|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Phase II Window of Idarubicin in Children With Extraocular RetinoblastomaFrom the Hemato-Oncology Unit, Ophthalmology Department, and Pharmacy Section, Hospital JP Garrahan, Buenos Aires, Argentina. Address reprint requests to Guillermo L. Chantada, MD, Hemato-oncología, Hospital JP Garrahan, Combate de los Pozos 1881, 1245 Buenos Aires, Argentina; email gchantada{at}intramed.net.ar
PURPOSE: The aim of this study was to evaluate in an upfront phase II study the response to idarubicin in children with extraocular retinoblastoma. PATIENTS AND METHODS: The starting dose of idarubicin was 15 mg/m2/d (days 1 and 2) weeks 0 and 3. After an interim evaluation, the dose was reduced to 10 mg/m2/d (days 1 and 2) weeks 0 and 3 because of hematopoietic toxicity. Response was evaluated at week 6. RESULTS: At the Hospital JP Garrahan (Buenos Aires, Argentina), 10 patients (five bilateral) were entered onto the study from 1995 to 1998. A total of 19 cycles were administered. Extraocular sites included orbit (n = 10), bone marrow (n = 3), bone (n = 1), lymph node (n = 1), and CNS (n = 1). The response rate was 60% (95% confidence interval, 30% to 90%). One complete response was achieved, in addition to five partial responses, two cases of stable disease, and two cases of progressive disease. All patients with bone marrow involvement achieved complete clearance of tumor cells. The patient with CNS disease had progressive disease. All patients had severe hematopoietic toxicity (grade 4 neutropenia and grade 3/4 thrombocytopenia after most cycles). Other toxicities included grade 2 diarrhea in 30%. No echocardiographic changes were detected. CONCLUSION: Idarubicin is active in extraocular retinoblastoma. The activity of this drug should be explored in future phase III studies.
DESPITE A RELATIVELY high response rate of metastatic retinoblastoma to conventional chemotherapy, long-term survival is uncommon for patients with systemic or CNS metastasis.1 Metastatic retinoblastoma occurs frequently in patients who live in developing countries, and the identification of newer, potentially active drugs is essential to increase the survival rate. One approach to testing new agents has been the upfront window, which provides the most accurate estimation of the true level of activity of the drug. This strategy has been used in a variety of pediatric malignancies, such as neuroblastoma and rhabdomyosarcoma,2,3 but seldom in retinoblastoma. Idarubicin (4-demethoxydaunomycycin) is an anthracycline analog with proven efficacy against adult and pediatric leukemia.4,5 Idarubicin is metabolized in vivo to its major active metabolite, idarubicinol. The use of idarubicin in metastatic retinoblastoma stems from the evidence that retinoblastoma has a similar drug sensitivity as neuroblastoma.6 Accordingly, cyclophosphamide, platinum compounds, vincristine, epipodophillotoxins, and anthracyclines have been the most commonly used drugs.6 The activity of doxorubicin as a single agent in retinoblastoma is not known in detail, but such activity was evident in some patients.7 Experimental studies in cell lines have shown that retinoblastoma cells are sensitive to doxorubicin.8 However, doxorubicin does not penetrate the blood-brain barrier, and long-term cardiac toxicity was reported in young children after the use of this drug. The favorable pharmacologic characteristics of idarubicin contributed to the decision to carry out this study, the aim of which was to determine the activity of idarubicin administered as an intravenous (IV) infusion in patients with extraocular retinoblastoma.
All patients with newly diagnosed extraocular retinoblastoma were eligible. Patients with recurrent extraocular retinoblastoma were also eligible, provided that they had not received any treatment with anthracycline drugs. Patients were to have at least one lesion that could be measured in two perpendicular dimensions within 7 days before the start of treatment. Patients with only intraocular retinoblastoma were not eligible for this study. Patients were required to have normal organ function and adequate cardiac function as defined by shortening fraction of greater than 29% by echocardiogram. Patients were not scheduled to receive any other concomitant treatment, such as radiotherapy, to any site. Written informed consent was obtained from parents or guardians of each child. The study was approved by our institutional review board.
