Non-Hodgkin lymphomas account for approximately 7% of cancers diagnosed in patients less than 20 years of age, with approximately 800 cases diagnosed annually at COG institutions. With current therapies, cure rates range from 70% to over 90%, even for children with disseminated disease. However, two major challenges need to be overcome: (i) to optimize upfront treatment to prevent relapse since prognosis for patients with relapsed disease remains poor and (ii) minimize long-term side effects in survivors. Hence, the future initiatives for the treatment of pediatric NHL are to utilize novel targeted therapies to not only improve outcomes but to decrease bystander organ toxicities and late effects.
children; children’s oncology group; lymphoma
The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well-defined.
We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse.
Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival.
In pediatric Hodgkin lymphoma, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted.
pediatric; childhood; Hodgkin lymphoma; relapse; surveillance; outcome
Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES.
Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing.
Latino patients were diagnosed at a younger age (p=0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (p=0.001), were less likely to have insurance (p=0.001), and were more likely to present to the emergency room at onset of symptoms (p= 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% p=0.37; OS: 77.6% vs. 68.6% p=0.54).
Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.
Ewing sarcoma; Latino; Hispanic; ethnicity; cancer disparities
Quisinostat (JNJ-26481585) is a second generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs.
Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP in vivo panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily x 21.
In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2 nM, (range <1 nM to 19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease.
Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts.
Preclinical Testing; Developmental Therapeutics; HDAC inhibitor
Hypersensitivity reactions to methotrexate are rare, but have been reported. Methotrexate has shown activity against many malignancies, and omission of methotrexate therapy may increase the risk of cancer-related death in some patients. Therefore, rechallenging patients with methotrexate following hypersensitivity may be beneficial. We report a case of a child with metastatic osteosarcoma who experienced a hypersensitivity reaction to high-dose methotrexate and was successfully rechallenged with methotrexate using a 6-hour infusion. Using this regimen, adequate peak methotrexate plasma concentrations were achieved and no further hypersensitivity reactions were noted.
methotrexate; pediatric; osteosarcoma; anaphylaxis; hypersensitivity
Although children with acute lymphoblastic leukemia (ALL) mount immune responses after vaccination with the trivalent influenza vaccine (TIV), these responses are lower compared to controls. Recently, a high dose (HD) TIV was found to increase the level of antibody response in elderly patients compared to the standard dose (SD) TIV. We hypothesized that the HD TIV would be well-tolerated and more immunogenic compared to the SD TIV in pediatric subjects with ALL.
This was a randomized, double-blind, phase I safety and immunogenicity trial comparing the HD to the SD TIV in children with ALL. Subjects were randomized 2:1 to receive either the HD (60µg) or the SD (15µg) TIV. Local and systemic reactions were solicited, hemagglutinin inhibition titers to influenza virus antigens were measured, and monitoring labs were collected prior to and/or after each vaccination.
Fifty subjects were enrolled (34 HD, 16 SD). Mean age was 8.5 years; 63% were male, and 80% were in maintenance therapy. There were no significant differences reported in local or systemic symptoms. No severe adverse events were attributed to vaccination. No significant differences between the HD and SD TIV groups were noted for immune responses.
No differences were noted between the HD and SD TIV groups for solicited systemic and local reactions. Since this study was not powered for immunogenicity, a phase II trial is needed to determine the immunogenicity of HD versus SD TIV in the pediatric ALL population.
Children; Influenza; Leukemia; Trivalent Inactivated Influenza Vaccine
To evaluate the growing skeleton for potential altered skeletalgenesis associated with antiangiogenesis therapy.
Patients and Methods
Knee radiographs and magnetic resonance imaging (MRI) were prospectively obtained on patients enrolled on two consecutive clinical trials using vandetanib, a potent oral (VEGF receptor 2) VEGFR-2 inhibitor alone or combined with dasatinib, a multiple tyrosine kinase inhibitor, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
Fifty-nine patients (32 females) underwent 119 MRIs; 51 patients underwent 89 radiographs of the knees. The median age at enrollment was 6.2 years (range, 2.4–17.6 years). The dose of vandetanib ranged from 50 to 145 mg/m2/day. The median treatment duration was 205 days. Only two patients have not experienced disease progression after 18 and 60 months from diagnosis. MRI identified clinically significant premature physeal fusion in both knees of one patient, focal physeal thickening in one, osteonecrosis in eight patients (present at enrollment in one), and bony spicules crossing the physis in two patients (bilateral in one). MRI follow-up period averaged 5.3 months (range, 0–25.5 months; median, 3.5 months). Radiographs delineated normally fused physes in two patients but no cases of premature physeal fusion, osteonecrosis or bony spicules.
