Publications (144)885.67 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: Sunitinib malate is a small multi-targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high-grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high-grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression-free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high-grade glioma. Most adverse events were of mild-to-moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high-grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.
- [Show abstract] [Hide abstract] ABSTRACT: Background: NSC 750854 is a purine analog with an antitumor activity profile distinctive from that of other anticancer purines. It has shown significant activity against adult cancer preclinical models. Procedure: NSC 750854 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered intraperitoneally at a dose of 5 mg/kg daily for 5 days repeated at day 15. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 32 nM (range from 11 to 124 nM), with consistent cytotoxicity across all cell lines. Acute lymphoblastic leukemia (ALL) cell lines were more sensitive to NSC 750854 than non-ALL cell lines. NSC 750854 induced significant differences in EFS distribution compared to control in 31 of 35 (89%) solid tumor xenografts. It induced tumor growth inhibition meeting criteria for intermediate or high event free survival (EFS) T/C activity in 17 of 32 (53%) evaluable solid tumor xenografts (most consistently in the rhabdomyosarcoma panel). Objective responses were observed in 15 of 37 (41%) solid tumor xenografts and in all eight leukemia models with complete response (CR) or maintained complete response (MCR) in seven of eight leukemia models. Conclusions: NSC 750854 has a unique spectrum of antitumor activity compared with other agents tested by the PPTP as it induces regression in tumor models with limited sensitivity to most agents tested to date. Given the promising level of activity observed for NSC 750854 against PPTP preclinical models, further exploration of its mechanism of action is warranted.
- [Show abstract] [Hide abstract] ABSTRACT: PR-104, a phosphate ester of the nitrogen mustard prodrug PR-104A, has shown evidence of efficacy in adult leukemia clinical trials. Originally designed to target hypoxic cells, PR-104A is independently activated by aldo-keto-reductase 1C3 (AKR1C3). The aim of this study was to test whether AKR1C3 is a predictive biomarker of in vivo PR-104 sensitivity. In a panel of 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 showed significantly greater efficacy against T-lineage ALL (T-ALL) than B-cell-precursor (BCP)-ALL xenografts. Single agent PR-104 was more efficacious against T-ALL xenografts compared with a combination regimen of vincristine, dexamethasone and L-asparaginase. Expression of AKR1C3 was significantly higher in T-ALL xenografts compared with BCP-ALL, and correlated with PR-104/PR-104A sensitivity in vivo and in vitro. Overexpression of AKR1C3 in a resistant BCP-ALL xenograft resulted in dramatic sensitization to PR-104 in vivo. Testing leukemic blasts from 11 patients confirmed that T-ALL cells were more sensitive than BCP-ALL to PR-104A in vitro, and that sensitivity correlated with AKR1C3 expression. Collectively, these results indicate that PR-104 shows promise as a novel therapy for relapsed/refractory T-ALL, and that AKR1C3 expression could be used as a biomarker to select patients most likely to benefit from such treatment in prospective clinical trials. Copyright © 2015 American Society of Hematology.
- [Show abstract] [Hide abstract] ABSTRACT: The treatment of children with embryonal brain tumors (EBT) includes craniospinal irradiation (CSI). There are limited data regarding the effect of CSI on pulmonary function. Protocol SJMB03 enrolled patients 3 to 21 years of age with EBT. Pulmonary function tests (PFTs) (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC] by spirometry, total lung capacity [TLC] by nitrogen washout or plethysmography, and diffusing capacity of the lung for carbon monoxide corrected for hemoglobin [DLCOcorr]) were obtained. Differences between PFTs obtained immediately after the completion of CSI and 24 or 60 months after the completion of treatment (ACT) were compared using exact Wilcoxon signed-rank tests and repeated-measures models. Between June 24, 2003, and March 1, 2010, 303 eligible patients (spine dose: ≤2345 cGy, 201; >2345 cGy, 102; proton beam, 20) were enrolled, 260 of whom had at least 1 PFT. The median age at diagnosis was 8.9 years (range, 3.1-20.4 years). The median thoracic spinal radiation dose was 23.4 Gy (interquartile range [IQR], 23.4-36.0 Gy). The median cyclophosphamide dose was 16.0 g/m(2) (IQR, 15.7-16.0 g/m(2)). At 24 and 60 months ACT, DLCOcorr was <75% predicted in 23% (27/118) and 25% (21/84) of patients, FEV1 was <80% predicted in 20% (34/170) and 29% (32/109) of patients, FVC was <80% predicted in 27% (46/172) and 28% (30/108) of patients, and TLC was <75% predicted in 9% (13/138) and 11% (10/92) of patients. DLCOcorr was significantly decreased 24 months ACT (median difference [MD] in % predicted, 3.00%; P=.028) and 60 months ACT (MD in % predicted, 6.00%; P=.033) compared with the end of radiation therapy. These significant decreases in DLCOcorr were also observed in repeated-measures models (P=.011 and P=.032 at 24 and 60 months ACT, respectively). A significant minority of EBT survivors experience PFT deficits after CSI. Continued monitoring of this cohort is planned. Copyright © 2015 Elsevier Inc. