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ABSTRACT: Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to the retina. Topotecan proved to be an promising agent for retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 μg of intravitreal topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecan after 0.5 μg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment of retinoblastoma. A cohort of rabbits was used to sudy topotecan disposition in the vitreous after a single dose of 0.5 μg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbits was employed to evaluate the clinical and retinal toxicity after four weekly injections of two different doses of intravitreal topotecan (Group A, 5μg/dose; Group B, 0.5 μg/dose) to the right eye of each animal. The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group of rabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were perfomed with an inverse ophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitation in plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses. One week after the last injection, topotecan concentrations were measured in vitreous of all eyes and samples for retinal histology were obtained. Our results indicate that topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5 to 5 μg in the rabbit. Vitreous concentration of lactone topotecan were close to the concentration assumed to be therapeutically active after 5 hours of 0.5 μg intravitreal administration. Eyes injected with four weekly doses of topotecan (0.5 or 5 μg/dose) showed no significant differences in their ERG wave amplitudes and implict times in comparison with control (p>0.05). Animals showed no weight, hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly intravitreal injection of 5 μg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 μg of topotecan are also safe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 hours of the administration. We postulate promising translation to clinics for retinoblastoma treatment.
Experimental Eye Research 01/2013; · 3.26 Impact Factor
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ABSTRACT: BACKGROUND: Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients. PATIENTS AND METHODS: Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy. RESULTS: No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42-0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications. CONCLUSIONS: IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 09/2012; · 1.89 Impact Factor
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ABSTRACT: To evaluate the outcome of children with different degrees of choroidal invasion, to compare different systems for grading the extent of choroidal invasion, and to assess the role of concomitant prelaminar optic nerve and anterior segment invasion as predictors of extraocular relapse.
Retrospective analysis of children included in 4 prospective protocols (January 1, 1989, through June 31, 2010). Children with postlaminar optic nerve or scleral involvement and overt extraocular disease were excluded. Adjuvant chemotherapy was not scheduled. All slides were reviewed, and massive involvement was classified according to 3 definitions: (1) extending at least 3 mm in any dimension, (2) through the choroid's whole thickness, and (3) more than 50% of the thickness and/or more than 1 cluster.
One hundred sixty-seven children (35 with massive invasion) were studied (136 did not receive adjuvant therapy). The probability of 5-year event-free survival was 98.1% and the probability of overall survival was 98.7% because 1 patient relapsed. Children with massive invasion had a significantly lower event-free survival probability (94.2%) compared with those with focal invasion (99.2%) (P = .04). However, no significant difference was found in overall survival probability (98.7% vs 99.2%; P = .29). No significant effect of other risk factors was found.
Survival was excellent without adjuvant therapy, and no other factors correlated with survival. Children with massive invasion have a higher relapse rate but comparable survival to those with focal invasion provided that aggressive therapy for extraocular relapse is available with adequate safety conditions.
Archives of ophthalmology 06/2012; 130(6):724-9. · 3.86 Impact Factor
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Paula Schaiquevich,
Emiliano Buitrago,
Paula Taich,
Ana Torbidoni,
Alejandro Ceciliano,
Adriana Fandino,
Marcelo Asprea,
Flavio Requejo,
David H Abramson,
Guillermo F Bramuglia, Guillermo L Chantada
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ABSTRACT: To characterize melphalan pharmacokinetics after superselective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma.
Vitreous and plasma samples of five Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan cytotoxicity was evaluated in retinoblastoma cell lines with and without topotecan. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage, and systemic toxicity was studied in patients.
In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, a large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (P<0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (P<0.05). These children had 50% probability of grades 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (P<0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines.
Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.