Pretherapy Evaluation
Study Design Idarubicin was administered when the absolute neutrophil count recovered to greater than 1,000/µL and the platelet count to greater than 100,000/µL on day 21 or thereafter. If there was any reduction of the shortening fraction, idarubicin was withheld and the patient would be removed from the study and given alternate therapy. Response was evaluated at week 6. Response criteria included the following: (1) complete response was defined as complete disappearance of all previously noted lesions or blasts and no new lesions; (2) partial response was defined as a reduction of at least 50% in the sum of the product of all measurable tumor or blast count in bone marrow or cerebrospinal fluid and no appearance of new lesions or progression of any lesion; (3) stable disease was defined as a decrease of less than 50% and/or increase of less than 25% in the sum of the products of the largest diameters of measurable lesions or blast count in bone marrow or CSF and no appearance of new tumors; and (4) progressive disease was defined as a 25% or greater increase in the sum of the products of the largest diameters of measurable lesions or blast count in bone marrow or CSF or appearance of new lesions. Patients with complete response or partial response were considered as responding to idarubicin. The study was conducted in a two-stage design. A first cohort of 10 patients was evaluated. If no responses occurred, termination of the trial was planned and idarubicin would be declared not effective for extraocular retinoblastoma. If there was at least one response among the first cohort of 10 patients, an additional 10 patients would be entered onto the study. If six or more patients responded, the trial would be stopped and idarubicin would be considered effective for extraocular retinoblastoma. Toxicity was evaluated using the modified Children's Cancer Group criteria.9 Differences in duration of neutropenia between the 15 mg/m2/d and 10 mg/m2/d cohorts were assessed with the Mann-Whitney U test.
A total of 10 consecutive patients admitted to the Hematology/Oncology Unit of the Hospital JP Garrahan from November 1995 to May 1998 were included in the study. Six patients had newly diagnosed extraocular disease and the remaining four patients had an extraocular relapse. Only patient no. 9 had previous exposure to chemotherapy (carboplatin/etoposide/vincristine). The overall response rate was 60% (95% confidence interval, 30% to 90%). Response according to each site and current survival status are listed in Table 1. Patient no. 9 was removed from the study after the first course because of progressive disease. Therefore, 19 courses are assessable for toxicity.
One complete response was achieved, in addition to five partial responses, two cases of stable disease, and two cases of progressive diseases. Patient no. 7 achieved a complete response in the bone marrow and a mild (< 25%) reduction of the soft tissue mass associated to a single bone metastasis without change of the bone involvement. He had marked clinical improvement that consisted of decreased swelling and pain. He was considered to have achieved stable disease. Patient no. 3 had extraocular orbital disease in the left eye and Reese-Ellsworth group V intraocular disease, with massive vitreous seeding in the contralateral eye. This eye showed a marked shrinkage of intraocular tumors and clearance of vitreous seeds after two courses of idarubicin. An example of a partial response in the orbit is shown in Figs 1 and 2.
Toxicity Twelve courses (63.1%) were complicated by fever and neutropenia, and in three courses (15.7%), a positive blood culture was obtained (all in the 15 mg/m2/d cohort). Grade 3 thrombocytopenia occurred in 10 (52.6%) courses. Grade 4 thrombocytopenia occurred in three courses (15.7%). A total of seven platelet transfusions were administered to prevent bleeding in three patients in the 15 mg/m2/d cohort. RBC transfusions were administered in 12 instances (nine in the 15 mg/m2/d cohort). There were no echocardiographic changes in any patient. Although grade 2 diarrhea occurred after six courses, total parenteral nutrition was not necessary in any case. However, four patients received enteral nutrition through a nasogastric tube during the study. There were no cases of grade 2 to 4 renal, CNS, or liver toxicity.
Idarubicin was found to have a high response rate in patients with extraocular retinoblastoma in this study. The response rate in this phase II trial was 60%. However, the sample size was small and the confidence intervals were wide. It was not possible to assess comparatively the activity of idarubicin and doxorubicin in this study. Idarubicin has a more favorable pharmacokinetic profile, because it has better penetration to the CNS and less cardiotoxicity; however, its cost is higher than that of doxorubicin.10,11 The high response rate of idarubicin compares with the activity of carboplatin plus etoposide, which is the only chemotherapy combination for retinoblastoma being tested in a phase II study on a large cohort.12 Due to the rarity of extraocular retinoblastoma in developed countries, there are few studies about response to chemotherapy of extraocular retinoblastoma. In 1975, Ragab et al7 showed that one of five patients with retinoblastoma responded to doxorubicin. In 1985, Pratt et al13 reported the activity of single drugs and drug combinations in 11 cases of extraocular retinoblastoma. Response to vincristine, cyclophosphamide, doxorubicin, cisplatin, teniposide, and ifosfamide, as single agents or in combination, was reported.13 However, response was assessed mostly in single cases. Advani et al14 reported the response to sequential combination chemotherapy incorporating cyclophosphamide, cisplatin, doxorubicin, and etoposide in eight patients with advanced or recurrent retinoblastoma from India. All patients achieved a complete response at the end of the 75-day cycle.14 All three patients with bone marrow invasion in our series showed a complete disappearance of retinoblastoma cells in the bone marrow in response to idarubicin. Speth et al15 found concentrations of idarubicin and idarubicinol 400 and 200 times greater in nucleated blood cells and bone marrow, respectively, than in plasma. This finding may explain the excellent response rate of idarubicin in this subset of patients. Idarubicinol can penetrate the blood-brain barrier, achieving low concentrations in the CSF11; however, the activity of idarubicin in patients with CNS invasion of retinoblastoma could not be assessed in our study, because only one such patient was included. In recent years, neoadjuvant chemotherapy was used in retinoblastoma to decrease the tumor size, making them amenable to local treatment and thus avoiding external beam radiation and/or enucleation. Most investigators use carboplatin, etoposide, and vincristine with or without cyclosporine.16 The high response rate of idarubicin in patients with extraocular disease in our study and the excellent response of a single patient with intraocular tumors make this drug an attractive option for these patients that should be further explored. Hematopoietic toxicity was the most frequent adverse effect in this study. Most patients experienced grade 4 neutropenia, with three infections. This complication was observed only in the cohort of patients who received the higher dose. Gastrointestinal toxicity was also encountered, but it was not severe. Idarubicin is less cardiotoxic than doxorubicin17; however, there are few data on long-term survivors with idarubicin. No echocardiographic changes were seen in our study population, even in survivors who have received a cumulative dose of 100 mg/m2 of idarubicin. Patients who responded to idarubicin were offered this drug in a phase III trial testing a combination of vincristine, high-dose cyclophosphamide, high-dose carboplatin, and etoposide, with promising preliminary results.
