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© 2003 American Society for Clinical Oncology Treatment of Intraocular Retinoblastoma With Vincristine and Carboplatin
From the Departments of Hematology-Oncology, Surgery, Division of Ophthalmology, Radiation Oncology, Biostatistics, and Diagnostic Imaging, St. Jude Children’s Research Hospital; and Departments of Pediatrics, Ophthalmology, Radiation Oncology, and Radiology, University of Tennessee Health Science Center, Memphis, TN. Address reprint requests to Carlos Rodriguez-Galindo, MD, Department of Hematology-Oncology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105; email: Carlos.Rodriguez-Galindo{at}stjude.org.
Purpose: To evaluate the efficacy of chemoreduction using vincristine and carboplatin in preventing or delaying external-beam radiotherapy (EBRT) or enucleation in patients with intraocular retinoblastoma. Patients and Methods: Twenty-five patients (43 eyes) with newly diagnosed intraocular retinoblastoma received primary treatment with eight courses of vincristine and carboplatin. Focal treatments were delayed until documentation of disease progression. Outcome measures for each eye were length of time to disease progression, avoidance or delay of EBRT, and globe survival. Event-free survival was defined as the length of time to EBRT or enucleation. Results: Disease in all eyes responded to chemotherapy and progressed in only two patients before completion of the eight courses of therapy. Disease in all but four eyes progressed and required focal treatments. Event-free survival estimates at 2 years were 59.2% ± 12.0% for Reese-Ellsworth group I, II, and III eyes and 26.3% ± 9.2% for group IV and V eyes. Nineteen eyes (44.2%) required EBRT and 13 eyes (30.2%) were enucleated. The ocular salvage rate was 83.3% for Reese-Ellsworth group I to III eyes and 52.6% for group IV and V eyes. For those patients receiving EBRT, the median time from enrollment to EBRT was 9.5 months (median age at EBRT, 21 months). Conclusion: In combination with appropriate early intensive focal treatments, chemoreduction with vincristine and carboplatin, without etoposide, may be an alternative treatment for patients with early-stage intraocular retinoblastoma, although additional studies are needed. Patients with advanced intraocular disease require more aggressive treatments.
RETINOBLASTOMA IS the most common neoplasm of the eye in children and represents approximately 3% of all childhood malignancies. An estimated 200 to 300 children develop retinoblastoma annually in the United States.1 Because retinoblastoma occurs among the very young, therapy must be directed at vision preservation with minimal long-term effects as well as cure. In developed countries, the prognosis for patients with nonmetastatic unilateral intraocular retinoblastoma is usually excellent, with good functional results and minimal morbidity.2 Enucleation is the treatment of choice and is curative in more than 90% of cases, although patients with high-risk histologic features, including deep choroidal invasion or involvement of the anterior chamber, iris, ciliary body, or optic nerve, require adjuvant chemotherapy.3,4 A minority with extraocular disease require more intensive treatments, usually including high-dose chemotherapy and radiation therapy.5,6 Approximately 40% of children with retinoblastoma are born with a germ-line mutation of the RB1 gene7 and develop multiple, bilateral retinoblastomas at an earlier age. These children are at risk of developing new tumors until retinal differentiation ends and are at risk of developing extraocular tumors throughout their lives.8–10 The treatment for bilateral retinoblastoma has been enucleation of eyes with advanced intraocular disease and no visual potential, and external-beam irradiation of the remaining eyes. Irradiation of the orbit during a period of rapid growth results in a hypoplastic orbit that causes midfacial deformities11,12 and significantly increases the risk of development of sarcoma in the radiation field. This risk is apparently age related and decreases with delay of radiation.13 These concerns have led to more conservative approaches. Systemic chemotherapy for cytoreduction, coupled with intensive focal therapies, has increased salvage of eyes and decreased (and delayed) use of irradiation. Retinoblastoma is chemosensitive. Several agents, including vincristine, cyclophosphamide, doxorubicin, epipodophyllotoxins, and platinum-based products, have proven effective in treating patients with metastatic disease. Most studies of patients with intraocular disease have used a three-drug regimen comprising vincristine, etoposide, and carboplatin coupled with focal therapies early in the cytoreductive process. Because of concerns with the systemic toxicity of a three-drug regimen and, in particular, the risk associated with the use of etoposide, to further investigate the true efficacy of chemotherapy, we elected to examine the use of vincristine and carboplatin alone and delay focal treatments until tumor progression was documented.14
