Bone Marrow Transplantation (2003) 31, 281–284 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Retinoblastoma High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma B Kremens1, R Wieland1, H Reinhard2, D Neubert5, JD Beck3, T Klingebiel4, N Bornfeld6 and W Havers1 1Department of Pediatrics, University Hospitals of Essen, Germany; 2Department of Pediatrics, University of Homburg/Saar, Germany; 3Department of Pediatrics, University of Erlangen, Germany; 4Department of Pediatrics, University of Frankfurt/Main, Germany; 5Department of Pediatrics of Klinikum Schwerin, Germany; and 6Department of Ophthalmology, University of Essen, Germany Summary: Retinoblastoma is the most common primary tumor of the eye in children.1 Its cure rate reaches 95% (10-year survival Children with metastatic retinoblastoma are considered to probability of 687 patients, German Childhood Cancer have a poor prognosis after conventional chemotherapy. Registry, 2). In most cases, the disease is diagnosed early We used high-dose chemotherapy (HDC)with peripheral and local treatment is instituted promptly. RB remains a hematopoietic stem cell transplantation in such patients in high-risk malignancy, however, under certain circum- an attempt to improve their survival. Four patients with stances, such as involvement of the cut end of the optic bone marrow metastases and one child with extraorbital nerve,3,4 extrascleral spread intothe orbita 5,6 or lymphatic, disease were treated with HDC after achieving complete or hematogenous dissemination.7 Central nervous system remission by enucleation and conventional chemotherapy. disease has a particularly bad prognosis.1,8 Attempts to The child with extraorbital tumor was the only one to control or even cure disseminated retinoblastoma have receive local irradiation. The conditioning regimen followed the strategies used in neuroblastoma, the other included thiotepa (900 mg/m2), etoposide (40 mg/kg) and and more frequent disseminated neuroectodermal malig- carboplatin (1.5 g/m2)in four patients, and BCNU nancy of childhood.9,10 Responses of metastatic retinoblas- (300 mg/m2), cyclophosphamide (6.8 g/m2)and etoposide toma have been shown to respond to cisplatin–etoposide (1.6 g/m2)in one child. Hematologic recovery occurred and cyclophosphamide–doxorubicin,5,11 and to etoposide without delay in all patients. The main toxicities were and carboplatin.12 Since it has been very difficult toconvert diarrhea, mucositis and infectious complications. No toxic such responses into cures,7 the dose–response concept has deaths or any major late toxicities were observed. The been advocated and tried for retinoblastoma as for child treated with the BCNU regimen developed a neuroblastoma, germ-cell tumors or brain tumors. Unlike meningeal relapse 10 months after HDC, which was these diseases, the paucity of patients has prevented a larger partially resected and treated with conventional che- prospective trial to date. motherapy, but not with radiotherapy. He is in complete We report our experience with four children who suffered remission (CR)105 months off treatment. The other from bone marrow metastases of retinoblastoma, re- patients are in CCR for 107, 57, 9 and 8 months after sponded to conventional chemotherapy and received HDC. HDC with thiotepa, etoposide and carboplatin may high-dose consolidation chemotherapy (HDC). A fifth represent a curative option for children with extrabulbar child received the same treatment for extraocular orbital or disseminated retinoblastoma responsive to chemother- disease. apy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be Patients and methods determined. Bone Marrow Transplantation (2003) 31, 281–284. Five children (two girls) received HDC for retinoblastoma doi:10.1038/sj.bmt.1703832 in Germany from 1992 until 2001. In all of them, a Keywords: retinoblastoma; high-dose chemotherapy; unilateral retinoblastoma had primarily been diagnosed at hematopoietic stem cell transplantation the age of 20, 31, 34, 64 and 110 months. In three children, histopathologic risk factors were seen: tumor at the cut end of the optic nerve (patient 2), invasion of the choroid (patients 2, 3) and microscopic extrascleral disease (patient 5). There was no evidence of CNS disease in any of them at Correspondence: Dr B Kremens, Department of Pediatrics, University the time of first diagnosis. The affected eye was enucleated Hospitals of Essen, Hufelandstr. 