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Aims: To compare high-risk histopathology of eyes with primary versus secondary enucleation from patients with retinoblastoma. Patients and methods: A retrospective histopathology review identified 207 eyes enucleated from 202 patients between March 1997 and August 2013. Our review considered high-risk histopathological features to include extraocular disease or invasion of the anterior chamber, iris, ciliary body, choroid (massive), postlaminar optic nerve or sclera. Results: Most eyes (144, 70%) were primarily enucleated; 63 (30%) were secondarily enucleated after neoadjuvant therapy. The primary enucleation group had more advanced disease (Reese-Ellsworth group V: 95% vs 59%; International Classification Group D/E: 97% vs 59%; p<0.001). The incidence of high-risk histopathology features was similar between groups (32% vs 21%, n=59; p=0.132). The type of prior therapy was not associated with high-risk histopathology features. Time to enucleation was longer for secondarily enucleated eyes with high-risk features. Choroid and postlaminar optic nerve invasion were more frequent in eyes primarily enucleated (p<0.001). Forty-six of the 59 (78%) patients with high-risk features received adjuvant chemotherapy and/or external beam radiation therapy. Three patients who received primary enucleation and adjuvant therapy died of metastatic recurrence. Conclusions: Despite the more favourable classification of eyes treated with neoadjuvant therapy, the risk of high-risk histopathology features at enucleation was comparable with eyes undergoing primary enucleation. Delayed enucleation was associated with these features, and the majority of patients required further adjuvant therapy. Caution must be exercised in treating recalcitrant intraocular retinoblastoma to promptly pursue definitive enucleation in an effort to minimise further treatment exposures and metastases.
- [Show abstract] [Hide abstract] ABSTRACT: To determine the incidence of and factors associated with the development of mydriasis and impaired accommodation in patients with refractory or recurrent neuroblastoma receiving the anti-GD2 antibody hu14.18K322A. The medical records of eligible patients with refractory or recurrent neuroblastoma who received escalating doses of hu14.18K322A, ranging from 2 to 70 mg/m(2)/dose for 4 consecutive days every 28 days, were retrospectively reviewed to identify ocular abnormalities arising during the treatment period. A total of 38 patients (median age, 7 years; 23 males) were included. All patients underwent comprehensive eye examinations prior to each course of therapy. Mydriasis was seen in 13 patients (34%), and impaired accommodation was seen in 9 (24%), indicating a dose-related effect between hu14.18K322A and both mydriasis (P = 0.021) and impaired accommodation (P = 0.029). Age and sex were not associated with ocular abnormalities. Ocular symptoms resolved in the majority of patients after the drug was discontinued. Side effects of mydriasis and impaired accommodation have a dose-dependent relationship with hu14.18K322A. These side effects do not warrant discontinuation of treatment, as they usually resolve after completion of therapy. Management of ocular side effects should focus on treating symptoms with manifest refraction, bifocals, or tinted spectacles. Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Diagnosis of childhood brain tumors is delayed more than diagnosis of other pediatric cancers. However, the contribution of the most common pediatric brain tumors, lowgrade gliomas (LGG), to this delay has never been investigated. We retrospectively reviewed cases of childhood LGG diagnosed from January 1995 through December 2005 at our institution. The pre-diagnosis symptom interval (PSI) was conservatively calculated, and its association with race, sex, age, tumor site, tumor grade, and outcome measures (survival, disease progression, shunt use, seizures, extent of resection) was analyzed. Cases of neurofibromatosis type 1 were reported separately. The 258 children had a median follow-up of 11.1 years, and 226 (88 %) remained alive. Greater pre-diagnosis symptom interval (PSI) was significantly associated with grade I (vs. grade II) tumors (p = 0.03) and age >10 years at diagnosis (p = 0.03). Half of the 16 spinal tumors had a PSI > 6 months. PSI was significantly associated with progression (p = 0.02) in grade I tumors (n = 195) and in grade I tumors outside the posterior fossa (n = 134, p = 0.03). Among children with grade I tumors, median PSI was longer in those who had seizures (10.3 months) than in those who did not (2.5 months) (p = 0.09). Delayed diagnosis of childhood LGG allows tumor progression. To reduce time to diagnosis, medical curricula should emphasize inclusion of LGG in the differential diagnosis of CNS neoplasm.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Inhibitors of poly-ADP ribose polymerase (PARP), an enzyme involved in base excision repair (BER) have demonstrated single agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Procedures: Talazoparib was tested in combination with temozolomide (0.3- 1000 μM) or topotecan (0.003 - 0.1 μM) against the PPTP in vitro and in vivo panels at a dose of 0.1 mg/kg BID x 5 combined with temozolomide (30 mg/kg/daily x 5; Combination A) or 0.25 mg/kg/daily x 5 combined with temozolomide (12 mg/kg/daily x 5; Combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. Results: In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and Combination A and Combination B represent the maximum tolerated doses when combined with low dose or high dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide. Conclusions: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation. Copyright © 2014, American Association for Cancer Research.