The RET-3 protocol, a single-arm, nonrandomized, prospective study approved by the Institutional Review Board of St. Jude Children’s Research Hospital (Memphis TN), was designed to evaluate the objective response of intraocular retinoblastoma to the combination of vincristine and carboplatin and to assess the success of this regimen in avoiding or delaying irradiation and/or enucleation. Patients received eight courses of chemotherapy every 3 weeks; focal treatments were administered only after documented disease progression. Patients with newly diagnosed, untreated intraocular retinoblastoma were eligible. Patients with inadequate renal or liver function were excluded. Before enrollment, patients underwent examination under anesthesia (EUA) to confirm the diagnosis of retinoblastoma. Drawings of the fundus were made, and clinical findings were documented by RetCam (Massie Industries, Dublin, CA). B-scan ultrasonography was used to determine tumor dimensions. Each eye was assigned a Reese-Ellsworth (R-E) classification. Computed tomographic and/or magnetic resonance imaging of the orbits and brain were performed to exclude gross optic nerve and CNS involvement. Additional metastatic evaluation in selected cases included bone scan, lumbar puncture, and bone marrow aspirates and/or biopsies. Informed consent was obtained from each patient’s parents or legally authorized representative. Vincristine was administered at a dose of 0.05 mg/kg. Because systemic exposure to carboplatin has been shown to be highly variable and depends on renal function, dosages were calculated on the basis of renal function.15 Because the glomerular filtration rate (GFR) can change during the rapid growth of infancy, GFR was calculated at diagnosis and weeks 6, 12, and 24 after enrollment. GFR was calculated using the serum clearance of technetium-99–diethylenetriamine pentaacetic acid.16 Patients with GFR greater than 50 mL/min/m2 received 560 mg/m2 of carboplatin, whereas patients with GFR less than 50 mL/min/m2 received doses targeted to achieve an area under the curve of 6.5 mg/mL/min. Although the ototoxicity of carboplatin at these doses is minimal, because of these patients’ young age, auditory function studies (including brain-auditory–evoked responses and, for some, stapedial reflex testing and sound field audiometry) were performed before chemotherapy and repeated at weeks 18, 24, and 48 of therapy. Sulfamethoxazole-trimethoprim (5 mg/kg of trimethoprim) was given during chemotherapy as prophylaxis for Pneumocystis carinii pneumonia. Complete blood counts were obtained at least weekly. Chemotherapy was delayed 1 week for absolute neutrophil counts lower than 500/µL and for platelet counts lower than 100,000/µL. If chemotherapy was delayed more than twice, the doses of carboplatin and vincristine were reduced 20%. Transfusions of packed RBCs and platelets were given at the physician’s discretion. Usually, RBCs were transfused for hemoglobin concentrations lower than 7 to 8 g/dL and platelet counts lower than 20,000/µL or in case of active bleeding. Patients underwent EUAs every 6 weeks during chemotherapy. Fundus drawings were made, and RetCam images were taken during each examination. Complete response was defined as complete regression of all apparent tumors; partial response was defined as greater than 50% reduction in the size of all apparent retinal and vitreous tumors, but less than complete regression; stable disease was defined as less than 50% decrease in size of all tumors; and progressive disease was defined as increase in retinal tumor size greater than 25%, vitreous or subretinal seed progression, or new tumor formation. Treatment failure was measured from time of study enrollment until detection of disease progression. Progressive disease received focal therapies, including cryotherapy, argon laser photocoagulation, diode laser, and episcleral plaque brachytherapy. Patients were re-examined every 3 weeks and received focal treatments as needed. Eyes failing to respond to local treatments received external-beam radiotherapy (EBRT) or were enucleated.
Statistical Methods We used exact Wilcoxon rank sum and Fisher’s exact tests to examine differences in age, sex, and race between patients with unilateral and bilateral retinoblastoma. Event-free survival (EFS), defined as the interval between date of diagnosis and date of external-beam radiation or enucleation, was calculated for each eye rather than each individual because independence of stage, response, and outcome by eye has been shown and cytogenetic evidence for the multifocal origin of primary retinoblastoma has been observed.18 We estimated EFS using the method of Kaplan and Meier; SEs were calculated using the method of Peto and Pike.19 Differences in EFS distributions by R-E stage (I, II, and III v IV and V) were examined using the exact log-rank test.
