application within 1 to 2 hours and second heat application to the tumor on day 7.2 Salvage treatment for pts who failed CT consisted of enucleation and/or EBR. The latter was given at our center by 6-MV linac x-ray at doses between 45 to 50.4 Gy and 1.8 to 2 Gy per fraction. Between May 1995 and May 1998, 33 of 66 pts with Rbl were treated with CT. Nine pts were not included in the study because they either refused any kind of treatment (one pt) or received CT for other reasons, including the following: infiltration of the lamina cribrosa, anterior chamber, or choroidea in the enucleated eye (three pts); meningeal relapse (one pt); TCT only (one pt); TCT before CT (one pt); CT for local relapse in an only and irradiated eye (one pt); and interruption of first-line CT on the parents’ demand after discovery of an important chromosomal abnormality associated with mental retardation in the child (one pt). Among the 24 pts in whom first-line CT was indicated, there were 10 boys and 14 girls, with a median age at diagnosis of 7.5 months (range, 2 to 43 months). Ten pts were living in Switzerland, and 14 came from abroad for treatment. In 19 pts, first-line CT was given with the intention to avoid EBR and, in five, to avoid primary enucleation. Eighteen pts presented with bilateral and six with unilateral disease, for a total of 42 eyes. Of these 42 eyes, eight were enucleated immediately and one after three courses of CT given for the contralateral eye. The stage distribution in the remaining 33 eyes treated with first-line CT was as follows: five were in group Va, nine in group Vb, one in group IVa, two in group IIIa, one in group IIIb, three in group IIa, seven in group IIb, and five in group Ib.
Statistics
The population under study consisted of 24 pts (33 eyes). The pt characteristics and their outcomes are outlined in Table 1. A mean ± SD of 3.1 ± 1.3 courses of first-line CT were administered. Tumor response was observed in all eyes (Fig 1A and B). Twenty-one of 24 pts showed a CR, which was achieved by CT and LT alone in 15 (71.4%) of 21 pts. These 15 pts showed the following group distribution: one eye was in Va, one in Vb, one in IIIa, one in IIIb, three in IIa, seven in IIb, and five in Ib. Six other pts relapsed (one eye in group III, one in group IV, and eight in group V) but achieved a CR with salvage treatment that consisted of enucleation (two pts) and EBR (three pts). The sixth pt with unilateral Vb disease underwent enucleation after successful CT and TCT on the parents’ demand, despite local control of the tumor, and cannot be considered, therefore, as having undergone real salvage treatment. Three of 24 pts, all of whom were in group V, failed first-line CT and relapsed intraocularly: one relapsed in her only group Va eye 8 months after CT and local ruthenium plaque radiotherapy. After enucleation, the histopathologic examination showed an invasion of the choroid and the ciliary body, but the pt was then lost to follow-up (FU) for further treatment. Another pt who underwent enucleation on one side relapsed 8 months after CT in his remaining group Vb eye but was then lost to FU. The third pt with bilateral Vb disease progressed after two courses of initial CT and died of metastatic spread despite bilateral EBR, ruthenium plaque radiotherapy, and, ultimately, bilateral enucleation. The median FU for the whole group since the end of treatment was 31 months (range, 4 to 41 months) and for the eyes that underwent salvage treatment 17 months (range, 4 to 28 months).
EBR was indicated in 19 pts at diagnosis. It could be avoided in 15, but two of 15 relapsed, one of whom underwent enucleation secondarily (the other of the two was lost to FU). This means that primary EBR was successfully avoided in 13 (68.4%) of 19 pts by first-line CT. The 16 eyes in these 13 pts were in groups Ib (n = 3), IIa (n = 4), IIb (n = 7), IIIa (n = 1), and Va (n = 1). Among the six pts with TF were the three who relapsed for whom salvage treatment was unsuccessful and three others who underwent successful salvage treatment by EBR. They had six eyes to be treated, which were classified in the following disease groups: Vb (n = 2), Va (n = 3), and IVa (n = 1). Enucleation was indicated in five pts. Two of five had to undergo enucleation for relapse that occurred at the end of two courses of CT in one pt and 5 months after CT in the other; both had group Vb disease. A third pt with a unilateral group Vb disease was the one who underwent enucleation after four courses of CT and two courses of TCT despite an excellent response, on the parents’ demand. Of the two pts in whom enucleation could be avoided, one had an eye with group IIIb disease and one had an eye with group Vb disease. TCT as LT was applied in six pts, five of whom achieved CR without enucleation or EBR and one of whom was the one who underwent enucleation on the parents’ demand. Collectively, they received one course of TCT after one course of first-line CT (two pts), one course of TCT after three of CT (one pt), two courses of TCT after four of CT (one pt), and three courses of TCT after two of CT (two pts). There was no additive intraocular toxicity observed at a median FU of 26 months (range, 10 to 41 months) after the end of treatment. Treatment toxicity was essentially hematologic, with grades 1 to 3 neutropenia and thrombocytopenia in most pts. There were no hearing abnormalities or renal function disturbances found. When pt groups 1 and 2 are compared (Table 1), it is found that none of 18 eyes with groups I to III disease needed salvage treatment by EBR and/or enucleation, whereas it was necessary in 13 of 15 eyes with groups IV and V disease. This difference was statistically significant (P < .0001).