55, D-45122 Essen, Germany in each case. Patient 5 had documented extrascleral disease, Received 6 June 2002; accepted 23 September 2002 and received additional external irradiation of 48 Gy and High-dose chemotherapy with autologous stem cell B Kremens et al 282 adjuvant chemotherapy according to the Essen Retino- numbers of 450/nl were noted by day 22 (median; range blastoma Protocol (cyclophosphamide, etoposide, carbo- 12–51). The main toxicities included diarrhea and severe platin and vincristine, cf. Bornfeld et al13); nolocal mucositis (WHO grade 3 and 4 in patients 2–5) requiring radiotherapy was given to the other patients. The opiate analgesics in all patients, and nausea and vomiting. characteristics of these patients are summarized in Table 1. All children developed fever and received antibiotics, but Four children (patients 1–4) developed metastatic bone septicemia could not be documented in any of them. marrow involvement 5, 6, 9 and 11 months after eye Transient elevation of liver enzymes was noted in three surgery. Bone scan was negative in all patients except patients. Further acute or late toxicities have not been patient 3, who had lesions in the left temporal bone and in observed to date. the third thoracic vertebra. At this time again, no CNS All patients are alive and well 8–119 months after HDC disease was detectable in them by imaging or CSF cytology. (cf. Table 2). A right frontal meningeal relapse occured in They received multiagent chemotherapy, two children patient 1 10 months after HDC. After partial metastasect- according to the Neuroblastoma Protocol NB 90, Protocol omy and conventional chemotherapy according to the of the German Society of Pediatric Oncology/Hematology, Essen Retinoblastoma Protocol13 plus multiple intrathecal (including cisplatin, etoposide, vindesine, vincristine, of methotrexate injections, this boy has been in second CR DTIC, ifosfamide and doxorubicin), and two children for 105 months (no radiotherapy). according to the Essen Retinoblastoma Protocol.13 In all five children, peripheral blood stem cells (PBSC) were mobilized using filgrastim 5 mg/kg/day subcutaneously after Discussion one of the chemotherapy blocks, in patient 2 after treatment with 4 g/m2 of cyclophosphamide. The PBSC For many years, retinoblastoma confined to the eye has were cryopreserved; in patients 3 and 4, a CD34+ selection been a curable disease with local therapy such as was performed beforehand. Informed consent was obtained enucleation, external beam irradiation, brachytherapy, from the parents of each patient. cryotherapy or laser coagulation.1 In contrast, systemic All patients were in complete remission (CR) at the time disease is difficult to cure, although it usually responds to of HDC (cf. Table 2). chemotherapy.5–7 As in other malignancies of similar During the period of HDC, supportive care was given prognosis, high dose intensification of chemotherapy has according to local standards, including barrier nursing, been tried for retinoblastoma. Two case reports of patients selective oral decontamination, oral antifungal treatment, with bone marrow metastases who received HDC in pneumocystis carinii prophylaxis with trimethoprim/sulfa- complete remission and survived in continuous remission methoxazole before day 0 and after hematopoietic recov- 13 and 17 months thereafter gave a first hint to the ery, and parenteral nutritional support as necessary. As possiblility of cure in metastatic retinoblastoma.14,15 Later, consolidation therapy, patient 1 received BCNU 300 mg/ the group of the Institut Curie in Paris published their m2, cyclophosphamide 6.8 g/m2 and etoposide 1.6 g/m2. results after treating 25 high-risk patients with retinoblas- Patients 2–5 received HDC treatment with thiotepa 900 mg/ toma, with HDC consisting of carboplatin, etoposide and m2, etoposide 40 mg/kg and carboplatin 1.5 g/m2 (cf. cyclophosphamide (CARBOPEC), followed by autologous Table 3). PBSC containing 1.7–21.0 Â 106 CD34+ cells/ bone marrow rescue. Among eight children with bone kg were thawed and infused on day 0. Concomitantly, marrow and bone metastases, five survived between 11 and treatment with filgrastim at a dose of 5 mg/kg/day was 70 months disease free, while three patients relapsed in the initiated and continued until stable neutrophil engraftment CNS and died.8 Among all 25 patients, a total of seven was reached. suffered from recurrence after this HDC, six of these seven within the CNS. The authors conclude that CNS disease cannot be cured with the CARBOPEC regimen.8 Results CNS involvement is well known to confer a very poor prognosis. Aggressive chemotherapy regimens including Prompt reconstitution of bone marrow occured in all CCNU, intrathecal therapy and cranial irradiation have patients. Neutrophil counts of 40.5/nl were reached on resulted in considerable toxicity, but have not yielded an day 10 (median; range 8–22). Rising unsupported platelet applicable