We thank Dr Federico Sackmann-Muriel for his advice in the design of the study.
1. Schvartzman E, Chantada G, Fandino A, et al: Results of a stage-based protocol for the treatment of retinoblastoma. J Clin Oncol 14:1532-1536, 1996 2. Kretschmar C, Kletzel M, Murray K: Upfront phase II therapy with Taxol (txl) and Topotecan (topo) in untreated children (>365 days) with disseminated neuroblastoma (NB): A Pediatric Oncology Group study. Med Pediatr Oncol 25:243, 1995 (abstr) 3. Horowitz ME, Etcubanas E, Christiensen M, et al: Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: A model of anticancer development. J Clin Oncol 6:303-314, 1988[Abstract] 4. Carella A, Carlier P, Pungolino E, et al: Idarubicin in combination with intermediate-dose cytarabine and VP16 in the treatment of refractory or rapidly relapsed patients with acute myeloid leukemia. Leukemia 7:196-199, 1993[Medline] 5. Sackmann-Muriel F, Zubizarreta P, Felice M, et al: Results of treatment of an intensive induction regimen using idarubicin in combination with cytarabine and etoposide in children with acute myeloblastic leukemia. Leukemia Res 20:973-981, 1996[Medline] 6. White L: Chemotherapy in retinoblastoma: Current status and future directions. Am J Pediatr Hematol Oncol 13:189-201, 1991[Medline] 7. Ragab AH, Sutow WW, Komp DM, et al: Adriamycin in the treatment of childhood solid tumors. Cancer 36:1572-1576, 1975[Medline] 8. Chan H, Canton M, Gallie B: Chemosensitivity and multidrug resistance to antineoplastic drugs in retinoblastoma cell lines. Anticancer Res 9:469-474, 1989[Medline] 9. Iacuone J, Steinhert L, Ablin A: Modifications for toxicity, Ablin A (ed):Supportive Care of Children with Cancer: Current Therapy and Guidelines from the Children's Cancer Group37-57Baltimore, MD, The Johns Hopkins University Press, 1993 10. Robert J: Clinical pharmacokinetics of idarubicin. Clin Pharmacokinet 24:275-288, 1993[Medline]
11.
Reid J, Pendergrass T, Krailo M, et al: Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: A Children's Cancer Study Group report. Cancer Res 50:6525-6528, 1990 12. Doz F, Neuenschwander S, Plantaz D, et al: Etoposide and carboplatin in extraocular retinoblastoma: A study by the Societé Francaise d'Oncologie Pédiatrique. J Clin Oncol 13:902-909, 1995[Abstract] 13. Pratt CB, Crom D, Howarth C: The use of chemotherapy for extraocular retinoblastoma. Med Pediatr Oncol 13:330-333, 1985[Medline] 14. Advani SH, Rao SR, Iyer R, et al: Pilot study of sequential combination chemotherapy in advanced and recurrent retinoblastoma. Med Pediatr Oncol 22:125-128, 1994[Medline] 15. Speth PAJ, van de Loo FAJ, Linssen PCM, et al: Plasma and human leukemic cell pharmacokinetics of oral and intravenous 4-demethoxydaunorubicin. Clin Pharmacol Ther 40:643-649, 1986[Medline] 16. Gallie B, Budning A, de Boer G, et al: Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114:1321-1328, 1996[Abstract] 17. Anderlini P, Benjamin R, Wong F, et al: Idarubicin cardiotoxicity: A retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol 13:2827-2834, 1995[Abstract] Submitted November 9, 1998; accepted January 28, 1999. This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