A major concern in children cured of cancer is their long-term morbidity. In pts with Rbl, it can be associated with functional and cosmetic deformities3,4 or radiation-induced second cancers.5 Pts who carry a germline RB1 mutation are at higher risk of developing a variety of second primary cancers.5 It has been shown that EBR that is frequently used to treat especially bilateral Rbl can increase that risk significantly.22 This risk is even more important in children who undergo irradiation when younger than 1 year, as recently reported.23 Furthermore, in diseases that carry a good long-term prognosis, preservation of the globe or vision becomes a new priority and an argument for more conservative therapeutic procedures.12,24 Many groups have been working in the last years on developing chemotherapeutic strategies for pts with Rbl to avoid EBR and/or enucleation. Drugs known as being effective in other neuroectodermal pediatric tumors such as neuroblastoma17,18 have also shown efficacy in advanced stages of Rbl such as extraocular6-9 and metastatic disease.10 Its application in intraocular Rbl has also been encouraging,11,13-16 although many issues remain to be resolved, regarding the drug combination, duration of CT, TF related to drug resistance, and treatment of advanced diseases. Although efficient in reducing tumor volume, CT alone cannot cure Rbl13,16 and needs to be associated with intensive LT, such as cryotherapy,25 laser photocoagulation,26 plaque radiotherapy,27 and TCT,2 that is applied to the tumors every 3 to 4 weeks. This strategy has been adopted by most of the national groups13,14-16,28 that treat pts with Rbl and was introduced at our center in May 1995. Because more than one half of the pts usually come from abroad, special care was given to ensure further FU before starting treatment. Despite these measures, two pts with relapsing disease were lost to FU. The aim of our study was to explore the possibility of avoiding EBR and/or enucleation by a two-drug CT regimen combined with LT. We did not evaluate, therefore, the percentage of tumor reduction after each CT course but defined as an end point for stopping CT the possibility to treat the remaining tumor by LT only. Tumor response was assessed by two ophthalmologists according to the international criteria.2 All tumors, independently of their disease groups, showed response to CT, an observation also made by other groups.12-16 Twenty-one of 24 pts showed a CR, including the six pts who underwent salvage treatment after initial CT, and remained without signs of active disease a median of 31 months (range, 4 to 41 months) after the end of treatment. Further FU is certainly necessary to confirm this result. Of the three pts who experienced treatment failure, two were lost to FU, one without salvage treatment, which biases the definite evaluation of the result. The third pt progressed under treatment and died of metastatic disease. Cytogenetic analysis revealed an interstitial deletion of the long arm of chromosome 13 associated with a psychomotor retardation. Her bilateral group Vb tumors demonstrated an extreme resistance to treatment with only a short time effect for each treatment modality since the beginning. This may be a result of a diagnostic delay of several months before referring the pt. Our experience must be considered as a warning not to postpone enucleation for too long in group Vb disease, as has been suggested by other authors.15 In 71.4% of pts, EBR or enucleation could be avoided by CT and LT at a median FU of 31 months, which is comparable to the 71% observed by Shields et al11 at, however, a shorter mean FU time of 6 months. In a study conducted by Kingston et al,12 a 70% globe preservation rate was obtained in a group of 14 pts with group Vb disease and a median FU of 60 months, but all were irradiated. A lower success rate was described by Murphree et al13 with CT and LT alone applied in 35 eyes, with more than one half of them having group Vb disease. Only four of 18 eyes with group Vb disease achieved CR without any salvage treatment. We found a similar unsatisfactory result in group V disease, with only two of 15 eyes with group V disease being able to escape salvage treatment. Promising results were presented by Gallie et al,14 with a relapse-free rate of 91% in new pts at a median FU of 2.5 years and of 70% in relapsed pts by CT and LT alone and adjunction of cyclosporine. Of 26 eyes with group V disease, 14 underwent enucleation and 12 received first-line CT with salvage treatment by enucleation and/or EBR in two pts. All 15 eyes in groups I to III and one in group IV responded completely to CT and LT alone. Among the relapsed eyes in group V, eight underwent enucleation and six received CT with cyclosporine, two of which had to undergo salvage treatment with enucleation. The remaining eyes with groups I to III disease pretreated with CT achieved CR, whereas one eye with group IV disease received EBR for TF after CT and cyclosporine. These encouraging results need to be confirmed on a larger scale, because the number of eyes with group V disease treated by CT and LT alone is small compared