As MRI provided greater information than radiographs, and thus would be a more sensitive test to assess skeletalgenesis in pediatric patients.
antiangiogenesis agents; chemotherapy; magnetic resonance imaging; pediatric brain tumors; skeletalgenesis; VEGF
PR-104 is rapidly hydrolyzed to PR-104A in vivo, which is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and amine (PR-104M) to produce DNA interstrand cross-links. PR-104 activation can occur via hypoxia-dependent reductases and also independently of hypoxia by aldo-keto reductase (AKR) 1C3.
PR-104A was tested against the PPTP in vitro panel (10 nM to 100 μM), and PR-104 in vivo using a weekly × 6 schedule at its maximum tolerated dose (MTD) of 550 mg/kg. Subsequently PR-104 was tested at 270 and 110 mg/kg. Pharmacokinetics for PR-104 and its metabolites were determined, as were levels of AKR1C3 RNA and protein in xenografts.
In vitro, the leukemia models were most sensitive to PR-104A. In vivo, PR-104 induced objective responses at its MTD in 21/34 solid tumor models and maintained complete responses against 7/7 acute lymphoblastic leukemia (ALL) models. At 270 mg/kg and lower dose levels, PR-104 did not induce solid tumor regressions, suggesting a steep dose–response relationship. Pharmacokinetic analysis suggests higher systemic exposures to PR-104A and its metabolites in mice compared to those achievable in patients. Levels of AKR1C3 protein did not correlate with tumor responsiveness.
As monotherapy, PR-104 demonstrated a high level of activity against both solid tumor and ALL models at its MTD, but the activity was almost completely lost at half the MTD dose for solid tumors. Pharmacokinetic data at the PR-104 MTD from human trials suggest that PR-104 metabolites may not reach the plasma exposures in children that were associated with high-level preclinical activity.
developmental therapeutics; preclinical testing; PR-104
AZD8055 is a small molecule ATP-competitive inhibitor of the serine/threonine kinase mTOR that regulates cap-dependent translation through the mTORC1 complex and Akt activation through the mTORC2 complex.
AZD8055 was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 μM and against the PPTP in vivo panels at a dose of 20 mg/kg administered orally daily × 7 for 4 weeks.
In vitro the median relative IC50 for AZD8055 against the PPTP cell lines was 24.7 nM. Relative I/O values >0% (consistent with a cytostatic effect) were observed in 8 cell lines and 15 cell lines showed Relative I/O values ranging from −4.7 to −92.2% (consistent with varying degrees of cytotoxic activity). In vivo AZD8055 induced significant differences in EFS distribution compared to controls in 23 of 36 (64%) evaluable solid tumor xenografts, and 1 of 6 evaluable ALL xenografts. Intermediate activity for the time to event activity measure (EFS T/C >2) was observed in 5 of 32 (16%) solid tumor xenografts evaluable. The best response was stable disease. PD2 (progressive disease with growth delay) was observed in 20 of 36 (55.6%) evaluable solid tumor xenografts. AZD8055 significantly inhibited 4E-BP1, S6, and Akt phosphorylation following day 1 and day 4 dosing, but suppression of mTORC1 or mTORC2 signaling did not predict tumor sensitivity.
AZD8055 demonstrated broad activity in vitro, but at the dose and schedule studied demonstrated limited activity in vivo against the PPTP solid tumor and ALL panels.
developmental therapeutics; mTOR inhibitor; preclinical testing
In the US, approximately 2,000 children are diagnosed with rare cancers each year, with 5-year survival ranging from <20% for children with advanced carcinomas to >95% for children with intraocular retinoblastoma or localized germ cell tumors. During the last years, 12 clinical studies have been successfully completed in children with retinoblastoma, liver tumors, germ cell tumors, and infrequent malignancies, including therapeutic, epidemiologic, and biologic studies. Current efforts are centered in the development of large international collaborations to consolidate evidence-based definitions and risk stratifications that will support international Phase 3 clinical trials in germ cell tumors, hepatoblastoma, and other rare cancers.
germ cell tumors; hepatoblastoma; rare cancers; retinoblastoma
To establish the maximum tolerated dose (MTD) and toxicity profile of cyclophosphamide with cisplatin, etoposide, and bleomycin (C-PEB) in children with high-risk malignant germ cell tumors (HR-MGCT).