Investigative ophthalmology & visual science 05/2012; 53(7):4205-12. · 3.43 Impact Factor
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ABSTRACT: The presenting features of retinoblastoma in developing countries and their correlation with disease stage and patient survival are poorly known and they may be useful as background information for planning early diagnosis initiatives. Therefore, we undertook a retrospective review of 508 patients (467 evaluable, 296 unilateral) treated in Argentina from 1988 to 2008. Patients presented at an older age than reported from high-income countries [mean age 24 mo (range, 0 to 165 mo), 31 mo for unilateral (range, 0 to 165 mo), and 13.3 mo (range, 0 to 62 mo) for bilateral disease]. Leukocoria was the most common presenting sign (n=402, 86%). Strabismus was the only complaint in 25 (5.3%) patients. Forty-two patients (9%) presented with an enlarged eyeball and 37 (7.9%) with a red eye. Retinoblastoma was diagnosed in 22 (4.7%) asymptomatic children. These patients and those with strabismus alone were significantly younger and had a significantly better survival. Children presenting with enlarged eyeballs were significantly older and had significantly lower survival. In multivariable analysis older age and presentation with enlarged eyeballs were independently associated to advanced stage and mortality (P<0.001). Retinoblastoma is diagnosed in later stages in our setting and presentation with eye enlargement and increasing age at diagnosis correlate with worse outcome.
Journal of Pediatric Hematology/Oncology 10/2011; 34(3):e97-101. · 1.16 Impact Factor
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ABSTRACT: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI).
The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan.
Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9-138.7] vs. 13.6 ng/mL [5.5-15.3], respectively; P < 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 ng·hour/mL [247.6-347.2] and 48.9 ng·hour/mL [11.8-63.4], respectively; P < 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 ng·hour/mL [6.8-13.4] vs. 18.7 ng·hour/mL [6.3-21.7]; P = 0.54).
Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.
Retina (Philadelphia, Pa.) 07/2011; 32(2):387-95. · 2.93 Impact Factor
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Guillermo L Chantada
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ABSTRACT: The survival of retinoblastoma patients in developing countries is lower than in the most affluent ones. Late diagnosis, poor treatment compliance and limitations for treatment are the major causes for these poor results. There is an association between the socioeconomic indicators of a country's development with the chances of survival and treatment adherence. Strategies for obtaining a better outcome are depicted in this review.
Ophthalmic Genetics 07/2011; 32(4):196-203. · 0.93 Impact Factor
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Guillermo L Chantada,
Ibrahim Qaddoumi,
Serife Canturk,
Vikas Khetan,
Zhigui Ma,
Kahaki Kimani,
Baris Yeniad,
Iyad Sultan,
Rita S Sitorus,
Nurdan Tacyildiz,
David H Abramson
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ABSTRACT: Survival of retinoblastoma is >90% in developed countries but there are significant differences with developing countries in stage at presentation, available treatment options, family compliance, and survival. In low-income countries (LICs), children present with advanced disease, and the reasons are socioeconomic and cultural. In middle-income countries (MICs), survival rates are better (>70%), but there is a high prevalence of microscopically disseminated extraocular disease. Programs for eye preservation have been developed, but toxicity-related mortality is higher. Although effective treatment of microscopically extraocular disease improved the outcome, worldwide survival will be increased only by earlier diagnosis and better treatment adherence.
Pediatric Blood & Cancer 03/2011; 56(3):341-8. · 1.89 Impact Factor
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ABSTRACT: Stage 4b retinoblastoma (central nervous system metastatic disease) has been lethal in virtually all cases reported. Here we describe a series of eight patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue.
Induction chemotherapy included cyclophosphamide and/or carboplatin with a topoisomerase inhibitor. High-dose chemotherapy regimens were carboplatin and thiotepa with or without etoposide (n = 3) or carboplatin, etoposide, and cyclophosphamide (n = 2).
Seven patients had leptomeningeal disease and one patient had only direct extension to the CNS via the optic nerve. Three patients had stage 4b disease at the time of original diagnosis of the intra-ocular retinoblastoma; five had later onset at a median of 12 months (range 3-69 months). One patient died of toxicity (septicemia and multi-organ system failure) during induction and two had disease progression prior to high-dose chemotherapy. Five patients received high-dose chemotherapy at a median of 6 months (range 4-6) post-diagnosis of stage 4b disease. Two patients survive event-free at 40 and 101 months; one was irradiated following recovery from the high-dose chemotherapy.