Patients Twenty-five patients aged from younger than 1 month to 37 months (median, 9.3 months) were enrolled in the RET-3 study from February 1996 to November 2000. Table 1  shows patient characteristics. The majority were male (17 of 25; 68%) and white (20 of 25; 80%). Eighteen patients had bilateral retinoblastoma, three patients had unilateral multifocal disease, one patient had unilateral unifocal disease, and three patients had unilateral disease that progressed to bilateral retinoblastoma at 210, 224, and 364 days, respectively, after initial diagnosis of unilateral disease. These three are represented as having unilateral disease in Table 1. There were apparently no differences in age, sex, or race (white v nonwhite) distributions between patients with unilateral or bilateral retinoblastoma (P = .74, P = .36, and P = .27, respectively).
Table 1  shows distributions within R-E groups. Most eyes had tumors located both centrally and peripherally (36 of 43 eyes, 84%). Six had central tumors only, and one had a single, peripherally located tumor.
Treatment and Response to Chemotherapy The observed objective response rate after eight courses of chemotherapy was lower than desired, 52.0% (13 of 25); most eyes progressed soon after cessation of chemotherapy. Despite this elevated progression rate, responses during chemotherapy were good; 41 eyes achieved partial response, and two eyes achieved complete response during chemotherapy. Each patient’s disease responded to chemotherapy early in the study (median, 7 weeks; range, 3 to 28 weeks). Four (9.3%) eyes (R-E groups Ib, IIa, IIIa, and Vb) in four patients required no local ophthalmic treatments. For the remaining 39 eyes, the median time from enrollment to first focal treatment was 7 months (range, 6 to 16 months). Nine eyes had 10 episcleral plaques. Five of them were salvaged without requiring EBRT, four subsequently received EBRT, and three of those were eventually enucleated.
Follow-Up and Outcome
Thirteen eyes in 11 patients have been enucleated (30.2%; 95% confidence interval, 17.2% to 46.1%). R-E groups at diagnosis for the 13 enucleated eyes were as follows: II, two eyes; III, two eyes; IV, three eyes; and V, six eyes. Median time to enucleation from enrollment was 13.9 months (range, 7.8 to 32.7 months). Median time to enucleation after completion of chemotherapy was 8.3 months (range, 1.4 to 27.3 months). Ten eyes were enucleated because of tumor progression and three eyes were enucleated because of neovascularization that caused glaucoma. The three eyes enucleated because of neovascularization had received EBRT, and one had also had plaque brachytherapy. The enucleated eyes of three patients showed evidence of deep choroidal invasion and/or extension into the ciliary body, and additional adjuvant chemotherapy with four courses of vincristine, doxorubicin, and cyclophosphamide was prescribed. Nineteen eyes in 14 patients required EBRT (44.2%; 95% confidence interval, 29.1% to 60.1%). Median radiation dose was 44 Gy (range, 36 to 46 Gy). Of the five patients with EBRT in both eyes, four received EBRT in both eyes at the same time, and one received EBRT in the second eye 276 days after the first eye was treated. The median time to radiation from enrollment was 9.5 months (range, 6.1 to 20.9 months); median age at time of EBRT was 21 months (range, 10 to 46 months). Of the 19 eyes receiving EBRT, nine were subsequently enucleated (four eyes in group V, one eye in group IV, two eyes in group III, and two eyes in group II).
Table 3
Toxicity Myelosuppression was tolerable. Ten patients (40%) required no transfusions of packed RBCs, four patients required one transfusion; one patient required two transfusions; four patients required three transfusions; four patients required four transfusions; and one patient required six transfusions. Thirteen patients (52%) received no platelet transfusions, eight patients received one platelet transfusion, three patients received three platelet transfusions, and one patient received five platelet transfusions. Thirteen patients (52%) were hospitalized at least once for febrile illness. On five occasions, a central line infection was documented. One patient developed hemodynamic decompensation on recovery from EUA that required admission to the intensive care unit; blood cultures were negative. No deaths were attributed to toxicity of treatment.