Eligibility criteria included untreated patients ≤ 21 years of age with stage III/IV extragonadal, extra cranial MGCT. Patients received four cycles (repeated every 3 weeks) of cisplatin (20 mg/m2/day × 5 days), etoposide (100 mg/m2/day × 5 days), and bleomycin (15 mg/m2 on Day 1) with escalating doses of cyclophosphamide on Day 1, assigned at the time of enrollment (1.2, 1.8, or 2.4 g/m2). Patients with complete response had therapy discontinued. Patients with residual disease underwent second-look surgery, those with pathologic evidence of residual MGCT or whose markers had not normalized received two more cycles. All other patients had protocol therapy stopped.
Nineteen patients were enrolled between July 2004 and August 2007. Three patients were non-evaluable. Sixteen patients completed four cycles. Eleven had complete response, one had progressive disease and four had partial response. All four with partial response underwent second look surgery followed by two more cycles. Only one patient, on dose 1.8 g/m2, experienced dose-limiting toxicity (DLT) during the first cycle of therapy (grade 3 hyperglycemia). The 4-year EFS and OS (± standard deviation) were 74 ± 7% and 89 ± 10%, respectively.
The addition of cyclophosphamide to the standard PEB regimen (cisplatin, etoposide, and bleomycin) is feasible and well-tolerated at all dose levels used on this study.
cyclophosphamide; germ cell tumors; maximum tolerated doses
Since the initial reports of human epidermal growth factor receptor 2 (HER-2) expression as being prognostic in osteosarcoma, numerous small studies varying in the interpretation of the immunohistochemical (IHC) staining patterns have produced conflicting results. The Children’s Oncology Group therefore embarked on a prospective biology study in a larger sample of patients to define in osteosarcoma the prognostic value of HER-2 expression using the methodology employed in the initial North American study describing an association between HER-2 expression and outcome.
The analytic patient population was comprised of 149 patients with newly diagnosed osteosarcoma, 135 with localized disease and 14 with metastatic disease, all of whom had follow up clinical data. Paraffin embedded material from the diagnostic biopsy was stained with CB11 antibody and scored by two independent observers. Correlation of HER-2 IHC score and demographic variables was analyzed using a Fisher’s exact test and correlation with survival using a Kaplan–Meier analysis.
No association was found with HER-2 status and any of the demographic variables tested including the presence or absence of metastatic disease at diagnosis. No association was found between HER-2 status and either event free survival or overall survival in the patients with localized disease.
HER-2 expression is not prognostic in osteosarcoma in the context of this large prospective study. HER-2 expression cannot be used as a basis for stratification of therapy. Identification of potential prognostic factors should occur in the context of large multi-institutional biology studies.
Her-2; human epidermal growth factor receptor; immunohistochemistry; osteosarcoma
Hepatoblastoma is a malignancy of young children. Low birth weight is associated with significantly increased risk of hepatoblastoma and neonatal medical exposures are hypothesized as contributors. This study represents the largest case–control study of hepatoblastoma to date and aimed to define the role of neonatal exposures in hepatoblastoma risk among low birth weight children.
Incident hepatoblastoma cases who were born <2,500 g (N = 60), diagnosed between 2000 and 2008, were identified through the Children's Oncology Group. Controls were recruited through state birth registries (N = 51). Neonatal medical exposures were abstracted from medical records. Subjects from the Vermont Oxford Network were used for further comparisons, as were existing reports on neonatal medical exposures.
Case–control comparisons were hindered by poor matching within birth weight strata. Cases were smaller and received more aggressive neonatal treatment compared to controls, and reflected high correlation levels between birth weight and treatments. Similar difficulty was encountered when comparing cases to Vermont Oxford Network subjects; cases were smaller and required more aggressive neonatal therapy. Furthermore, it appears hepatoblastoma cases were exposed to a greater number of diagnostic X-rays than in case series previously reported in the neonatal literature.
This study presents the largest case series of hepatoblastoma in <2,500 g birth weight infants with accompanying neonatal medical exposure data. Findings confirm that birth weight is highly correlated with exposure intensity, and neonatal exposures are themselves highly correlated, which hampers the identification of a causal exposure among hepatoblastoma cases. Experimental models or genetic susceptibility testing may be more revealing of etiology.
case–control study; exposure; hepatoblastoma; low birth weight; NICU
Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a “5-drug” oral regimen in children with recurrent or progressive cancer.
Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed.
One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days–21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009).