- [Show abstract] [Hide abstract] ABSTRACT: Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAKs). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor, AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient-derived xenografts were established in immune-deficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The anti-leukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK-mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAK-mutated ALL. Copyright © 2014, American Association for Cancer Research.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Late relapse and solitary lesion are positive prognostic factors in recurrent osteosarcoma. Methods: We reviewed the records of 39 patients treated at three major centres for recurrent osteosarcoma with a single pulmonary metastasis more than 1 year after diagnosis. We analysed their outcomes with respect to clinical factors and treatment with chemotherapy. Results: Median age at diagnosis was 14.6 years. Relapse occurred at a median of 2.5 years (range, 1.2-8.2 years) after initial diagnosis. At relapse, all patients were treated by metastasectomy; 12 (31%) patients also received chemotherapy. There was no difference in time to recurrence or nodule size between the patients who received or did not receive chemotherapy at relapse. Sixteen patients had no subsequent recurrence, 13 of whom survive without evidence of disease. The 5-year and 10-year estimates of post-relapse event-free survival (PREFS) were 33.0±7.5% and 33.0±9.6%, respectively, and of post-relapse survival (PRS) 56.8±8.6% and 53.0±11.0%, respectively. There was a trend for nodules <1.5 cm to correlate positively with PREFS (P=0.070) but not PRS (P=0.49). Chemotherapy at first relapse was not associated with PREFS or PRS. Conclusion: Approximately half of the patients with recurrent osteosarcoma presenting as a single pulmonary metastasis more than 1 year after diagnosis were long-term survivors. Metastasectomy was the primary treatment; chemotherapy did not add benefit.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. Procedures: Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21. Results: In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1-14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR. Conclusions: The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine.
- [Show abstract] [Hide abstract] ABSTRACT: Modular and non-invasive expandable prostheses have been developed to provide a functional knee joint that allows future expansion as growth occurs in the contralateral extremity in children with bone sarcomas that require removal of the growth plate. This study aimed to evaluate the functional outcomes of paediatric patients who received either a non-invasive expandable or modular prosthesis for bone sarcomas arising around the knee. We evaluated clinician-reported, patient-reported and measured function in 42 paediatric patients at least one year (median age at assessment 19.1years) after limb salvage surgery, and compared patients who received modular system prostheses (N=29, median age 15.5), who did not require lengthening procedures to those who received non-invasive expandable prostheses (N=13, median age 11.1) requiring lengthening procedures (median 5). The number of revisions and time to first revision did not differ between the two groups. There were no differences between the two groups in total scores on the Enneking Musculoskeletal Tumor Society Scale, the Toronto Extremity Salvage Scale, and the Functional Mobility Assessment. Children with non-invasive expandable prostheses climbed stairs (11.93±4.83 versus 16.73±7.24s, p=0.02) in less time than those with modular prostheses. Our results suggest that the non-invasive expandable prosthesis produces similar functional results to the more traditional modular prosthesis. Copyright © 2014 Elsevier Ltd. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer. Procedures: Glembatumumab vedotin was administered intravenously at a dose of 2.5 mg/kg using a weekly × 3 schedule, and its antitumor activity was evaluated against selected Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using standard PPTP response metrics. Results: Among PPTP xenografts, GPNMB was primarily expressed on the osteosarcoma xenografts, all of which expressed GPNMB at the RNA level, although at varying levels. Protein expression assessed by immunohistochemistry (IHC) showed variation across the osteosarcoma xenografts with one model showing no tumor cell expression. Glembatumumab vedotin induced statistically significant differences (P < 0.05) in event-free survival (EFS) distribution compared to control in each of the six osteosarcoma models studied. Three of six osteosarcoma xenografts demonstrated a maintained complete response (MCR). Two other xenografts showed progressive disease with growth delay, while the final xenograft showed progressive disease with no growth delay. Two of the osteosarcoma xenografts with MCRs showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB mRNA expression had the poorest response to glembatumumab vedotin. Two rhabdomyosarcoma xenografts that did not express GPNMB showed limited responses to glembatumumab vedotin. Conclusions: Glembatumumab vedotin yielded high-level activity against three of six osteosarcoma xenografts, with evidence for response being related to GPNMB expression levels.
- [Show abstract] [Hide abstract] ABSTRACT: PURPOSE: Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity. EXPERIMENTAL DESIGN: The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity. RESULTS: ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro coculture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%). CONCLUSION: These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy.
- [Show abstract] [Hide abstract] ABSTRACT: The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis. Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m(2) per day for 4 consecutive days every 28 days (one course). Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non-dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A α (initial phase) and β (terminal phase) half-lives were 1.74 and 21.1 days, respectively. The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m(2) per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.
- [Show abstract] [Hide abstract] ABSTRACT: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.
- [Show abstract] [Hide abstract] ABSTRACT: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma. Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated. Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y). Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.
Children's Cancer Institute AustraliaRandwick, New South Wales, Australia
The Children's Hospital of PhiladelphiaFiladelfia, Pennsylvania, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
- • Department of Biostatistics
- • Department of Pharmaceutical Sciences
Texas Children's HospitalHouston, Texas, United States
New York Medical College
New York, New York, United States
- Department of Pediatrics