In recent years, treatment of patients with bilateral retinoblastoma has evolved to incorporate primary chemotherapy followed by aggressive focal therapies. This approach intends to achieve maximum chemoreduction of the intraocular tumor burden early in treatment and ultimately avoid or delay EBRT and increase ocular salvage. On the basis of the proven chemosensitivity of metastatic retinoblastoma to platinum agents and etoposide,4,5 most chemoreduction protocols have included carboplatin and epipodophyllotoxins, usually with vincristine.20–26 Because of concerns regarding the increasing incidence of epipodophyllotoxin-related leukemias,27 we explored the use of chemoreduction without etoposide, and we sought to better characterize the role of chemotherapy by delaying focal treatments until disease progression was documented. Similar to patients treated with a three-drug regimen,20 all patients, regardless of the intraocular tumor burden, responded to the combination of vincristine and carboplatin. Disease progressed in only two patients during chemotherapy, and in both cases, after at least six courses of therapy. For the remaining patients, disease progressed once chemotherapy was completed. Of note, four eyes (9%) were cured with chemotherapy only. Among patients with eyes classified in R-E groups I, II, and III, ocular salvage was 83%, and 63% of the eyes were saved without EBRT. These results are inferior to those obtained with the three-drug regimens.20,23–25 Our less-intensive regimen may have an inferior antitumor effect. However, given the excellent early responses to chemotherapy and that tumor progression occurred in previously noted lesions, we believe that inclusion of aggressive focal treatments early after chemoreduction instead of after tumor progression could result in outcomes in eyes in R-E groups I to III similar to those of patients receiving more intense chemotherapy. The salvage rate for eyes in R-E groups IV and V treated with vincristine and carboplatin was 52.6%. For patients with advanced disease, reports of treatments that incorporate etoposide indicate better ocular salvage of between 50% and 80%.23–26 However, in those studies, 22% to 50% of the R-E group IV and V eyes were enucleated before enrollment, adding selection bias when ocular salvage is evaluated.23–25 No enucleations were performed in our patients before enrollment. Furthermore, in our study, five R-E group IV and V eyes (26%) were cured with chemotherapy and focal treatments only. However, the salvage rate for group Vb eyes was low (18%), stressing the need for better therapies for this group of patients. Excellent results have been reported for advanced intraocular disease with the addition of cyclosporine to a regimen of vincristine, teniposide, and carboplatin.25 The rationale for the use of cyclosporine originates from the documentation of the presence of the P-glycoprotein efflux pump in a significant proportion of retinoblastomas, an expression that seems to correlate with treatment failure.28 The concurrent administration of cyclosporine could potentially abrogate the efflux of drugs from the cancer cell.25,29 However, these results have yet to be confirmed. Although the proportion of patients with early intraocular stages that require salvage treatment with EBRT seems to be excessive, treatment with vincristine and carboplatin may achieve salvage rates comparable to those with more intensive regimens, and more aggressive and timely use of focal therapies could improve results. First, local control for most solid malignancies is better achieved early in the course of treatment, when maximum cytoreduction has been achieved and before chemoresistance develops. Second, the concurrent use of chemotherapy and focal therapies seems to have a synergistic effect. The sequential administration of carboplatin and thermotherapy enhances the antitumor effect by increasing the platinum-DNA adducts, which is why thermochemotherapy is becoming an important component in the treatment of intraocular retinoblastoma.30,31 In addition to its effect on tumor control, cryotherapy increases the intraocular penetration of carboplatin, presumably through disruption of the blood-vitreous barrier.32,33 However, the efficacy of this two-drug regimen when focal therapies are used early in the treatment and role of the regimen in treating early intraocular stages must be evaluated prospectively. The treatment of patients with advanced intraocular disease (R-E groups IV and V) remains a major challenge. Although randomized studies have not been performed, compared with EBRT and focal treatments alone, chemoreduction does not seem to significantly improve overall ocular salvage for patients with advanced intraocular disease.34–36 Chemotherapy intensification, however, seems to correlate with outcome, and better results are obtained with protocols that include at least six courses of vincristine, etoposide, and carboplatin.20,37,38 Central retinal tumors usually respond better to chemotherapy than do tumors in the peripheral retina,39 but large central tumors may be associated with subretinal seeds, which ultimately may cause treatment failure.40 With the addition of aggressive sequential focal therapies, globe retention is no better than 50% for R-E group V eyes, and most patients also require EBRT.20,24 A major proportion of treatment failures occur because of progression of tumor in the vitreous or as subretinal implants, two areas of difficult access for antineoplastic agents.23 In contrast to the highly protein-bound etoposide, which remains in the plasma and lacks intraocular penetration, carboplatin diffuses well into the vitreous.41 The intraocular penetration of carboplatin is enhanced by disruption of the blood-vitreous barrier by the tumor42 and it is enhanced after cryotherapy.32,33 Intraocular concentrations are seven to 10 times higher when carboplatin is administered subconjunctivally,41 and animal studies have shown a dose-dependent inhibition of intraocular tumor growth by subconjunctival carboplatin.33,43 These encouraging