The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636–642. © 2013 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.
angiogenesis; drug resistance; pediatric oncology; phase II clinical trials
The inhibitor-of-apoptosis protein survivin, encoded by BIRC5, regulates apoptosis, cell division and proliferation. Several survivin splice variants have been described however, the prognostic significance of their expression has not been well defined in pediatric acute myeloid leukemia (AML).
Quantitative expression analyses of BIRC5 mRNA (n = 306) and survivin transcript splice variants (n = 90) were performed on diagnostic bone marrow samples from children with de novo AML treated on the clinical trials CCG-2961 and AAML03P1, then correlated with disease characteristics and clinical outcome.
Total BIRC5 expression did not correlate with clinical outcome. Fragment length analysis and sequencing of the entire BIRC5 transcript demonstrated three splice variants. The most prominent product, wild-type survivin, was expressed in all samples tested. Two minor transcripts were present in 90 patients treated on CCG-2961; survivin-2B and a novel variant, survivin-ΔEx2, characterized by deletion of BIRC5 exon II. A high 2B/ΔEx2 expression ratio (≥1) correlated with increased diagnostic WBC count, monocytic phenotype, +8 cytogenetics, lower complete remission (45% [n = 10] vs. 88% [n = 59], P < 0.001) and higher induction failure rates (23% [n = 5] vs. 3% [n = 2], P = 0.009). Consistent with this poor induction response, patients with a 2B/ΔEx2 ratio ≥1 had inferior 5-year survival rates (OS 36% vs. 60%, P = 0.011; EFS 23% vs. 53% at 5 years, P = 0.001) and appear to have increased relapse risk (P = 0.056). Subset analyses suggest that relative over-expression of 2B, rather than under-expression of ΔEx2 determines clinical response.
High survivin-2B/ΔEx2 ratios are associated with refractory disease and inferior survival in childhood AML. Survivin splice variant expression warrants prospective evaluation in clinical trials.
Survivin; splice variant; acute myeloid leukemia; childhood AML; molecular genetics; refractory disease
Sinusoidal obstruction syndrome is a complication of therapy for pediatric ALL and may be modified by thiopurine methyltransferase activity as well as by MTHFR genotype. We assessed TPMT * 3A, * 3B, * 3C, and MTHFR C677T and A1298C germline genetic polymorphisms among 351 patients enrolled in the thioguanine treatment arm of CCG-1952 clinical trial. TPMT and MTHFR C677T genotypes were not associated with SOS risk. The combination of MTHFR and TPMT variant genotypes was not associated with SOS risk. These suggest that germline genetic variation in TPMT and MTHFR do not significantly alter SOS risk in patients exposed to thioguanine.
acute lymphoblastic leukemia; MTHFR; SOS; thioguanine; TPMT; toxicity
Despite higher cure rates, childhood acute lymphoblastic leukemia (ALL) may continue to result in considerable family strain. We sought to (i) measure incidence of divorce, reduced career opportunities, changes to work hours, home relocation, and changes to family planning at one year after ALL diagnosis; and (ii) Identify family and patient factors associated with these events.
We conducted a prospective cohort study of 159 children with average risk-ALL enrolled and treated on COG protocol AALL0331 at 31 selected sites. Eligibility criteria included age ≥2 years and English or Spanish comprehension. Parents completed surveys at three time points during the first 12 months of therapy.
Parents were at significantly increased risk of loss of employment (46% vs. 9.1%, P≤0.001) than peers nationally. 13% divorced/separated, 27% relocated homes, 22% decided not to have more children, 51% declined occupational opportunities, and 68% decreased work hours. In adjusted analyses, relocation correlated with less maternal education (OR: 4.27 [95% CI: 1.43–12.82]). Declining parental opportunities associated with family income <$50,000 (OR: 4.25 [95% CI: 1.50–12.02]) and child <5 years old (OR: 4.21 [95% CI: 1.73–10.25]). Deciding not to have more children correlated with smaller family size 2–3 versus 4–5 (OR: 3.62 [95% CI: 1.10–11.96]).
Families experience a high incidence of major life changes in the first year of ALL treatment. Understanding these burdens helps health care providers to provide appropriate anticipatory guidance and support. No unifying factor was associated with the different family events. Ongoing follow-up is planned to measure long-term outcomes.
family coping/functioning; leukemia; pediatric cancer
Sickle cell disease (SCD) is an inherited blood disorder characterized by a chronic hemolytic anemia that can contribute to fatigue and global cognitive impairment in patients. The study objective was to report on the feasibility, reliability, and validity of the PedsQL™ Multidimensional Fatigue Scale in SCD for pediatric patient self-report ages 5–18 years and parent proxy-report for ages 2–18 years.