Intensive multimodality therapy may be beneficial for some patients with stage 4b retinoblastoma. Longer follow-up will determine whether it has been curative.
Pediatric Blood & Cancer 07/2010; 55(1):149-52. · 1.89 Impact Factor
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ABSTRACT: Few prospective studies about the management of unilateral retinoblastoma with pathology risk factors (PRFs) have been published.
Patients (n = 114) were divided into four groups: Group 1 (initial chemoreduction) (n = 17). Groups 2 and 3, included patients initially enucleated with no, or lower risk PRFs: (n = 65) and with higher risk PRFs (n = 30), respectively. The later included postlaminar optic nerve involvement (PLONI) (n = 23), tumor at resection margin of optic nerve (n = 5) or isolated scleral invasion (n = 2). Group 3 received adjuvant chemotherapy including a total eight cycles of carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. Orbital radiotherapy (45 Gy) was given to patients with invasion to the resection margin. Group 4 included patients with metastatic disease (n = 2). They were given neoadjuvant therapy followed by surgery and high-dose chemotherapy and autologous stem cell rescue.
Five-year event-free survival is 0.94 (1 for Group 1, 0.94 for Group 2, 0.96 for Group 3, and 0 for Group 4). Events included. Group 2: Systemic relapse (n = 2) and combined orbital and CNS relapse (n = 1). Relapsing patients had PLONI (n = 2) and isolated focal choroidal invasion (n = 1). Group 3: CNS relapse (n = 1) in a patient with tumor at the resection margin of optic nerve. Group 4: CNS relapse (n = 2). Only one relapsed patient survived. Eight of 17 eyes treated conservatively were preserved.
The survival of patients with unilateral retinoblastoma was excellent and 60% were spared from adjuvant treatment. Our intensive regimen was likely to be effective for prevention of metastasis in patients with higher risk PRFs.
Pediatric Blood & Cancer 07/2010; 55(1):60-6. · 1.89 Impact Factor
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Ira J Dunkel,
Rima F Jubran,
Sri Gururangan, Guillermo L Chantada,
Jonathan L Finlay,
Stewart Goldman,
Yasmin Khakoo,
Joan M O'Brien,
Manuela Orjuela,
Carlos Rodriguez-Galindo,
Mark M Souweidane,
David H Abramson
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ABSTRACT: Trilateral retinoblastoma has been lethal in virtually all cases previously reported. We describe a series of 13 patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue.
Induction chemotherapy generally included vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide. Hematopoietic stem cells typically were harvested after the first or second cycle of induction chemotherapy, usually from peripheral blood. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan and cyclophosphamide (n = 3).
Trilateral sites were pineal (n = 11) and suprasellar (n = 2); 7 patients had localized (M-0) disease and six had leptomeningeal dissemination (M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intra-ocular retinoblastoma; eight later developed trilateral disease at a median of 35 months (range 3-60 months) following diagnosis of intra-ocular retinoblastoma. One patient died of toxicity (septicemia and multi-organ system failure) during induction and three developed disease progression prior to high-dose chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months (range 4-9) post-diagnosis of trilateral disease. Five patients survive event-free at a median of 77 months (range 36-104 months) and never received external beam radiation therapy. Four of seven patients with M-0 disease survive event-free versus only one of six patients with M-1+ disease.
Intensive chemotherapy is potentially curative for some patients with trilateral retinoblastoma, especially those with M-0 disease.
Pediatric Blood & Cancer 11/2009; 54(3):384-7. · 1.89 Impact Factor
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Angel M Carcaboso,
Diego A Chiappetta,
Javier A W Opezzo,
Christian Höcht,
Adriana C Fandiño,
J Oscar Croxatto,
Modesto C Rubio,
Alejandro Sosnik,
David H Abramson,
Guillermo F Bramuglia, Guillermo L Chantada
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ABSTRACT: Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.