preclinical data, however, have not translated effectively into improved outcomes in eyes with advanced disease. In children with refractory intraocular retinoblastoma, subconjunctival carboplatin shows antitumor effect against vitreous disease, but not against subretinal seeds.44 The role of subconjunctival carboplatin, however, will be better defined after studies are performed in newly diagnosed retinoblastoma. Radiation therapy seems the only valid alternative for patients with advanced disease, and early incorporation of EBRT in a situation of minimal disease, before disease progression occurs, may increase ocular salvage rates for R-E group V eyes up to 70%.26 Thus, the use of radiation therapy seems to be unavoidable for a significant proportion of children with advanced disease. The cumulative incidence of second cancers in patients with germ-line mutations of the RB1 gene correlates directly with the use and dose of radiation therapy, and this incidence is reported to increase steadily with age to up to 40% to 60% at 40 to 50 years of age.8–10 The risk of second cancer seems to correlate as well with timing of radiation; children receiving radiation therapy during their first year may have a higher risk of developing a second cancer in the radiation field than older children.13 However, the need for earlier radiation may also be an indication of a biologically and clinically more aggressive disease.45 Delay of radiation therapy should be a primary goal when designing treatment for children with bilateral retinoblastoma. Our study and others19 show that the therapeutic strategy of chemoreduction and aggressive focal treatments can successfully delay the use of radiation therapy for at least 6 or 7 months (median age, 21 months). In addition to theoretically decreasing the risk of second cancers, delaying radiation therapy may also allow more complete facial and orbital growth, thus reducing the degree of midfacial deformities.11,12 However, with the use of a multidisciplinary approach, the dose of EBRT needed for disease control may be reduced.46 Because our study was designed to use chemotherapy alone until disease progression, we were able to document that, in addition to its therapeutic effect, chemoreduction can be prophylactic; no new tumors developed in any of the 25 children while they received chemotherapy. This has two important implications. First, even in those patients with early diagnosis, in which the tumor or tumors can be treated successfully with focal treatments, the combination of vincristine and carboplatin may help prevent tumor development in areas in which the tumors or focal treatments of them may represent a threat to vision, such as in the macula or near the optic nerve. Second, this prophylactic effect may extend to the development of pineal tumors. The incidence of trilateral retinoblastoma has decreased dramatically since systemic chemotherapy protocols have been used routinely, and one small series indicates that these children may be considered to be protected against this fatal malignancy.47 The combination of vincristine and carboplatin may be as effective as the more intense three-drug regimen that also incorporates etoposide in preventing the development of trilateral retinoblastoma. For these two reasons, at our institution, we routinely recommend treatment with vincristine and carboplatin for the majority of patients with early-stage multifocal retinoblastoma, although in some patients the intraocular disease could be controlled with focal therapies alone. However, on an individual basis, the side effects of systemic chemotherapy should be balanced carefully against the use of focal therapies alone, especially in view of the rare incidence of pineal tumors. Finally, additional advantages of the vincristine-carboplatin regimen are its easy administration and low toxicity, two important factors when treatment is considered for any very young patient. In addition, although patients with germline mutation of the RB1 gene do not seem to have an increased risk of hematopoietic malignancies,8–10 the use of etoposide adds an additional risk to this already unfortunate patient population.48 Epipodophyllotoxin-related leukemia shows a dose-response relation, with the highest risk associated with cumulative doses greater than 4,000 mg/m2.27,49 Also associated with dosage schedule, there is a higher leukemogenic potential when the medication is administered weekly than when administered every 3 or 4 weeks,49 as in the treatment of retinoblastoma. However, it is widely (and wrongly) assumed that the risk of developing a treatment-related leukemia is only related to dose and schedule and that it occurs only after high cumulative doses of topoisomerase-II inhibitors. On the contrary, modest exposures to these agents can induce this fatal complication,50 so routine use of etoposide should be evaluated carefully. In summary, in patients with intraocular retinoblastoma, mainly those with eye disease classified in R-E groups I, II, and III, treatment with vincristine and carboplatin coupled with aggressive focal therapies may offer a valid alternative to regimens that incorporate etoposide, and this approach deserves further exploration. However, new approaches are needed for patients with more advanced intraocular disease.
We dedicate this work to the memory of Dr. Charles B. Pratt, whose legacy will forever impact the lives of children with retinoblastoma and their families. We thank Rosalyn Vu for scientific editing.
 Deceased.  Supported in part by grant CA23099; Cancer Center Support CORE Grant P30 CA 21765; the American Lebanese Syrian Associated Charities (ALSAC), Memphis, TN; and unrestricted grants from Research to Prevent Blindness, Inc, New York, NY, and the St. Giles Foundation, New York, NY.
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50. Blanco JG, Dervieux T, Edick MJ, et al: Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 98:10338–10343, 2001 Submitted September 19, 2002; accepted March 3, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