This was a cross-sectional multi-site study whereby 240 pediatric patients with SCD and 303 parents completed the 18-item PedsQL™ Multidimensional Fatigue Scale. Participants also completed the PedsQL™ 4.0 Generic Core Scales.
The PedsQL™ Multidimensional Fatigue Scale evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report α = 0.90; parent proxy-report α = 0.95), and acceptable reliability for the three individual scales (patient self-report α = 0.77–0.84; parent proxy-report α = 0.90–0.97). Intercorrelations of the PedsQL™ Multidimensional Fatigue Scale with the PedsQL™ Generic Core Scales were predominantly in the large (≥ 0.50) range, supporting construct validity. PedsQL™ Multidimensional Fatigue Scale Scores were significantly worse with large effects sizes (≥0.80) for patients with SCD than for a comparison sample of healthy children, supporting known-groups discriminant validity. Confirmatory factor analysis demonstrated an acceptable to excellent model fit in SCD.
The PedsQL™ Multidimensional Fatigue Scale demonstrated acceptable to excellent measurement properties in SCD. The results demonstrate the relative severity of fatigue symptoms in pediatric patients with SCD, indicating the potential clinical utility of multidimensional assessment of fatigue in patients with SCD in clinical research and practice.
Sickle Cell Disease; PedsQL; fatigue; pediatrics; children; patient-reported outcomes; health-related quality of life
Poly(ADP-ribose) polymerase (PARP) signals DNA damage and facilitates DNA repair. PARP inhibitors are being evaluated in cancers with defective DNA repair mechanisms or in combination with cytotoxic therapy or radiation. We evaluated the PARP inhibitor, olaparib, in combination with chemotherapy using in vitro and in vivo pediatric solid tumor models.
The IC50 of olaparib alone and in combination with cytotoxic agents was determined in 10 pediatric solid tumor cell lines. Synergy was assessed using the combination index of Chou-Talalay. Olaparib alone and in combination with topotecan/cyclophosphamide was evaluated in xenograft models of Ewing sarcoma (ES) and neuroblastoma (NGP). PAR activity was evaluated in cell lines and tumor lysates.
Olaparib induced growth inhibition, median (range) IC50=3.6 (1–33.8) µM, and inhibited PAR activity in pediatric solid tumor cell lines. The addition of olaparib to DNA damaging agents resulted in additive to synergistic interactions. In ES and NGP xenografts, olaparib inhibited PAR activity by 88% to 100% as a single agent and 100% when administered with cyclophosphamide/topotecan. Although the addition of olaparib did not antagonize the activity of cyclophosphamide/topotecan, clear evidence of synergy could not be demonstrated.
In pediatric solid tumor cell lines, clinically achievable concentrations of single agent olaparib caused growth inhibition. Although the in vitro data demonstrated synergistic efficacy of olaparib when added to the camptothecins and alkylating agents, synergy was not discernible in vivo. Clinical trials of PARP inhibitors in combination DNA damaging agents are necessary to establish the role of PARP inhibitors in childhood cancer.
pediatric; PARP inhibitor; olaparib; in vitro; in vivo
Intra-operative tumor spill increases the risk of local recurrence of Wilms tumor, and adversely impacts relapse-free (RFS) and overall survival (OS) rates.
Surgical checklists, operative notes, institutional pathology reports, central pathology review and flow sheets of 602 patients registered between August 1986 and September 1994 on National Wilms Tumor Study – 4 as randomized, followed or switched and coded as Final Stage II, favorable histology (FH) were reviewed. RFS and OS were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated using the Cox model and tested for statistical significance by the log-rank test.
Four hundred ninety-nine patients were found after review to have stage II, FH Wilms tumor. The eight-year RFS percentages were 85.0% (95% confidence interval (CI) – 81.1%, 88.1%) for those with no spill compared to 75.7% (65.8%, 83.2%) for those with spill. The eight-year OS percentages were 95.6% (93.1%, 97.3%) for those with no spill compared to 90.3% (82.2%, 94.9%) for those with spill. The HR for relapse among those with spill was 1.55 ((95%CI – 0.97,2.51), p = 0.067) and the HR for death was 1.94 ((0.92,4.09), p = 0.077).
RFS and OS were lower for patients who had intra-operative tumor spill. The majority of NWTS stage II, FH patients with intra-operative tumor spill have an overall excellent outcome when treated with two drug chemotherapy (vincristine and actinomycin D) and no abdominal irradiation.