with the number of conventionally treated eyes. Comparing pts with indication for EBR with those with indication for enucleation, there were more in the former group that were successfully treated with CT and LT than in the latter. In 68.4% of pts, EBR could be avoided. This is satisfactory considering that it concerned a population of children who, with a median age of 6 months (range, 2 to 18 months) at diagnosis, were particularly susceptible to long-term effects of EBR.23 With the exception of one eye in the Va group and one in the Vb group, all eyes had groups I to III disease. This corroborates the observation of Murphree et al13 that eyes in group Vb have almost no chance of avoiding a secondary treatment such as EBR or enucleation, which is, however, in contradiction with the data of Gallie et al.14 Looking at the relapse pattern in the eyes in groups Va and Vb that failed CT and LT in our study, they all had at diagnosis either massive vitreous seeding or complete retinal detachment. They usually relapsed with diffuse vitreous or subretinal seeding, even when the vitreous seeding initially disappeared under first-line CT or presented with multiple retinal seeds at the edges of the area of detached retina. In one pt with a unilateral Vb disease with moderate vitreous seeding but tumor-free macula and optic nerve, we observed during CT a fragmentation of the tumor with massive secondary vitreous expansion managed by secondary enucleation. Pts who had vitreous seeding at diagnosis did not necessarily relapse in the vitreous again. As far as globe preservation is concerned, new prosthetic techniques have improved cosmetic results and allow a better adaptation to growth and orbital development. Families, however, with better knowledge of the results that are obtained by CT and that, in the era of body-sparing techniques, are applied in many oncologic fields are more concerned about the necessity of enucleation. In our study, two of five pts with indication to enucleation escaped surgery, but the sample size was small and not representative. A recent analysis performed by Shields et al16 showed that the use of CT in group V disease reduced the number of cases to be enucleated, which, thus, resulted in a 78% globe preservation when CT was combined with LT and/or EBR, whereas the EBR rate remained unchanged. The globe preservation rate was worse when vitreous or subretinal seeds recurred (56%), which was usually the case when they were present at diagnosis. This group of pts might need longer CT, as also suggested by Murphree et al.13 Our sample size was too small to draw definite conclusions.
One concern about prolonged CT with topoisomerase II inhibitors such as etoposide is the risk of secondary leukemia.29 A recent report from the secondary leukemia monitoring plan of the Cancer Therapy Evaluation Program of the National Cancer Institute30 suggests that a cumulative dose of In conclusion, our results confirm the reported sensitivity of Rbl to first-line CT associated with intensive LT. This strategy can be considered as treatment of choice for pts with groups I to III tumors not accessible to primary LT. It will allow the majority of these young children to avoid EBR and will reduce considerably the risk of long-term effects. There is no satisfactory treatment available for group V disease, which is responsible for most of the TFs. There are probably subgroups, such as those with vitreous and subretinal seeds, that need a different approach than that used with the large retinal tumors. This issue will be addressed in a forthcoming international multicenter trial.
We thank Dr U. Caflisch, Dr P. Wacker, Dr K. Leibundgut, Dr T. Kühne, Dr P. Meyer, and Dr F. Niggli from the Pediatric Departments of Lucern, Geneva, Bern, Basel, and Zurich for having participated in the treatment of some of the patients.
1. Höpping W: The new Essen prognosis classification for conservative sight saving treatment of retinoblastoma, in Lommatzsch PK, Blodi FC (eds): Intraocular Tumors: International Symposium Under the Auspices of the European Ophthalmological Society. Berlin, West Germany,Springer-Verlag, 1983, pp 497-505 2. Murphree AL, Munier FL: Retinoblastoma, in Ryan SJ, Odgen TE, Schacat AP, et al (eds): Retina (ed 2). St Louis, MO,Mosby, 1994, pp 571-626 3. Imhof SM, Mourits MP, Hofman P, et al: Quantification of orbital and midfacial growth retardation after megavoltage external beam irradiation in children with retinoblastoma. Ophthalmology 103:263-268, 1993[Medline]
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Diamandidou E, Buzdar AU, Smith TL, et al: Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 14:2722-2730, 1996 32. Scaradavou A, Heller G, Sklar CA, et al: Second malignant neoplasms in long-term survivors of childhood rhabdomyosarcoma. Cancer 76:1860-1867, 1995[Medline] Submitted November 29, 1999; accepted March 31, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 g/m2 given on a daily schedule for 5 consecutive days does not significantly increase the risk of secondary leukemia above that contributed by other agents. The estimated risk at moderate cumulative doses of 