Investigative ophthalmology & visual science 10/2009; 51(4):2126-34. · 3.43 Impact Factor
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ABSTRACT: Retinoblastoma is the most common intraocular malignant childhood tumor in need of prospective clinical trials to address important unanswered questions about biology, treatment, and prognostic factors. Currently, there is controversy about the definitions for choroidal invasion and an inconsistency in the handling of eyes with retinoblastoma. The International Retinoblastoma Staging Working Group (IRSWG) composed of 58 participants from 24 countries on 4 continents had a series of Internet meetings to discuss the staging and tissue handling guidelines to reach consensus for adequate processing, establishing definitions of histopathologic risk factors, and reporting of enucleated eyes with retinoblastoma to serve as the basis for clinical trials and studies to validate the proposed criteria. The meetings were facilitated by the International Outreach Program of the St. Jude Children's Research Hospital through Cure4Kids. The retinoblastoma guidelines from the Children's Oncology Group, the French Society for Pediatric Cancers, the Association of Directors of Anatomic and Surgical Pathology, and some published data were the basis for this consensus document. Discussions of the feasibility, practicality, and efficacy of the guidelines and criteria resulted in this report. The consensus definitions reached included definition of massive choroidal invasion stated as a maximum diameter of invasive tumor focus of 3 mm or more that may reach the scleral tissue. Focal choroidal invasion is defined as a tumor focus of less than 3 mm and not reaching the sclera. Optic nerve invasion is classified as prelaminar, laminar, retrolaminar, or tumor at surgical margin, and the measurement of the depth of invasion should also be recorded. These guidelines also address handling of the enucleated eye with retinoblastoma in an efficient, practical, and feasible manner for a meaningful diagnosis. The consensus criteria reached by the IRSWG should be validated through prospective clinical trials and studies.
Archives of pathology & laboratory medicine 09/2009; 133(8):1199-202. · 2.58 Impact Factor
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ABSTRACT: To identify clinical features at presentation to help in detecting patients with retinoblastoma and pathology risk factors (PRFs) preoperatively, and therefore selecting a high-risk population that could benefit from preoperative treatment.
A retrospective analysis of a prospectively filled form of 182 consecutive patients with unilateral retinoblastoma treated with initial enucleation from 1988 to 2006. Univariate and multivariate analyses were carried out. Major choroidal invasion and postlaminar optic nerve and scleral extension were considered PRFs. Within this subgroup, a higher-risk cohort (microscopical residual disease caused by trans-scleral invasion or invasion to the resection margin of the optic nerve) was analyzed separately.
One hundred sixty-four patients had completely resected and 18 had microscopical residual disease. Seventy three had at least 1 PRF (massive invasion to the choroid in 25, to the postlaminar optic nerve in 41, intrascleral in 10, to the resection margin of the optic nerve in 12, and trans-scleral in 6). Seventy-one patients had glaucoma and 19 had buphthalmia. Intraocular pressure, glaucoma, and buphthalmia correlated significantly with the occurrence of both PRF and microscopical residual disease in multivariate analysis. Buphthalmia was the most specific factor but the sensitivity was lower. Glaucoma and buphthalmia had a high negative predictive value.
Patients presenting with glaucoma and/or buphthalmia have a significantly higher risk for the occurrence of PRF, including those resulting in microscopically residual disease.
Journal of Pediatric Hematology/Oncology 06/2009; 31(5):325-9. · 1.16 Impact Factor
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Guillermo L Chantada,
Ira J Dunkel,
Ibrahim Qaddoumi,
Celia B G Antoneli,
Alegria Totah,
Serife Canturk,
Ibrahim Nawaiseh,
Adriana Fandiño,
Imelda Pífano,
Gonul Peksayar,
Karina Braga Ribeiro,
David H Abramson
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ABSTRACT: Although screening for familial retinoblastoma has been shown to be beneficial we suspected that such screening programs may be less than optimal in developing countries (DC).
Retrospective cohort study comparing patients with familial retinoblastoma from five centers in DC (Argentina, Brazil, Turkey, Jordan, and Venezuela) versus a reference center in the USA.
Ninety-two (32 from the USA and 60 from DC) patients were included. Forty-one (44.6%) patients avoided enucleation, 42 (45.7%) had 1 eye removed, and 9 (9.8%) underwent bilateral enucleation. Eleven (11.9%) had major pathology risk factors at enucleation. There were no cases of metastatic disease at diagnosis. Detection via screening was significantly less common in DC than in the USA (23.3% vs. 71.8%, P < 0.0001). Patients in DC were diagnosed at a significantly later age and with more advanced intraocular disease that led to increased risk of bilateral enucleation. Patients detected by screening in DC were significantly younger at diagnosis, had less advanced intraocular disease, better ocular preservation rates and survival results than those whose retinoblastoma was not detected via early screening. Five-year pEFS was 0.92 for the patients treated in the USA and 0.81 for the patients in DC (P = 0.42). Seven events occurred (extraocular relapse four in patients from DC and second malignancies in three).
Patients with familial retinoblastoma are less likely to be diagnosed by screening in DC and had higher morbidity and mortality caused by recurrent extraocular retinoblastoma.
Pediatric Blood & Cancer 05/2009; 53(3):338-42. · 1.89 Impact Factor
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ABSTRACT: To identify the maximum tolerated dose and dose-limiting toxicity of periocular topotecan in patients with relapsed or resistant intraocular retinoblastoma who are facing imminent enucleation.
For this phase I study, a starting dose of 0.5 mg of periocular topotecan administered through a 25-gauge needle was given with intrapatient escalation at a rate of 0.5 mg/cycle according to toxicity, up to a maximum dose of 2 mg. Two courses separated by 2 weeks were scheduled. Plasma levels of topotecan were measured by high-performance liquid chromatography in patients with available intravenous catheters.
Seven eyes of five patients were treated with a total of 14 courses of periocular topotecan. Only mild orbital edema occurred, and grade 1 vomiting developed in the first patient that was controlled with ondansetron for the following courses. Dose-limiting toxicity was not reached and the maximum tolerated dose was set at the target dose of 2 mg (n=5 eyes). Lactone topotecan systemic exposure was lower than 55 ng/mL x h and it correlated linearly with dose in this small cohort. Even though the study was not designed to assess response, one eye was preserved after a partial response, but the remaining six were enucleated, either after a short period of disease stabilization followed by further therapy with other agents in five patients or by rapidly progressive disease in one.
The dose limiting toxicity was not reached. Up to 2 mg of periocular topotecan could be given safely, but further studies are necessary to determine its effect on retinoblastoma (ClinicalTrials.gov number, NCT00460876).
Investigative ophthalmology & visual science 11/2008; 50(4):1492-6. · 3.43 Impact Factor
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ABSTRACT: There is little information on the outcome of patients with retinoblastoma and tumor at the resection margin of the optic nerve.
Retrospective evaluation of three successive prospective protocols. Twenty-six consecutive patients were analyzed (International Staging System-IRSS-stage 2 = 21, stage 3 = 5) from three successive prospective protocols (1988-2006). Patients with stage 2 were enucleated upfront and those with stage 3 had neoadjuvant chemotherapy followed by enucleation and adjuvant therapy. Both groups received adjuvant chemotherapy and orbital radiotherapy after enucleation. Patients in protocol 1 received 1 year of the lower-dose chemotherapy regimen including cyclophosphamide, vincristine and doxorubicin along with intrathecal chemotherapy. Patients of protocols 2 and 3 received a more intense and shorter intravenous regimen including carboplatin and etoposide alternating with cyclophosphamide, idarubicin and vincristine with no intrathecal treatment. The components of protocol 2 and 3 were similar except for the dose of carboplatin which was 10% lower in protocol 3.
Thirteen were treated in protocol 1 and 13 in protocols 2 and 3. The probability of event-free survival was 0.70 at 5 years. Events included: CNS relapse = 3, second malignancies = 3, death in complete remission = 2. There were no significant differences in outcome between protocols or stages. Endocrinological disturbances related to the hypothalamus-hypophysis axis were evident in 6/8 patients evaluated. Severe orbital sequelae occurred in 12 cases.
A substantial number of patients with tumor at the resection margin of the optic nerve can be cured with current therapy; however, therapy related sequelae are frequent.
Pediatric Blood & Cancer 11/2008; 52(2):218-22. · 1.89 Impact Factor
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Guillermo L Chantada,
François Doz,
Manuela Orjuela,
Ibrahim Qaddoumi,
Rita S Sitorus,
Tomas Kepak,
Anna Furmanchuk,
Mauricio Castellanos,
Tarun Sharma,
Patricia Chevez-Barrios,
Carlos Rodriguez-Galindo
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ABSTRACT: Following from the publication of the International Retinoblastoma Staging System, an open internet discussion group was created at the www.cure4kids.org resource. The results of a survey distributed among participants are discussed. Although most patients with retinoblastoma were treated under prospective protocols, there was a wide variation in the definition of risk criteria and in the criteria for giving adjuvant chemotherapy following enucleation. Definition of high-risk histological features and the criteria for use of adjuvant therapy will be standardized in future studies. Internet meetings are a valuable mechanism for enabling participation from under-resourced countries in the development of cooperative studies.
Pediatric Blood & Cancer 04/2008; 50(3):692-4. · 1.89 Impact Factor
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ABSTRACT: To evaluate the outcome of patients with retinoblastoma and postlaminar optic nerve invasion (PLONI).
Retrospective interventional case series.
Sixty-one consecutive patients included in 3 successive protocols were analyzed.
Pathologic review was done in each case. Patients were stratified into 2 risk groups: the high-risk group included those with concomitant full choroidal and/or scleral invasion and were given adjuvant chemotherapy. Those without these features were considered low risk and chemotherapy was withheld after 1994.
Extraocular relapse and survival according to stratification.
The probability of event-free survival (pEFS) was 0.91 and the probability of overall survival (pOS) was 0.94 at 5 years. Patients in the high-risk group (n = 22) had pEFS of 0.86. Three had extraocular relapse (involving the central nervous system; all died of disease). Microscopic scleral invasion was associated to extraocular relapse (P = 0.05). Lower risk patients (n = 39) had a pEFS of 0.94 and pOS of 1. Eighteen received postenucleation chemotherapy and none relapsed. Twenty-one received no adjuvant therapy and 2 had a systemic relapse but were successfully retrieved. Relapsing patients had a higher ratio of affected optic nerve (>25% of it overall length; P = 0.02).
Patients with PLONI have an excellent outcome with current therapy. Risk stratification according to the presence of concomitant choroidal and/or scleral invasion may help in the decision of giving adjuvant therapy.
Ophthalmology 11/2007; 114(11):2083-9. · 5.45 Impact Factor
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ABSTRACT: To assess the outcome and determine risk factors for extraocular relapse in patients with retinoblastoma who had been enucleated after failure of chemoreduction.
Retrospective study (1995-2002) at three institutions. Pathological risk factors (PRF) were defined as invasion of the anterior segment, choroid, post-laminar optic nerve, subarachnoid space, or sclera according to the local pathology report. Extraocular relapse was defined as an event.
One hundred twenty-two patients were included (17 had bilateral enucleation). Chemoreduction included vincristine, carboplatin, and etoposide (n=80, 65.6%), vincristine, and carboplatin (n=17, 13.9%), or carboplatin (n=25, 20.5%). Thirty-five also received external beam radiotherapy (28.7%). PRF included: 39 with choroidal involvement, 9 with anterior segment, 9 with scleral, and 2 with post-laminar optic nerve with subarachnoid invasion. Adjuvant chemotherapy was given to eight patients (6.5%) because of scleral invasion. Four patients had an extraocular relapse after enucleation, two of whom survive after intensive treatment including stem cell rescue. Five-year probability of event-free survival is 0.96. Only scleral invasion and bilateral enucleation were significantly associated with extraocular relapse.
The risk of extraocular relapse is low after enucleation following failure of chemoreduction. Patients who underwent bilateral enucleation and those with scleral invasion are at higher risk of extraocular relapse.
Pediatric Blood & Cancer 10/2007; 49(3):256-60. · 1.89 Impact Factor
